Citations

Background— Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV–pulmonary artery (PA) functional reserve responses and RV–PA coupling at rest and during β-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results— In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV d P /d t max /IP and s′) and diastolic function (higher RV τ) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure–flow relationship when compared with controls (all P <0.001). RV–PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions— Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to β-adrenergic stimulation in HFpEF than controls, suggesting a potential role for β-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01418248.

Background— Invasive hemodynamic exercise testing is commonly used in the evaluation of patients with suspected heart failure with preserved ejection fraction (HFpEF) or pulmonary hypertension. Saline loading has been suggested as an alternative provocative maneuver, but the hemodynamic changes induced by the 2 stresses have not been compared. Methods and Results— Twenty-six subjects (aged, 67±10 years; n=14 HFpEF; n=12 control) underwent right heart catheterization at rest, during supine exercise, and with acute saline loading in a prospective study. Exercise and saline each increased cardiac output and pressures in the right atrium, pulmonary artery, and pulmonary capillary wedge positions. Changes in heart rate, blood pressure, rate–pressure product, and cardiac output were greater with exercise compared with saline. In controls subjects, right atrial pressure, pulmonary arterial pressure, and pulmonary capillary wedge pressure increased similarly with saline and exercise, whereas in HFpEF subjects, exercise led to ≈2-fold greater increases in right atrial pressure (10±4 versus 6±3 mm Hg; P =0.02), pulmonary arterial pressure (22±8 versus 11±4 mm Hg; P =0.0001), and pulmonary capillary wedge pressure (18±5 versus 10±4 mm Hg; P <0.0001) compared with saline. Systolic reserve assessed by stroke work and cardiac power output was lower in HFpEF subjects with both exercise and saline. Systemic and pulmonary arterial compliances were enhanced with saline but reduced with exercise. Conclusions— Exercise elicits greater pulmonary capillary wedge pressure elevation compared with saline in HFpEF but not controls, suggesting that hemodynamic stresses beyond passive stiffness and increased venous return explain the development of pulmonary venous hypertension in HFpEF. Exercise testing is more sensitive than saline loading to detect hemodynamic derangements indicative of HFpEF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01418248.

Background Myocardial strain imaging is a sensitive echocardiographic technique for identifying ventricular dysfunction. The aim of this study was to describe a reference range for right ventricular ( RV ) strain in subjects without cardiopulmonary disease and to report these values from a systematic review and meta‐analysis of the current literature. Methods Prospective online measurement of RV free wall longitudinal systolic strain using speckle tracking echocardiography ( STE ) was performed in 116 subjects with normal echocardiograms and without cardiopulmonary disease or risk factors. A systematic search of studies in EMBASE and Medline reporting RV strain values was performed through February 2014. Results The mean age was 48 ± 16 years and 58% were female. Mean RV strain was −26 ± 4%. Ten studies involving a total of 486 patients met our inclusion criteria. The mean age range was 43–57 years and 59% were female. All prior studies were performed with offline strain analysis, and 9 used a GE Healthcare strain analysis software system. The weighted estimate of RV free wall strain measured using tissue Doppler imaging (4 studies) was −27 ± 1% (95% confidence interval [ CI ] −30% to −25%) and with STE (8 studies, including the current study data) −27 ± 2% (95% CI −29% to −24%), respectively. Conclusions A reference range for RV strain in subjects without cardiopulmonary disease is presented. These data may help facilitate the routine clinical measurement of RV strain in patients referred for right heart echocardiography assessment.

Background Contractile discordance exacerbates cardiac dysfunction, aggravating heart failure outcome. Dissecting the genesis of mechanical dyssynchrony would enable an early diagnosis before advanced disease. Methods and Results High‐resolution speckle‐tracking echocardiography was applied in a knockout murine surrogate of adult‐onset human cardiomyopathy caused by mutations in cardioprotective ATP‐sensitive K + (K ATP ) channels. Preceding the established criteria of cardiac dyssynchrony, multiparametric speckle‐based strain resolved nascent erosion of dysfunctional regions within cardiomyopathic ventricles of the K ATP channel–null mutant exposed to hemodynamic stress. Not observed in wild‐type counterparts, intraventricular disparity in wall motion, validated by the degree, direction, and delay of myocardial speckle patterns, unmasked the disease substrate from asymptomatic to overt heart failure. Mechanical dyssynchrony preceded widening of the QRS complex and exercise intolerance and progressed into global myocardial discoordination and decompensated cardiac pump function, precipitating a low output syndrome. Conclusions The present study, with the use of high‐resolution imaging, prospectively resolved the origin and extent of intraventricular motion disparity in a K ATP channel–knockout model of dilated cardiomyopathy. Mechanical dyssynchrony established as an early marker of cardiomyopathic disease offers novel insight into the pathodynamics of dyssynchronous heart failure.

Background— Cross-sectional studies suggest that left ventricular (LV) and arterial elastance (stiffness) increase with age, but data examining longitudinal changes within human subjects are lacking. In addition, it remains unknown whether age-related LV stiffening is merely a reaction to arterial stiffening or caused by other processes. Methods and Results— Comprehensive echo-Doppler cardiography was performed in 1402 subjects participating in a randomly selected community-based study at 2 examinations separated by 4 years. From this population, 788 subjects had adequate paired data to determine LV end-systolic elastance (Ees), end-diastolic elastance (Eed), and effective arterial elastance. Throughout 4 years, blood pressure, arterial elastance, and LV mass decreased, coupled with significantly greater use of antihypertensive medications. However, despite reductions in arterial load, Ees increased by 14% (2.10±0.67–2.26±0.70 mm Hg/mL; P <0.0001) and Eed increased by 8% (0.13±0.03–0.14±0.04 mm Hg/mL; P <0.0001). Increases in Eed were greater in women than men, whereas Ees changes were similar. Age-related increases in Ees and Eed were correlated with changes in body weight, but were similar in subjects with or without cardiovascular disease. Changes in Ees were correlated with Eed ( r =0.5; P <0.0001), but not with other measures of contractility, indicating that the increase in Ees was reflective of passive stiffening rather than enhanced systolic function. Conclusions— Despite reductions in arterial load with medical therapy, LV systolic and diastolic stiffness increase over time in humans, particularly in women. In addition to blood pressure control, therapies targeting load-independent ventricular stiffening may be effective to treat and prevent age-associated cardiovascular diseases, such as heart failure.

Background— Although right ventricular (RV) dysfunction is a major determinant of outcome in patients with pulmonary hypertension (PH), the optimal measure of RV function is poorly defined. We hypothesized that RV strain measured by speckle-tracking echocardiography predicts outcome in PH over a broad range of pulmonary pressures. Methods and Results— Prospective peak RV longitudinal systolic strain measurement was performed on 575 patients (mean age, 56±18 years; 63% women) referred for echocardiography for known or suspected PH. Survival status was assessed over a median of 16.5 (interquartile range, 7.6–20.0) months. There were 406 patients with PH (71%) (74% group 1, 14% group 3, and 12% group 4) and 169 patients without evidence of PH (29%). Among patients with PH, 46% were World Health Organization functional class III–IV. The mean RV strain was −21.2±6.7% for all patients. RV strain declined with worse functional class, shorter 6-minute walk distances, higher N-terminal pro-B-type natriuretic peptide levels, and the presence of right heart failure. RV strain predicted outcome across pulmonary pressures and groups of PH. Eighteen-month survival was 92%, 88%, 85%, and 71% according to RV strain quartile ( P <0.001), with a 1.46 higher risk of death (95% confidence interval, 1.05–2.12) per 6.7% decline in RV strain. RV strain predicted survival when adjusted for pulmonary pressure, pulmonary vascular resistance, and right atrial pressure and provided incremental prognostic value over conventional clinical and echocardiographic variables. Conclusions— Quantitative assessment of RV free-wall systolic strain is feasible and is a powerful predictor of the clinical outcome of patients with known or suspected PH.

Background— Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and right heart failure. The right (RV) and left ventricles (LV) do not function in isolation, sharing a common pericardial sac and interventricular septum. We sought to define the clinical and prognostic significance of ventricular interdependence in PAH and its association with LV filling patterns through speckle-tracking strain echocardiography. Methods and Results— Echocardiography was performed in 71 adults with a new diagnosis of PAH. To analyze LV and RV function separately, we measured peak systolic longitudinal and circumferential strain of the LV and RV. Survival was assessed >2 years. Patients had dilated right-sided chambers (right atrial volume index, 44±19 mL/m 2 ; RV end-diastolic area, 34±9 cm 2 ), and reduced RV function (RV fractional area change, 28±12%). Speckle-tracking echocardiography revealed significant reductions in RV free wall peak systolic strain (−15±3%). Despite normal LV size and normal conventional measures of LV systolic function (end-diastolic dimension, 42±6 mm; ejection fraction, 65±8%; cardiac index, 2.6±0.8 L/min per m 2 ), patients had reduced LV free wall systolic strain (−15±3%). Decreased LV free wall systolic strain was associated with a delayed relaxation mitral inflow Doppler pattern, P =0.0002. During 2-year follow-up, 19 patients (27%) died. LV strain was associated with increased mortality (unadjusted hazard ratio, 2.40 per 5% decrease in LV free wall strain, 1.22–4.68), which remained significant when adjusted for age, sex, World Health Organization functional class, and PAH pathogenesis (hazard ratio, 3.11, 1.38–7.20). Conclusions— The pressure loading in PAH results in geometric alterations and functional decline of the RV, with marked reduction in RV systolic strain. Despite preservation of LV ejection fraction, LV systolic strain was also reduced and associated with early mortality, highlighting the significance of ventricular interdependence in PAH.

Although several studies have examined the cardiac functional determinants of exercise capacity, few have investigated the effects of structural remodeling. The current study evaluated the association between cardiac geometry and exercise capacity. Subjects with ejection fraction ≥50% and no valvular disease, myocardial ischemia, or arrhythmias were identified from a large prospective exercise echocardiography database. Left ventricular mass index and relative wall thickness were used to classify geometry into normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. All of the subjects underwent symptom-limited treadmill exercise according to standard Bruce protocol. Maximal exercise tolerance was measured in metabolic equivalents. Of 366 (60±14 years; 57% male) subjects, 166 (45%) had normal geometry, 106 (29%) had concentric remodeling, 40 (11%) had eccentric hypertrophy, and 54 (15%) had concentric hypertrophy. Geometry was related to exercise capacity: in descending order, the maximum achieved metabolic equivalents were 9.9±2.8 in normal, 8.9±2.6 in concentric remodeling, 8.6±3.1 in eccentric hypertrophy, and 8.0±2.7 in concentric hypertrophy (all P <0.02 versus normal). Left ventricular mass index and relative wall thickness were negatively correlated with exercise tolerance in metabolic equivalents ( r =−0.14; P =0.009 and r =−0.21; P <0.001, respectively). Augmentation of heart rate and ejection fraction with exercise were blunted in concentric hypertrophy compared with normal, even after adjusting for medications. In conclusion, the pattern of ventricular remodeling is related to exercise capacity among low-risk adults. Subjects with concentric hypertrophy display the greatest limitation, and this is related to reduced systolic and chronotropic reserve. Reverse remodeling strategies may prevent or treat functional decline in patients with structural heart disease.