Ayman Samman-Tahhan

Heart rate and the risk of adverse outcomes in patients with heart failure with preserved ejection fraction

Background Although high resting heart rates are associated with adverse outcomes in heart failure with reduced ejection, the reports for heart failure with preserved ejection fraction (HFpEF) are conflicting. Design A secondary analysis was conducted in order to examine the relationship between resting heart rate and adverse outcomes in 2705 patients (mean age = 68 ± 10 years; 47% men; 88% white) with HFpEF who were in sinus rhythm from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT). Methods Baseline heart rate was obtained from baseline electrocardiogram data. Outcomes were adjudicated by a clinical end-point committee and included the following factors: hospitalisation, hospitalisation for heart failure, death and cardiovascular death. Results Over a median follow-up of 3.4 years (25th–75th percentiles = 2.0–4.9 years), a total of 1157 hospitalisations, 311 hospitalizations for heart failure, 369 deaths and 233 cardiovascular deaths occurred. An increased risk (per 5-beats per minute [bpm] increase) for hospitalisation (hazard ratio [HR] = 1.03, 95% confidence interval [CI] = 1.004–1.060), hospitalisation for heart failure (HR = 1.10, 95% CI = 1.05–1.15), death (HR = 1.10, 95% CI = 1.06–1.16) and cardiovascular death (HR = 1.13, 95% CI = 1.07–1.19) was observed. When the analysis was limited to those who did not report the use of β-blockers, the magnitude of the association for each outcome (per 5-bpm increase) was not materially altered (hospitalisation: HR = 1.03, 95% CI = 0.97–1.09; hospitalisation for heart failure: HR = 1.12, 95% CI = 0.98–1.27; death: HR = 1.16, 95% CI = 1.05–1.28; cardiovascular death: HR = 1.12, 95% CI = 0.99–1.27). Conclusion High resting heart rate is a risk factor for adverse outcomes in patients with HFpEF, and future studies are needed in order to determine whether reducing heart rate improves outcomes in HFpEF.

Association Between Living in Food Deserts and Cardiovascular Risk

Background— Food deserts (FD), neighborhoods defined as low-income areas with low access to healthy food, are a public health concern. We evaluated the impact of living in FD on cardiovascular risk factors and subclinical cardiovascular disease (CVD) with the hypothesis that people living in FD will have an unfavorable CVD risk profile. We further assessed whether the impact of FD on these measures is driven by area income, individual household income, or area access to healthy food. Methods and Results— We studied 1421 subjects residing in the Atlanta metropolitan area who participated in the META-Health study (Morehouse and Emory Team up to Eliminate Health Disparities; n=712) and the Predictive Health study (n=709). Participants’ zip codes were entered into the United States Food Access Research Atlas for FD status. Demographic data, metabolic profiles, hs-CRP (high-sensitivity C-reactive protein) levels, oxidative stress markers (glutathione and cystine), and arterial stiffness were evaluated. Mean age was 49.4 years, 38.5% male and 36.6% black. Compared with those not living in FD, subjects living in FD (n=187, 13.2%) had a higher prevalence of hypertension and smoking, higher body mass index, fasting glucose, and 10-year risk for CVD. They also had higher hs-CRP (P=0.014), higher central augmentation index (P=0.015), and lower glutathione level (P=0.003), indicative of increased oxidative stress. Area income and individual income, rather than food access, were associated with CVD risk measures. In a multivariate analysis that included food access, area income and individual income, both low-income area and low individual household income, were independent predictors of a higher 10-year risk for CVD. Only low individual income was an independent predictor of higher hs-CRP and augmentation index. Conclusions— Although living in FD is associated with a higher burden of cardiovascular risk factors and preclinical indices of CVD, these associations are mainly driven by area income and individual income rather than access to healthy food.

The Prognostic Significance of Diabetes and Microvascular Complications in Patients With Heart Failure With Preserved Ejection Fraction

OBJECTIVE This study examined the prognostic significance of diabetes and microvascular complications in patients with heart failure with preserved ejection fraction (HFpEF). RESEARCH DESIGN AND METHODS This analysis included 3,385 patients (mean age 69 ± 9.6 years; 49% male; 89% white) with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT). Diabetes and microvascular complications were ascertained by self-reported history and medical record review. Microvascular complications included neuropathy, nephropathy, and retinopathy. Outcomes included hospitalization, hospitalization for heart failure, death, and cardiovascular death. Cox regression was used to examine the risk of each outcome associated with diabetes and microvascular complications. RESULTS Of the 1,109 subjects (32%) with diabetes, 352 (32%) had at least one microvascular complication. Patients with diabetes and microvascular complications had an increased risk for hospitalization (no diabetes: referent; diabetes + no microvascular complication: hazard ratio [HR] 1.18, 95% CI 1.01, 1.37; diabetes + microvascular complications: HR 1.54, 95% CI 1.25, 1.89; P-trend <0.001), hospitalization for heart failure (no diabetes: referent; diabetes + no microvascular complication: HR 1.51, 95% CI 1.14, 1.99; diabetes + microvascular complications: HR 1.97, 95% CI 1.38, 2.80; P-trend <0.001), death (no diabetes: referent; diabetes + no microvascular complication: HR 1.35, 95% CI 1.04, 1.75; diabetes + microvascular complications: HR 1.73, 95% CI 1.22, 2.45; P-trend = 0.0017), and cardiovascular death (no diabetes: referent; diabetes + no microvascular complication: HR 1.34, 95% CI 0.96, 1.86; diabetes + microvascular complications: HR 1.70, 95% CI 1.09, 2.65; P-trend = 0.018). When the analysis was limited to participants who reported prior hospitalization for heart failure (n = 2,449), a higher risk of rehospitalization for heart failure was observed across diabetes categories (no diabetes: referent; diabetes + no microvascular complication: HR 1.40, 95% CI 1.01, 1.96; diabetes + microvascular complications: HR 1.78, 95% CI 1.18, 2.70; P-trend = 0.0036). CONCLUSIONS Diabetes is associated with adverse cardiovascular outcomes in HFpEF, and the inherent risk of adverse outcomes in HFpEF patients with diabetes varies by the presence of microvascular complications.

Echocardiographic predictors of atrial fibrillation in patients with heart failure with preserved ejection fraction

Aims To determine if markers of diastolic dysfunction are associated with atrial fibrillation (AF) development among patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined the association of several echocardiographic measures of diastolic dysfunction with incident AF in 573 patients (mean age = 68 ± 9.5 years; 48% men; 79% white) with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT) who were free of baseline AF. Echocardiograms were analysed at a core laboratory. Incident AF cases were identified by follow-up study electrocardiograms and review of relevant medical records through May of 2013. Over a median follow-up of 3 years, 40 patients developed AF (incidence rate = 2.2 per 100 person years). Increasing values of the E/A ratio [per 0.1 increase: hazard ratio (HR) = 1.11, 95% confidence interval (CI) = 1.06–1.17], left atrial volume (per 5 mL increase: HR = 1.13, 95% CI = 1.03–1.23), and left atrial area (per 5 cm2 increase: HR = 1.51, 95% CI = 1.03–2.22) were associated with greater risk of AF. The risk of AF decreased with increasing peak A wave velocities (per 10 cm/s increase: HR = 0.83, 95% CI = 0.72–0.96). The risk of AF was not materially altered when peak A wave velocity was further adjusted for left atrial volume (HR = 0.83, 95% CI = 0.71–0.96) and area (HR = 0.83, 95% CI = 0.71–0.96). However, the associations of left atrial volume (HR = 1.10, 95% CI = 0.99–1.22) and area (HR = 1.48, 95% CI = 0.96–2.28) were no longer significant when accounting for peak A wave velocity. Conclusion Diastolic parameters of left atrial function possibly are more important markers of AF risk than left atrial dilation in HFpEF.

Diastolic Blood Pressure and Adverse Outcomes in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) Trial

Background Although diastolic blood pressure (DBP) is independently associated with an increased risk of adverse cardiovascular outcomes in the general population, it is unclear if a similar relationship exists in patients with heart failure with preserved ejection fraction. Methods and Results This analysis included 1703 (mean age, 72±10 years; 50% men; 78% white) patients with heart failure with preserved ejection fraction enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) Trial from the Americas who were treated for hypertension. Multivariable Cox regression was used to examine the risk of hospitalization for heart failure, death, and cardiovascular death associated with DBP. The relationship between hospitalization for heart failure and DBP was linear, with an increased risk observed with decreasing DBP values (≥90 mm Hg: referent; 80–89 mm Hg: hazard ratio [HR], 1.44; 95% confidence interval [CI], 0.85–2.44; 70–79 mm Hg: HR, 1.18; 95% CI, 0.69–2.01; 60–69 mm Hg: HR, 1.54; 95% CI, 0.90–2.63; <60 mm Hg: HR, 2.12; 95% CI, 1.20–3.74; P=0.0055 for trend). The associations of DBP with death (≥90 mm Hg: HR, 1.86; 95% CI, 1.12–3.06; 80–89 mm Hg: HR, 1.23; 95% CI, 0.89–1.70; 70–79 mm Hg: referent; 60–69 mm Hg: HR, 1.20; 95% CI, 0.90–1.59; <60 mm Hg: HR, 1.68; 95% CI, 1.21–2.33) and cardiovascular death (≥90 mm Hg: HR, 2.02; 95% CI, 1.10–3.71; 80–89 mm Hg: HR, 1.17; 95% CI, 0.77–1.79; 70–79 mm Hg: referent; 60–69 mm Hg: HR, 1.16; 95% CI, 0.80–1.70; <60 mm Hg: HR, 1.85; 95% CI, 1.21–2.82) were nonlinear, with a greater risk of each outcome observed with DBP values ≥90 and <60 mm Hg. Conclusions DBP values ≥90 and <60 mm Hg are associated with a significant risk of adverse outcomes in patients with heart failure with preserved ejection fraction who are treated for hypertension. Further research is needed to determine optimal DBP targets to reduce the risk of adverse events in patients with heart failure with preserved ejection fraction.

The association between acute mental stress and abnormal left atrial electrophysiology

Acute stress may trigger atrial fibrillation (AF), but the underlying mechanisms are unclear. We examined if acute mental stress results in abnormal left atrial electrophysiology as detected by more negative deflection of P‐wave terminal force in lead V1 (PTFV1), a well‐known marker of AF risk.

Comorbidities, Sociodemographic Factors, and Hospitalizations in Outpatients With Heart Failure and Preserved Ejection Fraction

Patients with heart failure and preserved ejection fraction (HFpEF) tend to be older and have a high co-morbidity burden. The impact of co-morbid conditions and sociodemographic risk factors on outcomes in these patients has not been quantified. We evaluated 445 consecutive outpatients with HFpEF, defined as established diagnosis of heart failure (HF) with left ventricular ejection fraction at presentation >40% and no previous left ventricular ejection fraction ≤40%. Patients with specific cardiomyopathies, congenital heart disease, primary right-sided disease, valvular disease, or previous advanced HF therapies were excluded. After 2 years, there were 44 deaths and 609 all-cause hospitalizations; of these, 260 (42.7%) were cardiovascular hospitalizations, including HF, and 173 (28.4%) were specifically for HF. The highest attributable risk for hospitalizations was associated with marital status (single, divorced, and widowed had higher hospitalization rates compared with married patients), hypoalbuminemia, diabetes, atrial fibrillation, and renal dysfunction. The proportion of hospitalizations potentially attributable to these factors was 66.6% (95% confidence interval [CI] 56.4 to 74.4) for all-cause hospitalizations, 76.9% (95% CI 65.2 to 84.6) for cardiovascular hospitalizations, and 83.0% (95% CI 70.3 to 90.3) for HF hospitalizations. For composite end points, the proportion was 46.9% (95% CI 34.0% to 57.3%) for death or all-cause hospitalization, 45.7% (95% CI 29.3% to 58.2%) for death or cardiovascular hospitalization, and 43.7% (95% CI 24.2% to 58.2%) for death or HF-related hospitalization. In conclusion, among outpatients with HFpEF, most hospitalizations could be attributed to co-morbidities and sociodemographic factors. Effects of HF therapies on hospitalizations and related end points may be difficult to demonstrate in these patients. Multidisciplinary approaches are more likely to impact hospitalizations in HFpEF.

Circulating Progenitor Cells and Racial Differences: A Possible Contribution to Health Disparity

Rationale: Blacks compared with whites have a greater risk of adverse cardiovascular outcomes. Impaired regenerative capacity, measured as lower levels of circulating progenitor cells (CPCs), is a novel determinant of adverse outcomes; however, little is known about racial differences in CPCs. Objective: To investigate the number of CPCs, PC-mobilizing factors, PC mobilization during acute myocardial infarction and the predictive value of CPC counts in blacks compared with whites. Methods and Results: CPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34+, CD133+, VEGF2R+, and CXCR4+ epitopes in 1747 subjects, mean age 58.4±13, 55% male, and 26% self-reported black. Patients presenting with acute myocardial infarction (n=91) were analyzed separately. Models were adjusted for relevant clinical variables. SDF-1&agr; (stromal cell-derived factor-1&agr;), VEGF (vascular endothelial growth factor), and MMP-9 (matrix metallopeptidase-9) levels were measured (n=561), and 623 patients were followed for median of 2.2 years for survival analysis. Blacks were younger, more often female, with a higher burden of cardiovascular risk, and lower CPC counts. Blacks had fewer CD34+ cells (−17.6%; [95% confidence interval (CI), −23.5% to −11.3%]; P<0.001), CD34+/CD133+ cells (−15.5%; [95% CI, −22.4% to −8.1%]; P<0.001), CD34+/CXCR4+ cells (−17.3%; [95% CI, −23.9% to −10.2%]; P<0.001), and CD34+/VEGF2R+ cells (−27.9%; [95% CI, −46.9% to −2.0%]; P=0.04) compared with whites. The association between lower CPC counts and black race was not affected by risk factors or cardiovascular disease. Results were validated in a separate cohort of 411 patients. Blacks with acute myocardial infarction had significantly fewer CPCs compared with whites (P=0.02). Blacks had significantly lower plasma MMP-9 levels (P<0.001) which attenuated the association between low CD34+ and black race by 19% (95% CI, 13%–33%). However, VEGF and SDF-1&agr; levels were not significantly different between the races. Lower CD34+ counts were similarly predictive of mortality in blacks (hazard ratio, 2.83; [95% CI, 1.12–7.20]; P=0.03) and whites (hazard ratio, 1.79; [95% CI, 1.09–2.94]; P=0.02) without significant interaction. Conclusions: Black subjects have lower levels of CPCs compared with whites which is partially dependent on lower circulating MMP-9 levels. Impaired regenerative capacity is predictive of adverse outcomes in blacks and may partly account for their increased risk of cardiovascular events.

Effect of Cigarette Smoking on Risk for Adverse Events in Patients With Heart Failure and Preserved Ejection Fraction

Smoking is an important risk factor in the development of heart failure with preserved ejection (HFpEF), and previous reports have identified smoking as a significant predictor of death in this population. However, the relation between smoking and heart failure-specific outcomes has not been examined in patients with HFpEF. This analysis included 1,717 patients (mean age = 71 ± 10 years; 50% men; 78% white) with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial from the Americas. Smoking was ascertained by self-reported history and categorized as never, former, or current. Multivariable Cox regression was used to examine the risk of hospitalization for heart failure, death, and cardiovascular death across smoking categories. There were 116 current smokers (7%), 871 former smokers (51%), and 729 never smokers (42%) in this analysis. Current smoking was associated with an increased risk of hospitalization for heart failure (never: hazard ratio [HR] 1.0; former: HR 1.25, 95% confidence interval [CI] 0.99 to 1.57; current: HR 1.68, 95% CI 1.08 to 2.61), death (never: HR 1.0; former: HR 1.02, 95% CI 0.81 to 1.29; current: HR 1.82, 95% CI 1.19 to 2.78), and cardiovascular death (never: HR 1.0; former: HR 1.00, 95% CI 0.74 to 1.35; current: HR 1.85, 95% CI 1.09 to 3.24) compared with former or never smokers in a multivariable model adjusted for cardiovascular risk factors. A similar increased risk of hospitalization for heart failure (former: HR 1.0; current: HR 1.54, 95% CI 1.01, 2.36), death (former: HR 1.0; current: HR 1.81, 95% CI 1.19, 2.75), and cardiovascular death (former: HR 1.0; current: HR 1.76, 95% CI 1.04, 2.98) was observed for current smokers when we limited the analysis to those with a history of smoking. In conclusion, current smoking is associated with an increased risk for adverse outcomes in HFpEF, including hospitalization for heart failure. Smoking cessation strategies possibly have a role to reduce the risk for adverse cardiovascular outcomes in patients with HFpEF.

Peripheral artery disease and risk of adverse outcomes in heart failure with preserved ejection fraction

Peripheral artery disease (PAD) in heart failure with preserved ejection fraction (HFpEF) is associated with an increased mortality risk, but the risk of individual outcomes associated with PAD in this patient group is less clear.