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 survival16). 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/eʹ 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.