Borlaug, Barry A.

Background— Mechanisms purported to contribute to the pathophysiology of heart failure with normal ejection fraction (HFnlEF) include diastolic dysfunction, vascular and left ventricular systolic stiffening, and volume expansion. We characterized left ventricular volume, effective arterial elastance, left ventricular end-systolic elastance, and left ventricular diastolic elastance and relaxation noninvasively in consecutive HFnlEF patients and appropriate controls in the community. Methods and Results— Olmsted County (Minn) residents without cardiovascular disease (n=617), with hypertension but no heart failure (n=719), or with HFnlEF (n=244) were prospectively enrolled. End-diastolic volume index was determined by echo Doppler. End-systolic elastance was determined using blood pressure, stroke volume, ejection fraction, timing intervals, and estimated normalized ventricular elastance at end diastole. Tissue Doppler e′ velocity was used to estimate the time constant of relaxation. End-diastolic volume (EDV) and Doppler-derived end-diastolic pressure (EDP) were used to derive the diastolic curve fitting (α) and stiffness (β) constants (EDP=αEDV β ). Comparisons were adjusted for age, sex, and body size. HFnlEF patients had more severe renal dysfunction, yet smaller end-diastolic volume index and cardiac output and increased EDP compared with both hypertensive and healthy controls. Arterial elastance and ventricular end-systolic elastance were similarly increased in hypertensive controls and HFnlEF patients compared with healthy controls. In contrast, HFnlEF patients had more impaired relaxation and increased diastolic stiffness compared with either control group. Conclusions— From these cross-sectional observations, we speculate that the progression of diastolic dysfunction plays a key role in the development of heart failure symptoms in persons with hypertensive heart disease.

Background— Nearly half of patients with heart failure have a preserved ejection fraction (HFpEF). Symptoms of exercise intolerance and dyspnea are most often attributed to diastolic dysfunction; however, impaired systolic and/or arterial vasodilator reserve under stress could also play an important role. Methods and Results— Patients with HFpEF (n=17) and control subjects without heart failure (n=19) generally matched for age, gender, hypertension, diabetes mellitus, obesity, and the presence of left ventricular hypertrophy underwent maximal-effort upright cycle ergometry with radionuclide ventriculography to determine rest and exercise cardiovascular function. Resting cardiovascular function was similar between the 2 groups. Both had limited exercise capacity, but this was more profoundly reduced in HFpEF patients (exercise duration 180±71 versus 455±184 seconds; peak oxygen consumption 9.0±3.4 versus 14.4±3.4 mL · kg −1 · min −1 ; both P <0.001). At matched low-level workload, HFpEF subjects displayed ≈40% less of an increase in heart rate and cardiac output and less systemic vasodilation (all P <0.05) despite a similar rise in end-diastolic volume, stroke volume, and contractility. Heart rate recovery after exercise was also significantly delayed in HFpEF patients. Exercise capacity correlated with the change in cardiac output, heart rate, and vascular resistance but not end-diastolic volume or stroke volume. Lung blood volume and plasma norepinephrine levels rose similarly with exercise in both groups. Conclusions— HFpEF patients have reduced chronotropic, vasodilator, and cardiac output reserve during exercise compared with matched subjects with hypertensive cardiac hypertrophy. These limitations cannot be ascribed to diastolic abnormalities per se and may provide novel therapeutic targets for interventions to improve exercise capacity in this disorder.

Background— Increases in vascular (Ea), ventricular systolic (Ees), and ventricular diastolic (Ed) elastance (stiffness) may contribute to the pathogenesis of heart failure (HF) with preserved ejection fraction (HFnlEF). The prevalence of HFnlEF increases strikingly with age, particularly in women. We hypothesized that ventricular-vascular stiffening may occur with age and be more pronounced in women in the general community. Methods and Results— In a cross-sectional sample of Olmsted County, Minn, residents ≥45 years old (n=2042), clinical data, Doppler echocardiography, and blood pressure (BP) measurements were obtained. Ea was calculated from stroke volume and systolic BP and indexed to body size (EaI). Ees was calculated by a modified single-beat method using systolic and diastolic BP, stroke volume, ejection fraction, timing intervals, and an estimated normalized ventricular elastance at arterial end diastole. Operant Ed was calculated from Doppler indices reflective of atrial pressures and the diastolic filling volume. EaI, Ees, and Ed all increased with age in men and in women ( P <0.0001 for all). Ees increased more steeply with age in women ( P =0.002). Adjusted for age, EaI, Ees, and Ed were higher in women than in men ( P <0.0001 for all). Findings were similar in those without known or suspected cardiovascular disease (n=623). Conclusions— In the community, advancing age and female gender are associated with increases in vascular and ventricular systolic and diastolic stiffness even in the absence of cardiovascular disease. We speculate that this combined ventricular-vascular stiffening may contribute to the increased prevalence of HFnlEF in elderly persons and particularly in elderly women.