Initial Diastolic Dysfunction is a Powerful Predictor of 5-year Mortality in Peripheral Arterial Disease Patients undergoing Percutaneous Transluminal Angioplasty

Initial Diastolic Dysfunction is a Powerful Predictor of 5-year Mortality in Peripheral Arterial Disease Patients undergoing Percutaneous Transluminal Angioplasty | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Initial Diastolic Dysfunction is a Powerful Predictor of 5-year Mortality in Peripheral Arterial Disease Patients undergoing Percutaneous Transluminal Angioplasty Kyung-Hee Kim, Seung Woon Rha, Byoung Geol Choi, Jae-Kyung Byun, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-41677/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Peripheral arterial disease (PAD) and heart failure share common risks and are associated with increased morbidity and mortality. However, it is unknown whether cardiac function can be an independent predictor of long-term mortality in patients with PAD. Methods In total, 902 patients who underwent percutaneous transluminal angioplasty for PAD were enrolled. The patients were categorized into three groups according to the left ventricular ejection fraction (LVEF): reduced EF (< 40%, n = 62); mid-range EF (40–49%, n = 76); and preserved EF (≥ 50%, n = 764). Echocardiographic (EF, ratio of mitral inflow velocity to annular velocity E/eʹ ≥ 15, and others) and clinical parameters were tested using stepwise logistic regression analysis to determine independent predictors of 5-year mortality. Results A higher proportion of patients with reduced EF had ischemic heart disease than those with preserved EF (77.4% vs. 56.8%, p < 0.001). Up to 5 years, patients with reduced EF and mid-range EF showed a higher incidence of total death than those with normal EF. However, there was no difference in the incidence of myocardial infarction, stroke, and revascularization among the three groups. After multivariable adjustment, the ratio of E/eʹ ≥ 15 was the only strong predictor of total mortality (hazard ratio, 6.14; 95% confidence interval, 3.7–10.1;p < 0.01). Conclusion Patients with PAD and reduced EF undergoing PTA had a higher incidence of total death during the 5-year follow-up. Initial tissue Doppler E/eʹ ≥ 15, a non-invasive estimate of left atrial filling pressure, was the only independent predictor of long-term mortality. Cardiac & Cardiovascular Systems Peripheral Artery Disease Heart Failure Systolic Dysfunction Diastolic Dysfunction Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Lower extremity peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis and is associated with increased cardiovascular morbidity and mortality 1)2) . Patients with PAD have a 3-fold increased risk of death from all causes and a 6-fold increased risk of death from cardiovascular disease within a 10-year period when compared with patients without PAD 3) . An estimated > 200 million people have PAD worldwide, with a spectrum of symptoms ranging from none to severe 4)5) . Despite the high morbidity and mortality, patients with PAD are often underdiagnosed and undertreated. Although the reason for the poor prognosis in patients with PAD is unknown, high prevalence of coexistent cardiovascular disease (coronary artery disease, chronic heart failure [HF], or stroke) has frequently been mentioned as the likely cause of PAD occurrence 6)7) . Patients with PAD have a high comorbidity burden, which has significant implications for clinical management. However, the cardiac function of patients with PAD has not been studied systematically. Limited data are available on the association between cardiac function and PAD, especially in patients who underwent percutaneous transluminal angioplasty (PTA). In addition, diastolic dysfunction has not been yet reported in patients with PAD who underwent PTA, whereas left ventricular (LV) systolic dysfunction has been described 8) . We aimed to evaluate the association between PAD and heart failure in patients with symptomatic PAD who underwent PTA. We also analyzed the effect of these abnormal cardiac findings on long-term cardiovascular outcomes in these patients. Method We obtained data from the PTA registry of Korea University Guro Hospital (KUGH), Seoul, South Korea. This registry has been described in detail in previous studies. This single-center, prospective, all-comers registry was started in 2004 and designed to reflect real-world clinical practice. The study protocol was approved by the Medical Device Institutional Review Board of KUGH (protocol #MD12018). The study population included a total of 902 consecutive patients with symptomatic PAD who underwent PTA of the iliac, femoral, popliteal, tibial, and peroneal arteries from September 2004 to August 2017. The data were collected by trained study coordinators using standardized case report forms 9) . . Coronary and Peripheral Angiography and Revascularization Standard techniques were used for PTA. Coronary and peripheral angioplasties were performed with a crossover approach or an anterograde ipsilateral femoral approach using 5 ~ 6 French sheaths. If there are significant coronary fixed stenosis (> 70% diameter stenosis), direct percutaneous coronary intervention (PCI) or staged PCI within the same hospitalization period was recommended and performed. Post-intervention dual antiplatelet therapy with aspirin 100 mg and clopidogrel 75 mg once daily or additional cilostazol 100 mg twice daily was given for at least 6 months, while aspirin 100 mg and/or clopidogrel 75 mg was given daily thereafter. Medications beneficial for cardiovascular health, including renin-angiotensin-aldosterone blockers, beta-blockers, and statins, were also prescribed according to practice guidelines. Echocardiography All patients underwent echocardiography examinations. Patients with transthoracic echocardiography (TTE) findings not suitable for the quantitative assessment of LV ejection fraction (LVEF) or diastology were excluded. The ratio of the transmitral Doppler E wave velocity and the early diastolic velocity (eʹ) at the septal annulus (E/eʹ ratio) was evaluated to estimate LV filling pressure. One best LVEF value for each patient was determined using a hierarchical approach: volumetric LVEF calculated using the 2D Simpson’s biplane method was preferred, followed by other calculated LVEF methods, followed by visual estimation if these other methods were unavailable. We divided the patients into three groups according to LVEF values: preserved LV function, LVEF ≥ 50%; mid-range LV function, 40% ≤ LVEF < 50%; and reduced LV function, LVEF < 40%. LV mass was calculated using ASE formula 10) . LV regional wall motion was analyzed visually using the standard 16-segment model. Pulmonary artery systolic pressure (PASP) was estimated from the peak tricuspid regurgitation (TR) velocity obtained using continuous-wave Doppler echocardiography and estimated right atrial pressure as previously described 11) . Baseline Clinical Characteristics Baseline patient characteristics were determined based on chart review and included age, sex, hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, coronary artery disease (CAD), renal insufficiency, current smoking, and family history of CAD. Study Endpoints and Major Clinical Outcomes The primary study endpoint was all-cause death, and the key secondary study endpoint was patient-oriented composite outcome (composite of all-cause death, any myocardial infarction [MI], stroke, or any repeat revascularization) at the 5-year or last follow-up. The cause of all deaths was considered cardiac unless an undisputed non-cardiac cause was present. MI was defined as symptom recurrence or the presence of electrocardiographic changes in association with an increase in cardiac biomarker levels above the upper limit of normal; cases of periprocedural MI were not included as clinical outcomes. Stroke was defined as the presence of neurological deficits confirmed by a neurologist on the basis of imaging study findings. Clinically driven revascularization that occurred after discharge from the index hospitalization was coded as a repeat revascularization event. Statistical Analysis Continuous variables are presented as mean and standard deviation when normally distributed or as median when not normally distributed. Demographic and echocardiographic factors were analyzed among groups using analysis of variance for continuous variables and chi-square for categorical variables. Kaplan-Meier and Cox regression analyses were used to determine associations between echocardiographic variables in patients with PAD and outcomes during the 5-year follow-up. Age, sex, hypertension, diabetes mellitus, dyslipidemia, CAD, and clinically important echocardiographic findings found to be univariate predictors of mortality were entered into multivariate models as predictors of mortality and for secondary study endpoints. A restricted cubic spline function allowed us to estimate a smooth nonlinear relationship between echocardiographic parameters and outcome in a regression model 12) . All statistical tests were 2-tailed, with probability values < 0.05 considered significant. All data analyses were performed using SPSS for Windows version 20 (SPSS, Inc., Chicago, IL, USA). Results Baseline Characteristics and Echocardiographic Findings according to LV Function The mean patient age was 68 ± 10 years; 77% of the patients were male. The patients’ baseline characteristics and cardiovascular risk factors according to LVEF are listed in Table 1 . Compared with patients with preserved EF, a higher proportion of patients with reduced EF had renal insufficiency, atrial fibrillation, and CAD. The other baseline characteristics were similar between groups. Over 80% of the enrolled patients underwent coronary angiography, and the reduced EF group had more left main lesions or multi-vessel disease. However, the limb characteristics were similar among the groups (supplementary Table 1). The echocardiographic findings are listed in Table 2 . The reduced EF group had more cases of RWMA, mitral regurgitation, elevated E/eʹ, and elevated PASP. Valve calcification descriptions by echocardiography specialist cardiologists were similar among groups (Table 2 ). Table 1 Baseline clinical characteristics according to EF Variables, n (%) Reduced EF (n = 62 pts) Mid-range EF (n = 76 pts) Preserved EF (n = 764 pts) p value Baseline characteristic Sex, male 48 (77.4) 62 (81.5) 590 (77.2) 0.685 Age, year 66.3 ± 10.2 68.3 ± 9.6 68.0 ± 10.7 0.255 Body mass index 22.2 ± 3.3 23.4 ± 3.5 23.1 ± 3.3 0.511 Blood pressure, mmHg Systolic 138.2 ± 25.1 143.2 ± 30.1 143.5 ± 24.7 0.308 Diastolic 72.6 ± 12.0 73.9 ± 15.4 72.4 ± 26.3 0.107 Heart rate, beats per minute 84.4 ± 19.0 80.8 ± 21.9 78.7 ± 13.9 0.052 Initial diagnosis Wound 43 (69.3) 39 (51.3) 481 (62.9) 0.069 Gangrene 18 (29.0) 15 (19.7) 213 (27.8) 0.299 Claudication 6 (9.6) 17 (22.3) 160 (20.9) 0.094 Resting pain 7 (11.2) 11 (14.4) 88 (11.5) 0.742 Berger’s disease 2 (3.2) 0 (0.0) 20 (2.6) 0.341 Patient risks Hypertension 46 (74.1) 56 (73.6) 541 (70.8) 0.758 Diabetes mellitus 46 (74.1) 47 (61.8) 570 (74.6) 0.055 Medications 43 (69.3) 39 (51.3) 488 (63.8) 0.056 Insulin 20 (32.2) 21 (27.6) 249 (32.5) 0.677 Dietary 0 (0.0) 4 (5.2) 22 (2.8) 0.199 Duration, years 19.8 ± 10.4 13.6 ± 11.3 16.3 ± 11.8 0.935 Dyslipidemia 9 (14.5) 7 (9.2) 106 (13.8) 0.511 Stroke 17 (27.4) 15 (19.7) 127 (16.6) 0.088 Hemorrhage 2 (3.2) 2 (2.6) 15 (1.9) 0.545 Ischemia 15 (24.1) 13 (17.1) 112 (14.6) 0.127 Chronic renal insufficiency 31 (50.0) 29 (38.1) 209 (27.3) < 0.001 Dialysis 20 (32.2) 20 (26.3) 125 (16.3) 0.001 Atrial fibrillation 16 (25.8) 15 (19.7) 56 (7.3) < 0.001 Persistent or permanent AF 9 (14.5) 9 (11.8) 28 (3.6) < 0.001 History of smoking 28 (45.1) 47 (61.8) 392 (51.3) 0.120 Current smoker 13 (20.9) 31 (40.7) 248 (32.4) 0.046 Alcohol consumption 14 (22.5) 20 (26.3) 236 (30.8) 0.300 Currently 6 (9.6) 17 (22.3) 183 (23.9) 0.036 Coronary artery disease 48 (77.4) 57 (75.0) 434 (56.8) < 0.001 Prior CABG 7 (11.2) 4 (5.2) 28 (3.6) 0.021 Prior PCI 20 (32.2) 23 (30.2) 171 (22.3) 0.080 PCI during PTA 23 (37.0) 27 (35.5) 186 (24.3) 0.014 AF, atrial fibrillation; CABG, coronary artery bypass grafting; EF, ejection fraction; PCI, percutaneous coronary intervention; PTA, percutaneous transluminal angioplasty Data are shown as mean ± SD or number (percentage). Table 2 Baseline echocardiographic parameters Echocardiographic variables, n (%) Reduced EF (n = 62 pts) Mid-range EF (n = 76 pts) Preserved EF (n = 764 pts) p value LV ejection fraction, % 33.2 ± 7.7 48.3 ± 4.0 63.8 ± 3.3 < 0.001 Regional wall motion abnormalities 55 (88.7) 59 (77.6) 67 (8.7) < 0.001 LAD 48 (77.4) 29 (38.1) 21 (2.7) < 0.001 LCX 34 (54.8) 30 (39.4) 20 (2.6) < 0.001 RCA 42 (67.7) 36 (47.3) 40 (5.2) < 0.001 Mitral annular calcification* 12 (19.3) 13 (17.1) 107 (14) 0.423 Aortic valve calcification* 9 (14.5) 9 (11.8) 82 (10.7) 0.644 Mitral regurgitation † 28 (45.1) 21 (27.6) 128 (16.7) < 0.001 Aortic valve regurgitation† 15 (24.1) 15 (19.7) 130 (17.0) 0.324 Tricuspid valve regurgitation‡ 14 (22.5) 7 (9.2) 65 (8.5) 0.001 Left ventricular hypertrophy§ 24 (38.7) 31 (40.7) 187 (24.5) 0.001 LV diastolic dysfunction grade# 0.96 ± 0.78 0.85 ± 0.60 0.88 ± 0.4 0.902 E/eʹ ratio 20.6 ± 10.0 15.4 ± 7.0 13.0 ± 5.3 < 0.001 PASP, mmHg 37.8 ± 12.3 33.1 ± 9.0 31.5 ± 8.2 < 0.001 *Evaluation by the echocardiography specialist †More than mild ‡Reduced EF patient group had more than moderate tricuspid regurgitation. §Left ventricular hypertrophy (LVH) was defined as increased LV mass index (LVMI) (≥ 96 g/m 2 in females, ≥ 116 g/m 2 in males). # Diastolic dysfunction is considered in our laboratory when Doppler inflow is consistent with a normal pattern (1 point), abnormal relaxation (1 point), pseudonormalization (2 points), or restrictive patterns (3 points). LAD, left anterior descending artery; LCx, left circumflex artery; LV, left ventricle; PASP, pulmonary artery systolic pressure; RCA, right coronary artery In-Hospital Complications according to LV Function Reduced EF was associated with a higher incidence of red blood cell transfusion (p = 0.025), post-procedural aneurysm (p = 0.009), and significantly longer stay in the intensive care unit (ICU, p < 0.001) than the other LVEF types (supplementary Table 2). All-Cause Mortality and Major Cardiovascular Events according to EF The overall 30-day postoperative mortality rate was 2.0%. The mortality and cardiovascular morbidity rates did not differ significantly according to EF at 30 days (supplementary Table 2). During a median follow-up of 5 years, 140 total cardiovascular events occurred: 81 deaths, 8 MIs, 48 percutaneous coronary intervention (PCI) and 28 cerebral infarctions. The causes of death were stroke, MI, HF aggravation, or sudden cardiac death. Despite our best efforts, we could not identify the causes of 29 cases of sudden death. Total deaths were higher in the reduced EF group (n = 12 [19.7%]) than in the preserved EF group (n = 59 [8.9%]). Kaplan-Meier curves showed significant differences in survival among each of the two groups according to EF (reduced EF vs. preserved EF, p < 0.01; mid-range EF vs. preserved EF, p < 0.01; Fig. 1A). However, there was no significant difference in survival between the reduced and mid-range EF groups. Similar trends were found in total cardiovascular events: these events were 1.4 time more common in patients with reduced EF than in those with preserved EF (reduced EF vs. preserved EF, p = 0.04; Fig. 1B). Predictors of All-Cause Mortality and Major Cardiovascular Events The independent predictors of long-term mortality and combined events were identified using multiple stepwise Cox regression analysis (Fig. 2). After adjustment for age, chronic kidney disease, and HbA1c values, EF remained the only significant predictor of all-cause mortality (hazard ratio [HR], 0.96; 95% CI, 0.96–0.99; p = 0.04]. Interestingly, after additional adjustment for other variables, E/eʹ and longer ICU stay were independent predictors of all-cause mortality (E/eʹ: HR, 1.11; 95% CI, 1.07–1.16; p < 0.001; and longer ICU stay: HR, 1.06; 95% CI, 1.03–1.09; p < 0.01; Fig. 1A). Heart rate was the other independent predictor of mortality (HR, 1.02; 95% CI, 1.00–1.04; p = 0.01). However, heart rate was not an independent predictor of major cardiovascular events (Fig. 2B). Each of these models was then re-run with the sequential replacement of E/eʹ with left atrial (LA) size, transmitral E wave velocity, transmitral E/A ratio, PASP, and tissue Doppler eʹ velocity. None of these measures significantly predicted all-cause mortality or major cardiovascular events with adjustment for covariates. E/eʹ remained the only significant echocardiographic predictor of risk. All-Cause Mortality and Major Cardiovascular Events according to E/e ʹ To estimate a smooth nonlinear relationship between E/eʹ and outcome in a regression model, we used a restricted cubic spline function. Figure 3 shows the predicted 5-year probability of death as a function of E/eʹ using splines and by varying the degrees of freedom. Mortality rate was increased abruptly after the range of E/eʹ was over 15. E/eʹ values were subsequently divided into two groups for Kaplan-Meier survival analysis (E/eʹ < 15 vs. E/eʹ ≥ 15). Using the log-rank test, we found that patients with E/eʹ ≥ 15 had more than 6 times higher risk of mortality (Fig. 4A) as those with E/eʹ < 15 (HR, 6.14; 95% CI, 3.7–10.1; p < 0.01). Similarly, all-cause cardiovascular events were 2.8 times more common (95% CI, 2.0–4.0; p < 0.01) in patients with E/eʹ ≥ 15 than in patients with E/eʹ < 15 (Fig. 4B). Survival Analysis in Patients with Preserved EF Most of the patients (n = 764 [85%]) had preserved EF. Additional analysis was performed considering only patients with preserved EF to confirm that E/eʹ was the most important echocardiogram variable in this group. Similarly, E/eʹ was found to be an independent predictor of all-cause mortality and major cardiovascular events in the subgroup of patients with preserved EF (HR, 1.12; 95% CI, 1.07–1.17 for all-cause mortality; HR, 1.07; 95% CI, 1.03–1.12 for major cardiovascular events; p < 0.01). Kaplan-Meier curves showed significant intergroup differences according to E/eʹ cut-off values (p < 0.001; Figs. 5A, 5B). The 5-year survival rate was 97.1% among patients with E/eʹ < 15, compared to the 81% observed among those with E/eʹ ≥ 15 and preserved EF. Patients with higher E/eʹ (≥ 15) had a 6.8 times higher risk of death (HR, 6.8; 95% CI, 3.8–12.3; p < 0.01) and a 3.1 times higher risk of a major cardiovascular event (HR, 3.1; 95% CI, 2.1–4.5; p < 0.01). Patients with E/eʹ ≥ 15 were more likely to have multi-vessel disease (43% for E/eʹ ≥ 15 vs. 28% for E/eʹ < 15; p < 0.01), chronic total occlusion (11% for E/eʹ ≥ 15 vs. 5.5% for E/eʹ <15; p = 0.02), elevated creatinine (2.8 ± 3.1 mg/dL for E/eʹ ≥ 15 vs. 1.6 ± 2.0 mg/dL for E/eʹ < 15; p < 0.01), and longer ICU stay (1.2 ± 5.2 days for E/eʹ ≥ 15 vs. 0.5 ± 2.5 days for E/eʹ < 15; p = 0.04). Other variables were similar between the two groups. Discussion There were three main findings of the present study in patients with PAD who underwent PTA. First, patients with PAD undergoing PTA with reduced LVEF had higher incidence of total death during the 5-year follow-up. Second, an initial tissue Doppler E/eʹ ≥ 15, a non-invasive estimate of high LA filling pressure, was the only independent predictor of long-term mortality. Third, patients with preserved EF who have high LV filling pressure and PAD might be at increased risk of myocardial ischemia, which was related to a higher 5-year mortality rate. To the best of our knowledge, this is the first study to demonstrate echocardiographic prognostic predictors in patients with PAD undergoing PTA during long-term follow-up. LV Systolic Dysfunction and PAD The presence of PAD is associated with a 2-fold increase in the prevalence of HF. Given that HF and PAD share many risk factors including increased age, diabetes, smoking, atherosclerosis, and poor renal function, it is not surprising that the prevalence of LV systolic dysfunction in patients with PAD is 5.3–13.9% 5)13) . The association between PAD and cardiovascular disease and the increasing prevalence of HF in industrialized countries suggest that PAD is an important medical concern in patients with HF. In this study, over 70% of patients had hypertension and diabetes mellitus and approximately 50% of patients were smokers. Among patients with PAD who underwent PTA, 6.8% had reduced LV systolic function (≤ 40%), whereas 15% had LV systolic dysfunction including mid-range EF (EF ≤ 50%); this prevalence of LV systolic dysfunction was similar to those reported in other studies. Patients with LV dysfunction had increased chronic renal insufficiency and atrial fibrillation. However, in 2002, Kelly et al. reported a 28% prevalence of moderate or greater LV systolic dysfunction in 255 patients with PAD 14) . Although the characteristics of their patients were similar to those of our patients in terms of age, sex, and prevalence of ischemic heart disease, the patients in their study were considerably more often current smokers (78%) and had different ethnicities. Our study findings demonstrate that the prevalence and burden of CAD were high among patients with LV systolic dysfunction who had PAD (77.4% of those with reduced EF vs. 56.8% of those with preserved EF; p < 0.001) and LV dysfunction was associated with an increased risk of mortality and major cardiovascular events in patients with PAD who underwent PTA. Based on current guidelines, patients who are smokers and have known CAD and/or diabetes mellitus should undergo an ABI assessment to screen the presence of PAD. Obtaining ABI measurements in these patients at risk and with concomitant systolic HF will enhance PAD detection in this specific population. Similarly, patients with symptomatic PAD confirmed by a low ABI must be referred for echocardiography to screen LV dysfunction and detect RWMA. Ward et al. reported that, among patients with symptomatic PAD referred for echocardiography, there was a high prevalence of clinically important echocardiographic findings, including LV dysfunction 15) . In addition, evaluation of the coronary arteries along with subsequent optimal treatment of patients of PAD who underwent PTA may improve survival 16) . However current indications for screening TTE in patients with PAD are limited. Prospective echocardiographic screening studies and detection of LV dysfunction are warranted in patients with symptomatic PAD. LV Diastolic Dysfunction and PAD Another interesting finding in our study is the association of diastolic dysfunction and long-term cardiovascular outcomes in patients with PAD. We have confirmed that E/e' is the most important variable affecting survival rates in all patients with PAD. As reduced LV function has some correlation with E/e', the analysis was conducted again only in patients with preserved EF. In this study, E/e’ was found to be an independent predictor of all-cause mortality and major cardiovascular events in patients with preserved EF (HR, 1.12; 95% CI, 1.07–1.17 for all-cause mortality; HR, 1.07; 95% CI, 1.03–1.12 for major cardiovascular events; p < 0.01). Some meta- analyses reported that PAD and HF are associated with increased mortality, hospitalization, and adverse health outcomes 13)17) . However, the studies included in these analyses delineated HF with regard to clinically apparent systolic dysfunction. Asymptomatic patients with diastolic HF or structural heart changes were not included in those reviews. Yamasaki et al. suggested the association of diastolic dysfunction in patients with PAD 18) . However, the number of patients in that study was small (n = 120), and the relationship between PAD and LV diastolic function remains unclear. Yanaka et al. evaluated LV diastolic function using echocardiography in 1,121 patients and applied the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines for the diagnosis of LV diastolic dysfunction 19) . They showed a higher prevalence of LV diastolic dysfunction in patients with PAD (n = 200) regardless of the severity of PAD (non-PAD, n = 921). Additionally, multivariate logistic regression analysis showed that PAD was an independent predictor of LV diastolic dysfunction (adjusted OR, 1.77; p = 0.01). They showed that the prevalence of LV diastolic dysfunction was higher in patients with PAD than in those without PAD. These findings suggest that patients with PAD should be evaluated for LV systolic and diastolic function in echocardiography. However, the authors did not imply the role of diastolic dysfunction in survival among patients with PAD, and the number of patients with PAD was relatively small (n = 200) to evaluate clinical outcome differences. In our study, we enrolled 764 patients with significant and symptomatic PAD who had preserved EF and who underwent PTA, and the mean E/eʹ was 13.0 ± 5.3. This value is relatively higher than that of normal healthy people 20) . Among patients with preserved EF, the 5-year mortality rate was 2.9% in those with E/eʹ < 15 (n = 15 of 525), whereas it was high, that is, 19%, in those with E/eʹ ≥ 15 (n = 44 of 239). This result has a very important clinical interpretation. In patients with PAD and HF, claudicating calf pain and wounds from critical limb ischemia limits their ability to exercise and potentially precludes them from achieving exercise training. Moreover, as reported by Fowkes et al., patients with PAD are often asymptomatic, but even when symptoms are present, it may be extremely difficult for some patients with HF to discern claudication symptoms from fatigue owing to a chronic low output state or poor effort tolerance 21) . Therefore, PAD can often be missed in the risk stratification of patients with HF and functional limitations. Because of functional limitations, many patients with HF may not ambulate to the extent to which symptoms of PAD occur, thereby precluding its identification. The inspection and recognition of diastolic function in patients with PAD is essential because most physicians recognize reduced EF to a certain extent, and preserved EF can be confirmed on normal ultrasonography. Why Would E/e ʹ Predict Cardiovascular Outcomes? An elevated E/eʹ is a marker for high LV filling pressure 22) . Using a cut-off of > 15 for an elevated medial E/eʹ ratio with exercise, the sensitivity and specificity for predicting elevated LV filling pressure (measured invasively) were in excess of 80–85%, similar to the diagnostic accuracy of myocardial ischemia with stress echocardiography and quite acceptable for clinical practice 23) . An elevated E/eʹ is a strong predictor of death following MI 24) and superior to other clinical or echocardiographic features. More recently, it was also demonstrated to predict cardiac events in subjects following coronary angiography and survival in those with established cardiac arrhythmias, but the predictor has not been examined prospectively in terms of primary prevention until now. One possible explanation is that the cumulative burden of atherosclerosis per patient is proportionate to the degree of diastolic dysfunction. Therefore, this measure may act as a surrogate for the overall effect of PAD on the myocardium, which, in turn, may predict adverse cardiovascular outcomes. In our study, patients with preserved EF and elevated E/eʹ were more likely to have multi-vessel disease (43% for E/eʹ ≥ 15 vs. 28% E/eʹ < 15; p < 0.01) and chronic total occlusion (11% for E/eʹ ≥ 15 vs. 5.5% E/eʹ < 15; p = 0.02). Hidden ischemic insult might be a cause for high LV filling pressure and eventual mortality. Limitations This study has several limitations. First, it was conducted in a single tertiary referral hospital. Although we prospectively enrolled all consecutive patients, referral bias could not be excluded; thus, the results might be difficult to generalize. However, considering the wide range of clinical and echocardiographic parameters in our study population, the validity of our study might not be altered. Second, this was a retrospective investigation, and our patient population was a subgroup selected from overall patients who had undergone routine echocardiography with angiography; thus, some selection bias is unavoidable. Conclusions Patients with symptomatic significant PAD and reduced LVEF had a higher incidence of total mortality during the 5-year follow-up. In addition, diastolic dysfunction was the only independent predictor of long-term mortality in patients with PAD. These findings suggest that the systolic and diastolic function of patients with PAD should be evaluated. In patients with diastolic dysfunction, presence of coexisting CAD should be cautiously evaluated and monitored during follow-up. Abbreviations EF: ejection fraction HF: heart failure LV: left ventricle MI: myocardial infarction PAD: peripheral arterial disease PCI: percutaneous coronary intervention PTA: percutaneous transluminal angioplasty RWMA: regional wall motion abnormality TTE: transthoracic echocardiography Declarations - Ethical Approval and Consent to participate: It is approved by the hospital’s IRB. Informed consent to participate in the study were obtained from participants. - Consent for publication: All authors read and approved the final manuscript - Availability of data and materials: All data can be checked by sending an email to Correspondence. - Competing interests: none - Funding: none - Authors' contributions: KHK and SWR contributed to the idea and design of this study, prepared and verified the clinical coding, analyzed the data, wrote the first draft, and contributed to the subsequent drafts. BGC, JKB, WHK prepared and verified the clinical coding and analyzed the data. BGC, JKB, CUC, and HSS contributed to the data collection and revised the manuscript. KHK and SWR are the principal investigators and contributed to the idea and design of this study, interpreted and analyzed the data, and contributed to the subsequent drafts. All authors have read and approved the final version for publication. - Acknowledgements: None of the authors have any financial relationships with any company or any other bias or conflict of interest to declare. References Feringa HH, Bax JJ, Hoeks S, et al. A prognostic risk index for long-term mortality in patients with peripheral arterial disease. Arch Intern Med. 2007;167:2482–9. Diehm C, Allenberg JR, Pittrow D, et al. CLINICAL PERSPECTIVE Circulation. 2009;120:2053–61. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381–6. Savji N, Rockman CB, Skolnick AH, et al. 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Circulation: Heart Failure. 2010;3:118–24. Lee MS, Rha S-W, Han SK, et al. Gender differences in endovascular revascularization for peripheral arterial disease. In: VDM. P.117 – 25, 2015. Mizukoshi K, Takeuchi M, Nagata Y, et al. Normal values of left ventricular mass index assessed by transthoracic three-dimensional echocardiography. J Am Soc Echocardiogr. 2016;29:51–61. McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation. 2001;104:2797–802. Harre FE Jr, Lee KL, Pollock BG. Regression models in clinical studies: determining relationships between predictors and response. JNCI: Journal of the National Cancer Institute. 1988;80:1198–202. Anand RG, Ventura HO, Mehra MR. Is heart failure more prevalent in patients with peripheral arterial disease? A meta-analysis. Congestive Heart Failure. 2007;13:319–22. Kelly R, Staines A, MacWalter R, Stonebridge P, Tunstall-Pedoe H, Struthers AD. The prevalence of treatable left ventricular systolic dysfunction in patients who present with noncardiac vascular episodes: a case-control study. J Am Coll Cardiol. 2002;39:219–24. Ward RP, Min JK, McDonough KM, Lang RM. High prevalence of important cardiac findings in patients with peripheral arterial disease referred for echocardiography. J Am Soc Echocardiogr. 2005;18:844–9. Jeremias A, Gruberg L, Patel J, Connors G, Brown DL. Effect of peripheral arterial disease on in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction. The American journal of cardiology. 2010;105:1268–71. Inglis SC, Hermis A, Shehab S, Newton PJ, Lal S, Davidson PM. Peripheral arterial disease and chronic heart failure: a dangerous mix. Heart Fail Rev. 2013;18:457–64. Yamasaki S, Izawa A, Shiba Y, et al. Presence of diastolic dysfunction in patients with peripheral artery disease. Angiology. 2013;64:540–3. Yanaka K, Akahori H, Imanaka T, et al. The impact of peripheral artery disease on left ventricular diastolic function. Journal of cardiology. 2019;73:453–8. D'Andrea A, Vriz O, Ferrara F, et al. Reference ranges and physiologic variations of left E/e'ratio in healthy adults: Clinical and echocardiographic correlates. Journal of cardiovascular echography. 2018;28:101. Fowkes FGR, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. The Lancet. 2013;382:1329–40. Andersen OS, Smiseth OA, Dokainish H, et al. Estimating left ventricular filling pressure by echocardiography. J Am Coll Cardiol. 2017;69:1937–48. Obokata M, Kane GC, Reddy YN, Olson TP, Melenovsky V, Borlaug BA. Role of diastolic stress testing in the evaluation for heart failure with preserved ejection fraction: a simultaneous invasive-echocardiographic study. Circulation. 2017;135:825–38. Hillis GS, Møller JE, Pellikka PA, et al. Noninvasive estimation of left ventricular filling pressure by E/e′ is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol. 2004;43:360–7. Supplementary Files SupplementaryTables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-41677","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":853156,"identity":"89c0aa38-9208-4c4b-8ad0-3e10ff298d9a","order_by":0,"name":"Kyung-Hee Kim","email":"","orcid":"","institution":"Sejong General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kyung-Hee","middleName":"","lastName":"Kim","suffix":""},{"id":853157,"identity":"5c6c6af9-0183-4986-9c2d-026240956ba1","order_by":1,"name":"Seung Woon Rha","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYHACNgaGCon6fjADJkBYyxkLxpkNJGlhbKlg3HCAWC3yM3KfPfjZIMFsfCP52YMPFQzy/AxsaR/waTG4kW5u2LtDgs3sRpq54YwzDIYzG9gOz8CrRTqNTYL3jASP2Y0EM2neNoYEgwPszfgdNjuNTfJvm4SE8Yz0b8RpYbidxgZUKWFgIJEDs4XtMF4dBvefsUnLnJFIkDjzpkxyxhkJw5nNbMn4HdZzjE3yTUVdAn97+jaJDxU28vzsbcb4HQYHAgkgUoKBgZlIDQwM/AeIVjoKRsEoGAUjDAAAUkxAQot7liUAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-9456-9852","institution":"Korea University Guro Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Seung","middleName":"Woon","lastName":"Rha","suffix":""},{"id":853158,"identity":"fe1a3d7d-1c27-4a98-b341-73fdf3ea59a9","order_by":2,"name":"Byoung Geol Choi","email":"","orcid":"","institution":"Korea University Guro Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Byoung","middleName":"Geol","lastName":"Choi","suffix":""},{"id":853159,"identity":"e4442cdf-fbc0-4882-b37f-926710f9ebd8","order_by":3,"name":"Jae-Kyung Byun","email":"","orcid":"","institution":"Korea University Guro Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jae-Kyung","middleName":"","lastName":"Byun","suffix":""},{"id":853160,"identity":"752c127d-2253-4304-8242-fc67b792d24f","order_by":4,"name":"Woohyeun Kim","email":"","orcid":"","institution":"Korea University Guro Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Woohyeun","middleName":"","lastName":"Kim","suffix":""},{"id":853161,"identity":"c844bdd5-107b-4cdc-89f0-f1b4c12f2bbe","order_by":5,"name":"Cheol Ung Choi","email":"","orcid":"","institution":"Korea University Guro Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cheol","middleName":"Ung","lastName":"Choi","suffix":""},{"id":853162,"identity":"9fe838ab-c6a6-4912-b4cb-48e0c834c2ea","order_by":6,"name":"Hong-Seog Seo","email":"","orcid":"","institution":"Korea University Guro Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hong-Seog","middleName":"","lastName":"Seo","suffix":""}],"badges":[],"createdAt":"2020-07-13 11:36:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-41677/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-41677/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":1581634,"identity":"c0076c84-c7c1-488b-9cf4-b9bb35e43801","added_by":"auto","created_at":"2020-07-16 14:27:27","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45098,"visible":true,"origin":"","legend":"Kaplan-Meier curves showing freedom from death (A) and cardiovascular events (B) according to ejection fraction. CV, cardiovascular; EF, ejection fraction","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-41677/v1/Fig1.JPG"},{"id":1581635,"identity":"a485de08-e381-4428-a807-79635b168be1","added_by":"auto","created_at":"2020-07-16 14:27:27","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":30504,"visible":true,"origin":"","legend":"Forest plot displaying hazard ratios predicting all-cause death (A) and major cardiovascular events (B) Red dots show significant prognostic factors for death and major cardiovascular events (p \u003c0.01). \nBP, blood pressure; CKD, chronic kidney disease; EF, ejection fraction; ICU, intensive care unit; LV, left ventricle; PASP, pulmonary artery systolic pressure \n","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-41677/v1/Fig2.JPG"},{"id":1581636,"identity":"f5b10b7c-6bb9-4417-a2d8-3d238b3c74ef","added_by":"auto","created_at":"2020-07-16 14:27:28","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":24784,"visible":true,"origin":"","legend":"A smooth nonlinear relationship between E/eʹ and outcome in a regression model.","description":"","filename":"Fig3.JPG","url":"https://assets-eu.researchsquare.com/files/rs-41677/v1/Fig3.JPG"},{"id":1581637,"identity":"f80dc63b-23a8-491d-87d0-e1140c91da87","added_by":"auto","created_at":"2020-07-16 14:27:28","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":40595,"visible":true,"origin":"","legend":"Kaplan-Meier curves showing freedom from death (A) and cardiovascular events (B) according to E/eʹ among all patients PAD.\nCV, cardiovascular; PAD, peripheral arterial disease \n","description":"","filename":"Fig4.JPG","url":"https://assets-eu.researchsquare.com/files/rs-41677/v1/Fig4.JPG"},{"id":1581638,"identity":"4962933d-acb3-416e-93b9-26186bbfb22f","added_by":"auto","created_at":"2020-07-16 14:27:28","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":42966,"visible":true,"origin":"","legend":"Kaplan-Meier curves showing freedom from death (A) and cardiovascular events (B) according to E/eʹ among patients with preserved ejection fraction.\nEF, ejection fraction\n","description":"","filename":"Fig5.JPG","url":"https://assets-eu.researchsquare.com/files/rs-41677/v1/Fig5.JPG"},{"id":13551400,"identity":"836490ba-cfe0-4b9f-abe8-c24526bb10dc","added_by":"auto","created_at":"2021-09-17 02:28:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":788560,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-41677/v1/338b5db0-6fcb-43ff-a71b-3b6d0b59f795.pdf"},{"id":1581640,"identity":"6965756f-a3e5-4574-8c29-3d6b7774855b","added_by":"auto","created_at":"2020-07-16 14:27:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24766,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-41677/v1/SupplementaryTables.docx"}],"financialInterests":"","formattedTitle":"Initial Diastolic Dysfunction is a Powerful Predictor of 5-year Mortality in Peripheral Arterial Disease Patients undergoing Percutaneous Transluminal Angioplasty","fulltext":[{"header":"Introduction","content":" \u003cp\u003eLower extremity peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis and is associated with increased cardiovascular morbidity and mortality \u003csup\u003e1)2)\u003c/sup\u003e. Patients with PAD have a 3-fold increased risk of death from all causes and a 6-fold increased risk of death from cardiovascular disease within a 10-year period when compared with patients without PAD \u003csup\u003e3)\u003c/sup\u003e. An estimated\u0026thinsp;\u0026gt;\u0026thinsp;200\u0026nbsp;million people have PAD worldwide, with a spectrum of symptoms ranging from none to severe \u003csup\u003e4)5)\u003c/sup\u003e. Despite the high morbidity and mortality, patients with PAD are often underdiagnosed and undertreated.\u003c/p\u003e \u003cp\u003eAlthough the reason for the poor prognosis in patients with PAD is unknown, high prevalence of coexistent cardiovascular disease (coronary artery disease, chronic heart failure [HF], or stroke) has frequently been mentioned as the likely cause of PAD occurrence \u003csup\u003e6)7)\u003c/sup\u003e. Patients with PAD have a high comorbidity burden, which has significant implications for clinical management.\u003c/p\u003e \u003cp\u003eHowever, the cardiac function of patients with PAD has not been studied systematically. Limited data are available on the association between cardiac function and PAD, especially in patients who underwent percutaneous transluminal angioplasty (PTA). In addition, diastolic dysfunction has not been yet reported in patients with PAD who underwent PTA, whereas left ventricular (LV) systolic dysfunction has been described\u003csup\u003e8)\u003c/sup\u003e. We aimed to evaluate the association between PAD and heart failure in patients with symptomatic PAD who underwent PTA. We also analyzed the effect of these abnormal cardiac findings on long-term cardiovascular outcomes in these patients.\u003c/p\u003e "},{"header":"Method","content":" \u003cp\u003eWe obtained data from the PTA registry of Korea University Guro Hospital (KUGH), Seoul, South Korea. This registry has been described in detail in previous studies. This single-center, prospective, all-comers registry was started in 2004 and designed to reflect real-world clinical practice. The study protocol was approved by the Medical Device Institutional Review Board of KUGH (protocol #MD12018). The study population included a total of 902 consecutive patients with symptomatic PAD who underwent PTA of the iliac, femoral, popliteal, tibial, and peroneal arteries from September 2004 to August 2017. The data were collected by trained study coordinators using standardized case report forms \u003csup\u003e9)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e.\u003cb\u003eCoronary and Peripheral Angiography and Revascularization\u003c/b\u003e\u003c/p\u003e \u003cp\u003eStandard techniques were used for PTA. Coronary and peripheral angioplasties were performed with a crossover approach or an anterograde ipsilateral femoral approach using 5\u0026thinsp;~\u0026thinsp;6 French sheaths. If there are significant coronary fixed stenosis (\u0026gt;\u0026thinsp;70% diameter stenosis), direct percutaneous coronary intervention (PCI) or staged PCI within the same hospitalization period was recommended and performed. Post-intervention dual antiplatelet therapy with aspirin 100\u0026nbsp;mg and clopidogrel 75\u0026nbsp;mg once daily or additional cilostazol 100\u0026nbsp;mg twice daily was given for at least 6 months, while aspirin 100\u0026nbsp;mg and/or clopidogrel 75\u0026nbsp;mg was given daily thereafter. Medications beneficial for cardiovascular health, including renin-angiotensin-aldosterone blockers, beta-blockers, and statins, were also prescribed according to practice guidelines.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEchocardiography\u003c/h2\u003e \u003cp\u003eAll patients underwent echocardiography examinations. Patients with transthoracic echocardiography (TTE) findings not suitable for the quantitative assessment of LV ejection fraction (LVEF) or diastology were excluded. The ratio of the transmitral Doppler E wave velocity and the early diastolic velocity (eʹ) at the septal annulus (E/eʹ ratio) was evaluated to estimate LV filling pressure. One best LVEF value for each patient was determined using a hierarchical approach: volumetric LVEF calculated using the 2D Simpson\u0026rsquo;s biplane method was preferred, followed by other calculated LVEF methods, followed by visual estimation if these other methods were unavailable. We divided the patients into three groups according to LVEF values: preserved LV function, LVEF\u0026thinsp;\u0026ge;\u0026thinsp;50%; mid-range LV function, 40% \u0026le; LVEF\u0026thinsp;\u0026lt;\u0026thinsp;50%; and reduced LV function, LVEF\u0026thinsp;\u0026lt;\u0026thinsp;40%. LV mass was calculated using ASE formula \u003csup\u003e10)\u003c/sup\u003e. LV regional wall motion was analyzed visually using the standard 16-segment model. Pulmonary artery systolic pressure (PASP) was estimated from the peak tricuspid regurgitation (TR) velocity obtained using continuous-wave Doppler echocardiography and estimated right atrial pressure as previously described \u003csup\u003e11)\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Clinical Characteristics\u003c/h2\u003e \u003cp\u003eBaseline patient characteristics were determined based on chart review and included age, sex, hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, coronary artery disease (CAD), renal insufficiency, current smoking, and family history of CAD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy Endpoints and Major Clinical Outcomes\u003c/h2\u003e \u003cp\u003eThe primary study endpoint was all-cause death, and the key secondary study endpoint was patient-oriented composite outcome (composite of all-cause death, any myocardial infarction [MI], stroke, or any repeat revascularization) at the 5-year or last follow-up. The cause of all deaths was considered cardiac unless an undisputed non-cardiac cause was present. MI was defined as symptom recurrence or the presence of electrocardiographic changes in association with an increase in cardiac biomarker levels above the upper limit of normal; cases of periprocedural MI were not included as clinical outcomes. Stroke was defined as the presence of neurological deficits confirmed by a neurologist on the basis of imaging study findings. Clinically driven revascularization that occurred after discharge from the index hospitalization was coded as a repeat revascularization event.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous variables are presented as mean and standard deviation when normally distributed or as median when not normally distributed. Demographic and echocardiographic factors were analyzed among groups using analysis of variance for continuous variables and chi-square for categorical variables. Kaplan-Meier and Cox regression analyses were used to determine associations between echocardiographic variables in patients with PAD and outcomes during the 5-year follow-up. Age, sex, hypertension, diabetes mellitus, dyslipidemia, CAD, and clinically important echocardiographic findings found to be univariate predictors of mortality were entered into multivariate models as predictors of mortality and for secondary study endpoints. A restricted cubic spline function allowed us to estimate a smooth nonlinear relationship between echocardiographic parameters and outcome in a regression model \u003csup\u003e12)\u003c/sup\u003e. All statistical tests were 2-tailed, with probability values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered significant. All data analyses were performed using SPSS for Windows version 20 (SPSS, Inc., Chicago, IL, USA).\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Characteristics and Echocardiographic Findings according to LV Function\u003c/h2\u003e \u003cp\u003eThe mean patient age was 68\u0026thinsp;\u0026plusmn;\u0026thinsp;10 years; 77% of the patients were male. The patients\u0026rsquo; baseline characteristics and cardiovascular risk factors according to LVEF are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Compared with patients with preserved EF, a higher proportion of patients with reduced EF had renal insufficiency, atrial fibrillation, and CAD. The other baseline characteristics were similar between groups. Over 80% of the enrolled patients underwent coronary angiography, and the reduced EF group had more left main lesions or multi-vessel disease. However, the limb characteristics were similar among the groups (supplementary Table\u0026nbsp;1). The echocardiographic findings are listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The reduced EF group had more cases of RWMA, mitral regurgitation, elevated E/eʹ, and elevated PASP. Valve calcification descriptions by echocardiography specialist cardiologists were similar among groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline clinical characteristics according to EF\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReduced EF\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;62 pts)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMid-range EF\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;76 pts)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePreserved EF\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;764 pts)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline characteristic\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48 (77.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e62 (81.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e590 (77.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.685\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e66.3\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e68.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e68.0\u0026thinsp;\u0026plusmn;\u0026thinsp;10.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.255\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood pressure, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e138.2\u0026thinsp;\u0026plusmn;\u0026thinsp;25.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e143.2\u0026thinsp;\u0026plusmn;\u0026thinsp;30.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e143.5\u0026thinsp;\u0026plusmn;\u0026thinsp;24.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.308\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e72.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e73.9\u0026thinsp;\u0026plusmn;\u0026thinsp;15.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e72.4\u0026thinsp;\u0026plusmn;\u0026thinsp;26.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.107\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart rate, beats per minute\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e84.4\u0026thinsp;\u0026plusmn;\u0026thinsp;19.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e80.8\u0026thinsp;\u0026plusmn;\u0026thinsp;21.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e78.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWound\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43 (69.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39 (51.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e481 (62.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGangrene\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18 (29.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (19.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e213 (27.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.299\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClaudication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17 (22.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e160 (20.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResting pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (14.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e88 (11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.742\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBerger\u0026rsquo;s disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient risks\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46 (74.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e56 (73.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e541 (70.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.758\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46 (74.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47 (61.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e570 (74.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43 (69.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39 (51.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e488 (63.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsulin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (32.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e249 (32.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.677\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDietary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.199\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.3\u0026thinsp;\u0026plusmn;\u0026thinsp;11.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.935\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyslipidemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e106 (13.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17 (27.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (19.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e127 (16.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.088\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.545\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIschemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (24.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e112 (14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChronic renal insufficiency\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e31 (50.0)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e29 (38.1)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e209 (27.3)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDialysis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e20 (32.2)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e20 (26.3)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e125 (16.3)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAtrial fibrillation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e16 (25.8)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e15 (19.7)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e56 (7.3)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePersistent or permanent AF\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e9 (14.5)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e9 (11.8)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e28 (3.6)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of smoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28 (45.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47 (61.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e392 (51.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.120\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13 (20.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31 (40.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e248 (32.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol consumption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14 (22.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20 (26.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e236 (30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.300\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrently\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17 (22.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e183 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCoronary artery disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e48 (77.4)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e57 (75.0)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e434 (56.8)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior CABG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e28 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior PCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (32.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23 (30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e171 (22.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePCI during PTA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e23 (37.0)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e27 (35.5)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e186 (24.3)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAF, atrial fibrillation; CABG, coronary artery bypass grafting; EF, ejection fraction; PCI, percutaneous coronary intervention; PTA, percutaneous transluminal angioplasty\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are shown as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or number (percentage).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline echocardiographic parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEchocardiographic variables, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReduced EF\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;62 pts)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMid-range EF\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;76 pts)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePreserved EF\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;764 pts)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLV ejection fraction, %\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e33.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e48.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e63.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRegional wall motion abnormalities\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e55 (88.7)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e59 (77.6)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e67 (8.7)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48 (77.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (38.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLCX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (54.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (39.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (67.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (47.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMitral annular calcification*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (19.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e107 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.423\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAortic valve calcification*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (11.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.644\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMitral regurgitation\u003c/b\u003e\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e28 (45.1)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e21 (27.6)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e128 (16.7)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAortic valve regurgitation\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (24.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (19.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e130 (17.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.324\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTricuspid valve regurgitation\u0026Dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (22.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65 (8.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft ventricular hypertrophy\u0026sect;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (38.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (40.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e187 (24.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLV diastolic dysfunction grade#\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.96\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.902\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eE/eʹ ratio\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e20.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e15.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e13.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePASP, mmHg\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e37.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e33.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e31.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Evaluation by the echocardiography specialist\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u0026dagger;More than mild\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u0026Dagger;Reduced EF patient group had more than moderate tricuspid regurgitation.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u0026sect;Left ventricular hypertrophy (LVH) was defined as increased LV mass index (LVMI) (\u0026ge;\u0026thinsp;96\u0026nbsp;g/m\u003csup\u003e2\u003c/sup\u003e in females, \u0026ge;\u0026thinsp;116\u0026nbsp;g/m\u003csup\u003e2\u003c/sup\u003e in males).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e# Diastolic dysfunction is considered in our laboratory when Doppler inflow is consistent with a normal pattern (1 point), abnormal relaxation (1 point), pseudonormalization (2 points), or restrictive patterns (3 points).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eLAD, left anterior descending artery; LCx, left circumflex artery; LV, left ventricle; PASP, pulmonary artery systolic pressure; RCA, right coronary artery\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eIn-Hospital Complications according to LV Function\u003c/h2\u003e \u003cp\u003eReduced EF was associated with a higher incidence of red blood cell transfusion (p\u0026thinsp;=\u0026thinsp;0.025), post-procedural aneurysm (p\u0026thinsp;=\u0026thinsp;0.009), and significantly longer stay in the intensive care unit (ICU, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than the other LVEF types (supplementary Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eAll-Cause Mortality and Major Cardiovascular Events according to EF\u003c/h2\u003e \u003cp\u003eThe overall 30-day postoperative mortality rate was 2.0%. The mortality and cardiovascular morbidity rates did not differ significantly according to EF at 30\u0026nbsp;days (supplementary Table\u0026nbsp;2). During a median follow-up of 5 years, 140 total cardiovascular events occurred: 81 deaths, 8 MIs, 48 percutaneous coronary intervention (PCI) and 28 cerebral infarctions. The causes of death were stroke, MI, HF aggravation, or sudden cardiac death. Despite our best efforts, we could not identify the causes of 29 cases of sudden death. Total deaths were higher in the reduced EF group (n\u0026thinsp;=\u0026thinsp;12 [19.7%]) than in the preserved EF group (n\u0026thinsp;=\u0026thinsp;59 [8.9%]). Kaplan-Meier curves showed significant differences in survival among each of the two groups according to EF (reduced EF vs. preserved EF, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; mid-range EF vs. preserved EF, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Fig.\u0026nbsp;1A). However, there was no significant difference in survival between the reduced and mid-range EF groups. Similar trends were found in total cardiovascular events: these events were 1.4 time more common in patients with reduced EF than in those with preserved EF (reduced EF vs. preserved EF, p\u0026thinsp;=\u0026thinsp;0.04; Fig.\u0026nbsp;1B).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePredictors of All-Cause Mortality and Major Cardiovascular Events\u003c/h2\u003e \u003cp\u003eThe independent predictors of long-term mortality and combined events were identified using multiple stepwise Cox regression analysis (Fig.\u0026nbsp;2). After adjustment for age, chronic kidney disease, and HbA1c values, EF remained the only significant predictor of all-cause mortality (hazard ratio [HR], 0.96; 95% CI, 0.96\u0026ndash;0.99; p\u0026thinsp;=\u0026thinsp;0.04]. Interestingly, after additional adjustment for other variables, E/eʹ and longer ICU stay were independent predictors of all-cause mortality (E/eʹ: HR, 1.11; 95% CI, 1.07\u0026ndash;1.16; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; and longer ICU stay: HR, 1.06; 95% CI, 1.03\u0026ndash;1.09; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Fig.\u0026nbsp;1A). Heart rate was the other independent predictor of mortality (HR, 1.02; 95% CI, 1.00\u0026ndash;1.04; p\u0026thinsp;=\u0026thinsp;0.01). However, heart rate was not an independent predictor of major cardiovascular events (Fig.\u0026nbsp;2B). Each of these models was then re-run with the sequential replacement of E/eʹ with left atrial (LA) size, transmitral E wave velocity, transmitral E/A ratio, PASP, and tissue Doppler eʹ velocity. None of these measures significantly predicted all-cause mortality or major cardiovascular events with adjustment for covariates. E/eʹ remained the only significant echocardiographic predictor of risk.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAll-Cause Mortality and Major Cardiovascular Events according to E/e\u003c/b\u003eʹ\u003c/p\u003e \u003cp\u003eTo estimate a smooth nonlinear relationship between E/eʹ and outcome in a regression model, we used a restricted cubic spline function. Figure\u0026nbsp;3 shows the predicted 5-year probability of death as a function of E/eʹ using splines and by varying the degrees of freedom. Mortality rate was increased abruptly after the range of E/eʹ was over 15. E/eʹ values were subsequently divided into two groups for Kaplan-Meier survival analysis (E/eʹ \u0026lt; 15 vs. E/eʹ \u0026ge; 15). Using the log-rank test, we found that patients with E/eʹ \u0026ge; 15 had more than 6 times higher risk of mortality (Fig.\u0026nbsp;4A) as those with E/eʹ \u0026lt; 15 (HR, 6.14; 95% CI, 3.7\u0026ndash;10.1; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Similarly, all-cause cardiovascular events were 2.8 times more common (95% CI, 2.0\u0026ndash;4.0; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) in patients with E/eʹ \u0026ge; 15 than in patients with E/eʹ \u0026lt; 15 (Fig.\u0026nbsp;4B).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSurvival Analysis in Patients with Preserved EF\u003c/h2\u003e \u003cp\u003eMost of the patients (n\u0026thinsp;=\u0026thinsp;764 [85%]) had preserved EF. Additional analysis was performed considering only patients with preserved EF to confirm that E/eʹ was the most important echocardiogram variable in this group. Similarly, E/eʹ was found to be an independent predictor of all-cause mortality and major cardiovascular events in the subgroup of patients with preserved EF (HR, 1.12; 95% CI, 1.07\u0026ndash;1.17 for all-cause mortality; HR, 1.07; 95% CI, 1.03\u0026ndash;1.12 for major cardiovascular events; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Kaplan-Meier curves showed significant intergroup differences according to E/eʹ cut-off values (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Figs.\u0026nbsp;5A, 5B). The 5-year survival rate was 97.1% among patients with E/eʹ \u0026lt; 15, compared to the 81% observed among those with E/eʹ \u0026ge; 15 and preserved EF. Patients with higher E/eʹ (\u0026ge;\u0026thinsp;15) had a 6.8 times higher risk of death (HR, 6.8; 95% CI, 3.8\u0026ndash;12.3; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and a 3.1 times higher risk of a major cardiovascular event (HR, 3.1; 95% CI, 2.1\u0026ndash;4.5; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Patients with E/eʹ \u0026ge; 15 were more likely to have multi-vessel disease (43% for E/eʹ \u0026ge; 15 vs. 28% for E/eʹ \u0026lt; 15; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), chronic total occlusion (11% for E/eʹ \u0026ge; 15 vs. 5.5% for E/eʹ \u0026lt;15; p\u0026thinsp;=\u0026thinsp;0.02), elevated creatinine (2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u0026nbsp;mg/dL for E/eʹ \u0026ge; 15 vs. 1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u0026nbsp;mg/dL for E/eʹ \u0026lt; 15; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and longer ICU stay (1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u0026nbsp;days for E/eʹ \u0026ge; 15 vs. 0.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u0026nbsp;days for E/eʹ \u0026lt; 15; p\u0026thinsp;=\u0026thinsp;0.04). Other variables were similar between the two groups.\u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion","content":" \u003cp\u003eThere were three main findings of the present study in patients with PAD who underwent PTA. First, patients with PAD undergoing PTA with reduced LVEF had higher incidence of total death during the 5-year follow-up. Second, an initial tissue Doppler E/eʹ \u0026ge; 15, a non-invasive estimate of high LA filling pressure, was the only independent predictor of long-term mortality. Third, patients with preserved EF who have high LV filling pressure and PAD might be at increased risk of myocardial ischemia, which was related to a higher 5-year mortality rate. To the best of our knowledge, this is the first study to demonstrate echocardiographic prognostic predictors in patients with PAD undergoing PTA during long-term follow-up.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLV Systolic Dysfunction and PAD\u003c/h2\u003e \u003cp\u003eThe presence of PAD is associated with a 2-fold increase in the prevalence of HF. Given that HF and PAD share many risk factors including increased age, diabetes, smoking, atherosclerosis, and poor renal function, it is not surprising that the prevalence of LV systolic dysfunction in patients with PAD is 5.3\u0026ndash;13.9% \u003csup\u003e5)13)\u003c/sup\u003e. The association between PAD and cardiovascular disease and the increasing prevalence of HF in industrialized countries suggest that PAD is an important medical concern in patients with HF. In this study, over 70% of patients had hypertension and diabetes mellitus and approximately 50% of patients were smokers. Among patients with PAD who underwent PTA, 6.8% had reduced LV systolic function (\u0026le;\u0026thinsp;40%), whereas 15% had LV systolic dysfunction including mid-range EF (EF\u0026thinsp;\u0026le;\u0026thinsp;50%); this prevalence of LV systolic dysfunction was similar to those reported in other studies. Patients with LV dysfunction had increased chronic renal insufficiency and atrial fibrillation. However, in 2002, Kelly et al. reported a 28% prevalence of moderate or greater LV systolic dysfunction in 255 patients with PAD \u003csup\u003e14)\u003c/sup\u003e. Although the characteristics of their patients were similar to those of our patients in terms of age, sex, and prevalence of ischemic heart disease, the patients in their study were considerably more often current smokers (78%) and had different ethnicities. Our study findings demonstrate that the prevalence and burden of CAD were high among patients with LV systolic dysfunction who had PAD (77.4% of those with reduced EF vs. 56.8% of those with preserved EF; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and LV dysfunction was associated with an increased risk of mortality and major cardiovascular events in patients with PAD who underwent PTA. Based on current guidelines, patients who are smokers and have known CAD and/or diabetes mellitus should undergo an ABI assessment to screen the presence of PAD. Obtaining ABI measurements in these patients at risk and with concomitant systolic HF will enhance PAD detection in this specific population. Similarly, patients with symptomatic PAD confirmed by a low ABI must be referred for echocardiography to screen LV dysfunction and detect RWMA. Ward et al. reported that, among patients with symptomatic PAD referred for echocardiography, there was a high prevalence of clinically important echocardiographic findings, including LV dysfunction \u003csup\u003e15)\u003c/sup\u003e. In addition, evaluation of the coronary arteries along with subsequent optimal treatment of patients of PAD who underwent PTA may improve survival\u003csup\u003e16)\u003c/sup\u003e. However current indications for screening TTE in patients with PAD are limited. Prospective echocardiographic screening studies and detection of LV dysfunction are warranted in patients with symptomatic PAD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eLV Diastolic Dysfunction and PAD\u003c/h2\u003e \u003cp\u003eAnother interesting finding in our study is the association of diastolic dysfunction and long-term cardiovascular outcomes in patients with PAD. We have confirmed that E/e' is the most important variable affecting survival rates in all patients with PAD. As reduced LV function has some correlation with E/e', the analysis was conducted again only in patients with preserved EF. In this study, E/e\u0026rsquo; was found to be an independent predictor of all-cause mortality and major cardiovascular events in patients with preserved EF (HR, 1.12; 95% CI, 1.07\u0026ndash;1.17 for all-cause mortality; HR, 1.07; 95% CI, 1.03\u0026ndash;1.12 for major cardiovascular events; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Some meta- analyses reported that PAD and HF are associated with increased mortality, hospitalization, and adverse health outcomes \u003csup\u003e13)17)\u003c/sup\u003e. However, the studies included in these analyses delineated HF with regard to clinically apparent systolic dysfunction. Asymptomatic patients with diastolic HF or structural heart changes were not included in those reviews. Yamasaki et al. suggested the association of diastolic dysfunction in patients with PAD \u003csup\u003e18)\u003c/sup\u003e. However, the number of patients in that study was small (n\u0026thinsp;=\u0026thinsp;120), and the relationship between PAD and LV diastolic function remains unclear. Yanaka et al. evaluated LV diastolic function using echocardiography in 1,121 patients and applied the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines for the diagnosis of LV diastolic dysfunction \u003csup\u003e19)\u003c/sup\u003e. They showed a higher prevalence of LV diastolic dysfunction in patients with PAD (n\u0026thinsp;=\u0026thinsp;200) regardless of the severity of PAD (non-PAD, n\u0026thinsp;=\u0026thinsp;921). Additionally, multivariate logistic regression analysis showed that PAD was an independent predictor of LV diastolic dysfunction (adjusted OR, 1.77; p\u0026thinsp;=\u0026thinsp;0.01). They showed that the prevalence of LV diastolic dysfunction was higher in patients with PAD than in those without PAD. These findings suggest that patients with PAD should be evaluated for LV systolic and diastolic function in echocardiography. However, the authors did not imply the role of diastolic dysfunction in survival among patients with PAD, and the number of patients with PAD was relatively small (n\u0026thinsp;=\u0026thinsp;200) to evaluate clinical outcome differences. In our study, we enrolled 764 patients with significant and symptomatic PAD who had preserved EF and who underwent PTA, and the mean E/eʹ was 13.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3. This value is relatively higher than that of normal healthy people \u003csup\u003e20)\u003c/sup\u003e. Among patients with preserved EF, the 5-year mortality rate was 2.9% in those with E/eʹ \u0026lt; 15 (n\u0026thinsp;=\u0026thinsp;15 of 525), whereas it was high, that is, 19%, in those with E/eʹ \u0026ge; 15 (n\u0026thinsp;=\u0026thinsp;44 of 239). This result has a very important clinical interpretation. In patients with PAD and HF, claudicating calf pain and wounds from critical limb ischemia limits their ability to exercise and potentially precludes them from achieving exercise training. Moreover, as reported by Fowkes et al., patients with PAD are often asymptomatic, but even when symptoms are present, it may be extremely difficult for some patients with HF to discern claudication symptoms from fatigue owing to a chronic low output state or poor effort tolerance \u003csup\u003e21)\u003c/sup\u003e. Therefore, PAD can often be missed in the risk stratification of patients with HF and functional limitations. Because of functional limitations, many patients with HF may not ambulate to the extent to which symptoms of PAD occur, thereby precluding its identification. The inspection and recognition of diastolic function in patients with PAD is essential because most physicians recognize reduced EF to a certain extent, and preserved EF can be confirmed on normal ultrasonography.\u003c/p\u003e \u003cp\u003e \u003cb\u003eWhy Would E/e\u003c/b\u003eʹ \u003cb\u003ePredict Cardiovascular Outcomes?\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAn elevated E/eʹ is a marker for high LV filling pressure \u003csup\u003e22)\u003c/sup\u003e. Using a cut-off of \u0026gt;\u0026thinsp;15 for an elevated medial E/eʹ ratio with exercise, the sensitivity and specificity for predicting elevated LV filling pressure (measured invasively) were in excess of 80\u0026ndash;85%, similar to the diagnostic accuracy of myocardial ischemia with stress echocardiography and quite acceptable for clinical practice \u003csup\u003e23)\u003c/sup\u003e. An elevated E/eʹ is a strong predictor of death following MI \u003csup\u003e24)\u003c/sup\u003e and superior to other clinical or echocardiographic features. More recently, it was also demonstrated to predict cardiac events in subjects following coronary angiography and survival in those with established cardiac arrhythmias, but the predictor has not been examined prospectively in terms of primary prevention until now. One possible explanation is that the cumulative burden of atherosclerosis per patient is proportionate to the degree of diastolic dysfunction. Therefore, this measure may act as a surrogate for the overall effect of PAD on the myocardium, which, in turn, may predict adverse cardiovascular outcomes. In our study, patients with preserved EF and elevated E/eʹ were more likely to have multi-vessel disease (43% for E/eʹ \u0026ge; 15 vs. 28% E/eʹ \u0026lt; 15; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and chronic total occlusion (11% for E/eʹ \u0026ge; 15 vs. 5.5% E/eʹ \u0026lt; 15; p\u0026thinsp;=\u0026thinsp;0.02). Hidden ischemic insult might be a cause for high LV filling pressure and eventual mortality.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis study has several limitations. First, it was conducted in a single tertiary referral hospital. Although we prospectively enrolled all consecutive patients, referral bias could not be excluded; thus, the results might be difficult to generalize. However, considering the wide range of clinical and echocardiographic parameters in our study population, the validity of our study might not be altered. Second, this was a retrospective investigation, and our patient population was a subgroup selected from overall patients who had undergone routine echocardiography with angiography; thus, some selection bias is unavoidable.\u003c/p\u003e \u003c/div\u003e "},{"header":"Conclusions","content":" \u003cp\u003ePatients with symptomatic significant PAD and reduced LVEF had a higher incidence of total mortality during the 5-year follow-up. In addition, diastolic dysfunction was the only independent predictor of long-term mortality in patients with PAD. These findings suggest that the systolic and diastolic function of patients with PAD should be evaluated. In patients with diastolic dysfunction, presence of coexisting CAD should be cautiously evaluated and monitored during follow-up.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eEF: ejection fraction\u003c/p\u003e\n\u003cp\u003eHF: heart failure\u003c/p\u003e\n\u003cp\u003eLV: left ventricle\u003c/p\u003e\n\u003cp\u003eMI: myocardial infarction\u003c/p\u003e\n\u003cp\u003ePAD: peripheral arterial disease\u003c/p\u003e\n\u003cp\u003ePCI: percutaneous coronary intervention\u003c/p\u003e\n\u003cp\u003ePTA: percutaneous transluminal angioplasty\u003c/p\u003e\n\u003cp\u003eRWMA: regional wall motion abnormality\u003c/p\u003e\n\u003cp\u003eTTE: transthoracic echocardiography\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e- Ethical Approval and Consent to participate: It is approved by the hospital\u0026rsquo;s IRB. Informed consent to participate in the study were obtained from participants.\u003c/p\u003e\n\u003cp\u003e- Consent for publication: All authors read and approved the final manuscript\u003c/p\u003e\n\u003cp\u003e- Availability of data and materials: All data can be checked by sending an email to Correspondence.\u003c/p\u003e\n\u003cp\u003e- Competing interests: none\u003c/p\u003e\n\u003cp\u003e- Funding: none\u003c/p\u003e\n\u003cp\u003e- Authors' contributions: KHK and SWR contributed to the idea and design of this study, prepared and verified the clinical coding, analyzed the data, wrote the first draft, and contributed to the subsequent drafts. BGC, JKB, WHK prepared and verified the clinical coding and analyzed the data. BGC, JKB, CUC, and HSS contributed to the data collection and revised the manuscript. KHK and SWR are the principal investigators and contributed to the idea and design of this study, interpreted and analyzed the data, and contributed to the subsequent drafts. All authors have read and approved the final version for publication.\u003c/p\u003e\n\u003cp\u003e- Acknowledgements: None of the authors have any financial relationships with any company or any other bias or conflict of interest to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e \u003cspan\u003eFeringa HH, Bax JJ, Hoeks S, et al. A prognostic risk index for long-term mortality in patients with peripheral arterial disease. Arch Intern Med. 2007;167:2482\u0026ndash;9.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eDiehm C, Allenberg JR, Pittrow D, et al. CLINICAL PERSPECTIVE Circulation. 2009;120:2053\u0026ndash;61.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eCriqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381\u0026ndash;6.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eSavji N, Rockman CB, Skolnick AH, et al. Association between advanced age and vascular disease in different arterial territories: a population database of over 3.6 million subjects. J Am Coll Cardiol. 2013;61:1736\u0026ndash;43.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eHirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. Jama. 2001;286:1317\u0026ndash;24.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eJones WS, Clare R, Ellis SJ, et al. Effect of peripheral arterial disease on functional and clinical outcomes in patients with heart failure (from HF-ACTION). The American journal of cardiology. 2011;108:380\u0026ndash;4.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eInglis SC, McMurray JJ, B\u0026ouml;hm M, et al. Intermittent claudication as a predictor of outcome in patients with ischaemic systolic heart failure: analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure trial (CORONA). Eur J Heart Fail. 2010;12:698\u0026ndash;705.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eAhmed MI, Aronow WS, Criqui MH, et al. Effects of peripheral arterial disease on outcomes in advanced chronic systolic heart failure: a propensity-matched study. Circulation: Heart Failure. 2010;3:118\u0026ndash;24.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eLee MS, Rha S-W, Han SK, et al. Gender differences in endovascular revascularization for peripheral arterial disease. In: VDM. P.117 \u0026ndash; 25, 2015.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eMizukoshi K, Takeuchi M, Nagata Y, et al. Normal values of left ventricular mass index assessed by transthoracic three-dimensional echocardiography. J Am Soc Echocardiogr. 2016;29:51\u0026ndash;61.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eMcQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation. 2001;104:2797\u0026ndash;802.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eHarre FE Jr, Lee KL, Pollock BG. Regression models in clinical studies: determining relationships between predictors and response. JNCI: Journal of the National Cancer Institute. 1988;80:1198\u0026ndash;202.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eAnand RG, Ventura HO, Mehra MR. Is heart failure more prevalent in patients with peripheral arterial disease? A meta-analysis. Congestive Heart Failure. 2007;13:319\u0026ndash;22.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKelly R, Staines A, MacWalter R, Stonebridge P, Tunstall-Pedoe H, Struthers AD. The prevalence of treatable left ventricular systolic dysfunction in patients who present with noncardiac vascular episodes: a case-control study. J Am Coll Cardiol. 2002;39:219\u0026ndash;24.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eWard RP, Min JK, McDonough KM, Lang RM. High prevalence of important cardiac findings in patients with peripheral arterial disease referred for echocardiography. J Am Soc Echocardiogr. 2005;18:844\u0026ndash;9.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eJeremias A, Gruberg L, Patel J, Connors G, Brown DL. Effect of peripheral arterial disease on in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction. The American journal of cardiology. 2010;105:1268\u0026ndash;71.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eInglis SC, Hermis A, Shehab S, Newton PJ, Lal S, Davidson PM. Peripheral arterial disease and chronic heart failure: a dangerous mix. Heart Fail Rev. 2013;18:457\u0026ndash;64.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eYamasaki S, Izawa A, Shiba Y, et al. Presence of diastolic dysfunction in patients with peripheral artery disease. Angiology. 2013;64:540\u0026ndash;3.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eYanaka K, Akahori H, Imanaka T, et al. The impact of peripheral artery disease on left ventricular diastolic function. Journal of cardiology. 2019;73:453\u0026ndash;8.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eD'Andrea A, Vriz O, Ferrara F, et al. Reference ranges and physiologic variations of left E/e'ratio in healthy adults: Clinical and echocardiographic correlates. Journal of cardiovascular echography. 2018;28:101.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eFowkes FGR, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. The Lancet. 2013;382:1329\u0026ndash;40.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eAndersen OS, Smiseth OA, Dokainish H, et al. Estimating left ventricular filling pressure by echocardiography. J Am Coll Cardiol. 2017;69:1937\u0026ndash;48.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eObokata M, Kane GC, Reddy YN, Olson TP, Melenovsky V, Borlaug BA. Role of diastolic stress testing in the evaluation for heart failure with preserved ejection fraction: a simultaneous invasive-echocardiographic study. Circulation. 2017;135:825\u0026ndash;38.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eHillis GS, M\u0026oslash;ller JE, Pellikka PA, et al. Noninvasive estimation of left ventricular filling pressure by E/e\u0026prime; is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol. 2004;43:360\u0026ndash;7.\u003c/span\u003e \u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Peripheral Artery Disease, Heart Failure, Systolic Dysfunction, Diastolic Dysfunction","lastPublishedDoi":"10.21203/rs.3.rs-41677/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-41677/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePeripheral arterial disease (PAD) and heart failure share common risks and are associated with increased morbidity and mortality. However, it is unknown whether cardiac function can be an independent predictor of long-term mortality in patients with PAD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn total, 902 patients who underwent percutaneous transluminal angioplasty for PAD were enrolled. The patients were categorized into three groups according to the left ventricular ejection fraction (LVEF): reduced EF (\u0026lt;\u0026thinsp;40%, n\u0026thinsp;=\u0026thinsp;62); mid-range EF (40\u0026ndash;49%, n\u0026thinsp;=\u0026thinsp;76); and preserved EF (\u0026ge;\u0026thinsp;50%, n\u0026thinsp;=\u0026thinsp;764). Echocardiographic (EF, ratio of mitral inflow velocity to annular velocity E/eʹ \u0026ge; 15, and others) and clinical parameters were tested using stepwise logistic regression analysis to determine independent predictors of 5-year mortality.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA higher proportion of patients with reduced EF had ischemic heart disease than those with preserved EF (77.4% vs. 56.8%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Up to 5 years, patients with reduced EF and mid-range EF showed a higher incidence of total death than those with normal EF. However, there was no difference in the incidence of myocardial infarction, stroke, and revascularization among the three groups. After multivariable adjustment, the ratio of E/eʹ \u0026ge; 15 was the only strong predictor of total mortality (hazard ratio, 6.14; 95% confidence interval, 3.7\u0026ndash;10.1;p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePatients with PAD and reduced EF undergoing PTA had a higher incidence of total death during the 5-year follow-up. Initial tissue Doppler E/eʹ \u0026ge; 15, a non-invasive estimate of left atrial filling pressure, was the only independent predictor of long-term mortality.\u003c/p\u003e","manuscriptTitle":"Initial Diastolic Dysfunction is a Powerful Predictor of 5-year Mortality in Peripheral Arterial Disease Patients undergoing Percutaneous Transluminal Angioplasty","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-07-16 14:27:00","doi":"10.21203/rs.3.rs-41677/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b2219905-5695-447d-bbdb-cb4a1e3e6658","owner":[],"postedDate":"July 16th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":163524,"name":"Cardiac \u0026 Cardiovascular Systems"}],"tags":[],"updatedAt":"2020-08-05T14:38:10+00:00","versionOfRecord":[],"versionCreatedAt":"2020-07-16 14:27:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-41677","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-41677","identity":"rs-41677","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}