Andersen, Mads J.

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— Patients with severe tricuspid regurgitation (TR) frequently present with exertional fatigue and dyspnea, but the hemodynamic basis for exercise limitation in people with TR remains unclear. Methods and Results— Twelve subjects with normal left ventricular (LV) ejection fraction and grade ≥3 TR underwent high-fidelity invasive hemodynamic exercise testing with simultaneous expired gas analysis and were compared with 13 age- and sex-matched controls. At rest, TR subjects had lower pulmonary blood flow (3.6±0.4 versus 5.1±1.9 L/min; P =0.01), increased right atrial pressure (12±5 versus 4±1 mm Hg; P =0.0002), and higher pulmonary capillary wedge pressure (17±5 versus 9±3 mm Hg; P =0.0001). However, LV transmural pressure (pulmonary capillary wedge pressure−right atrial pressure), which reflects LV preload independent of right heart congestion and pericardial restraint, was similar in TR and controls (6±3 versus 4±2 mm Hg; P =0.3). With exercise, TR subjects displayed lower peak V O 2 (10.3±2.8 versus 13.8±4.2 mL/min per kg; P =0.02), lower pulmonary blood flow (6.4±1.3 versus 10.3±3.3 L/min; P =0.001), and less increase in pulmonary blood flow relative to V O 2 (+4.6±1.1vs +6.2±0.7; P =0.001). TR subjects displayed higher pulmonary capillary wedge pressure with exercise, but this was solely because of RA hypertension (27±9 versus 8±3 mm Hg; P <0.0001), because LV transmural pressure dropped with exercise in subjects with TR (−5±6 versus +3±3 mm Hg; P =0.0007), suggesting inadequate LV diastolic filling, despite high pulmonary capillary wedge pressure. Conclusions— Impaired exercise capacity in people with severe TR is related to low cardiac output reserve relative to metabolic needs, coupled with elevated systemic and pulmonary venous pressures. Left heart pressures are elevated with exercise in subjects with TR, despite low LV preload, secondary to enhanced ventricular interaction.

Background— Diastolic dysfunction is frequently seen after myocardial infarction and is characterized by a disproportionate increase in filling pressure during exercise to maintain stroke volume. We hypothesized that sildenafil would reduce filling pressure during exercise in patients with diastolic dysfunction after myocardial infarction. Methods and Results— Seventy patients with diastolic dysfunction and near normal left ventricular ejection fraction on echocardiography were randomly assigned sildenafil 40 mg thrice daily or matching placebo for 9 weeks. Before randomization and after 9 weeks of treatment patients underwent simultaneous echocardiography and right heart catheterization at rest and during exercise. Primary end point was pulmonary capillary wedge pressure, and secondary end points comprised cardiac index and pulmonary arterial pressure at rest and during exercise after 9 weeks. After 9 weeks there were no differences in pulmonary capillary wedge pressure at rest (13±4 versus 13±3 mm Hg, P =0.25) or at peak exercise (35±8 mm Hg versus 31±7 mm Hg, P =0.07). However, with treatment cardiac index increased at rest ( P =0.006) and peak exercise ( P =0.02) in the sildenafil group, and systemic vascular resistance index (resting, P =0.0002; peak exercise, P =0.007) and diastolic blood pressure (resting, P =0.005; peak exercise, P =0.02) were lower in the sildenafil group. Resting left ventricular end-diastolic volume index increased ( P =0.001) within the sildenafil group but was unchanged in the placebo group. Conclusions— Sildenafil did not decrease filling pressure at rest or during exercise in post–myocardial infarction patients with diastolic dysfunction. However, there were effects on secondary end points, which require further studies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov/ct2/show/NCT01046838 . Unique identifier: NCT01046838.

Background— Left ventricular diastolic dysfunction (DD) is common after myocardial infarction (MI) despite preservation of left ventricular ejection fraction, yet it remains unclear how or whether DD affects cardiac hemodynamics with stress. Methods and Results— Invasive hemodynamic exercise testing was performed in 46 patients with a recent MI and left ventricular ejection fraction >45% and in 10 healthy volunteers. MI patients were enrolled prospectively and divided into those with DD (MI+DD; left atrial volume index >34 mL/m 2 and diastolic E/e′ ratio>8; n=35) and those without DD (MI–DD; left atrial volume index <34 mL/m 2 and E/e′ ratio<8; n=11). All underwent a supine cycle ergometer test with simultaneous right heart catheterization and echocardiography. At rest, 10 patients in MI+DD (29%) had pulmonary capillary wedge pressure >15 (14±4 mm Hg), whereas none of the MI−DD (10±2 mm Hg) or controls (9±2 mm Hg) displayed pulmonary capillary wedge pressure elevation ( P =0.03). During exercise, an abnormal rise in pulmonary capillary wedge pressure (>25 mm Hg) was observed in 94% of MI+DD (36±6 mm Hg) compared with 36% of MI−DD (24±6 mm Hg) and none of the controls (16±6 mm Hg; P <0.0001). Exercise right atrial pressure was the highest in MI+DD followed by MI−DD and control (15±5 versus 9±4 versus 7±5 mm Hg; P <0.001), whereas no difference in cardiac index was found between groups. Conclusions— In post-MI patients with preserved ejection fraction and left ventricular DD, cardiac output with exercise is maintained at the expense of substantially increased filling pressure. DD and loss of diastolic reserve may promote progression from stage B to stage C heart failure after MI. (Circ Heart Fail. 2012;5:-451.)