Methods

This prospective single-center cohort study included a study population of 1,321 consecutive patients with PAD referred for elective major vascular surgery. All patients were scheduled for a vascular surgery procedure from 2002 to 2009, and procedures included lower extremity revascularization, abdominal aortic surgery (dilatating or stenotic), or carotid surgery. The study complied with the Declaration of Helsinki. Patient enrollment was performed after approval of the hospital’s ethics committee and after informed consent of all patients (or their guardians) at time of inclusion.

At baseline, a detailed history was obtained from every patient. Cerebro-cardiovascular history was assessed and included a history of cerebrovascular accident/transient ischemic attack, and ischemic heart disease (composite of angina pectoris, previous myocardial infarction, percutaneous coronary intervention/coronary artery bypass grafting). Presence of polyvascular disease was defined as the presence of >1 affected vascular territory. Before surgery, all cardiac risk factors and markers were recorded, including age, gender, body mass index, smoking status, hypertension (defined as systolic blood pressure ≥140 mm Hg and diastolic blood pressure ≥90 mm Hg in nondiabetics, systolic blood pressure ≥130 mm Hg and diastolic blood pressure ≥80 mm Hg in diabetics or use of antihypertensive medication), hypercholesterolemia (low-density lipoprotein cholesterol >135 mg/dl and/or requirement of lipid-lowering medication), chronic obstructive pulmonary disease (according to Global Initiative on Obstructive Lung Diseases classification ), and chronic renal insufficiency (serum creatinine >2.0 mg/dl). Use of β blockers, statins, aspirin, oral anticoagulants, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, diuretics, and nitrates was recorded.

Preoperatively, cardiac evaluation was performed in all patients using a portable Acuson Cypress Ultrasound System (SonoSite Titan, SonoSite Inc., Bothell, Washington) with a 3V2C transducer (3.0/3.5/2.5/2.0 MHz). During rest with the patient in the left lateral decubitus position, standard parasternal and apical 2- and 4-chamber views were obtained, as recommended previously. LV end-systolic and end-diastolic volumes were determined and LV ejection fraction (LVEF) was calculated using the biplane Simpson technique. Previous analyses showed inter- and intraobserver variabilities of 9% to 12% and 6% for determining LVEF. Using the apical 4-chamber view, systolic and diastolic pulmonary vein flow, deceleration time, and mitral inflow ratios of early rapid filling to late filling due to atrial contraction (E/A) of peak velocities were calculated. Of note, echocardiographic data were for research purposes and were not used for clinical management.

According to European Society of Cardiology guidelines, LVEF <50% was defined as systolic LVD. Diastolic LVD was confirmed in patients with E/A <0.8 (impaired relaxation) or >2 (restrictive relaxation). Abnormal pulmonary vein flow (systolic/diastolic <1) was used to distinguish normal from pseudonormal diastolic LV function in patients with E/A from 0.8 to 2.0. Deceleration time >220 ms (impaired relaxation) or <140 ms (restrictive relaxation) defined diastolic LVD in patients with atrial fibrillation. Patients with LVEF ≥50% and no signs of diastolic LVD comprised the reference group. Diastolic LVD, regardless of whether EF was normal or abnormal and whether a patient was symptomatic or asymptomatic, defined diastolic LVD. LVEF <50% without diastolic LVD defined the presence of systolic LVD. Combined LVD was defined as LVEF <50% and diastolic LVD. DM was diagnosed in patients treated with oral blood glucose-lowering drugs or insulin therapy. In remaining patients, fasting plasma glucose measurement (>6.1 mmol/L [110 mg/dl]) was used to determine the presence of newly detected DM.

Mean follow-up of all patients was 2.5 ± 1.9 years. The primary study end point was occurrence of cardiovascular mortality. Survival status was assessed by approaching the municipal civil registries. Cause of death was ascertained by examining death certificates and otherwise by reviewing medical records. Cardiovascular death was defined as any death with a cerebro-cardiovascular complication as the primary or secondary cause and included death after myocardial infarction, serious cardiac arrhythmias (defined as presence of sustained cardiac rhythm disturbance that required urgent medical intervention), congestive heart failure, and stroke (cerebrovascular event or transient ischemic attack). Sudden unexpected death was classified as cardiovascular death.

Continuous data were compared using analysis of variance and are expressed as mean ± SD. Categorical data are presented as percent frequencies and compared using chi-square tests. All analyses regarding survival parameters were separately performed in patients with DM and patients without DM. Cumulative survival of patients with normal LV function and diastolic, systolic, or combined LVD was determined by the Kaplan-Meier method and compared using log-rank test. Univariate and multivariate Cox regression models were used to investigate the association between LVD (patients without LVD as reference group) and mortality during long-term follow-up. All multivariate analyses were primarily adjusted for demographics (age and gender), site of surgery (carotid artery, abdominal aorta, or lower extremity), type of surgery (open/endovascular), previous cerebrovascular disease, ischemic heart disease, cardiovascular risk factors (smoking, hypertension, dyslipidemia, chronic renal dysfunction, and chronic obstructive pulmonary disease), and European Society of Cardiology guideline-recommended therapy for LVD (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, and nitrates). These covariates were prospectively locked into the model based on the clinical knowledge and belief that these factors might (1) contribute to study outcomes and (2) confound the association between the primary echocardiographic predictors and study end points. Statistical analyses were performed using SPSS 15.0 (SPSS, Inc., Chicago, Illinois). Hazard ratios were calculated from these models, as were their 95% confidence intervals. A p value <0.05 (2-sided) was considered statistically significant.

Results

The study population consisted of 1,321 patients with PAD. Before surgery, DM was diagnosed in 519 patients (39%), with DM newly detected using fasting plasma glucose measurement in 134 (26%). Demographic characteristics and cardiovascular risk factors and markers were compared between these groups and are listed in Table 1 . Normal cardiac function was observed in 707 patients (54%). The distribution of different types of LVD in nondiabetic and diabetic patients is shown in Figure 1 . Asymptomatic LVD was observed in 80% of patients, and the remaining 20% had a history or present signs of symptomatic heart failure.

Distribution of different types of LVD between patients with (striped bars) and without (gray bars) DM.

The primary end point of cardiovascular death occurred in 27 patients (6%) with normal LV function compared to 33 (16%), 15 (29%), and 31 (37%) with diastolic, systolic, and combined LVD, respectively (p <0.001). Kaplan-Meier estimates for cardiovascular mortality stratified according to the 4 groups of LVD/LV function demonstrated that patients with diastolic, systolic, or combined LVD had lower survival compared to patients without LVD ( Figure 2 ). Log-rank test compared survival between no LVD and diastolic (p = 0.007), systolic (p <0.001), or combined (p <0.001) LVD. In addition, diastolic was compared to systolic LVD using log-rank test and demonstrated no difference in survival rates (p = 0.07). Multivariate regression analyses demonstrated an increased long-term cardiovascular mortality risk for patients with diastolic, systolic, or combined LVD compared to normal cardiac function ( Table 2 ).

Kaplan-Meier estimates for long-term cardiovascular mortality stratified according to normal LV function (top solid line) , diastolic LVD (dashed line) , systolic LVD (dotted line) , and combined LVD (bottom solid line) in nondiabetic patients.

Table 2

Long-term cardiovascular survival

Variable	Events	Cardiovascular Mortality
		HR	95% CI
No diabetes (n = 802)
Normal left ventricular function (n = 461)	27 (6%)	Reference
Left ventricular dysfunction
Isolated diastolic (n = 208)	33 (16%)	2.2	1.30–3.74
Isolated systolic (n = 51)	15 (29%)	3.9	2.00–7.52
Combined (n = 83)	30 (37%)	4.7	2.62–8.29
Diabetes (n = 519)
Normal left ventricular function (n = 246)	29 (12%)	Reference
Left ventricular dysfunction
Isolated diastolic (n = 148)	29 (20%)	1.8	1.03–3.03
Isolated systolic (n = 51)	12 (24%)	3.1	1.46–6.38
Combined (n = 73)	28 (38%)	3.7	2.1–6.47

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