Bishnu P. Dhakal

Exercise-induced Pulmonary Hypertension: Physiological Basis and Methodological Concerns

Exercise stresses the pulmonary circulation through increases in cardiac output (.Q) and left atrial pressure. Invasive as well as noninvasive studies in healthy volunteers show that the slope of mean pulmonary artery pressure (mPAP)-flow relationships ranges from 0.5 to 3 mm Hg.min.L(-1). The upper limit of normal mPAP at exercise thus approximates 30 mm Hg at a .Q of less than 10 L.min(-1) or a total pulmonary vascular resistance at exercise of less than 3 Wood units. Left atrial pressure increases at exercise with an average upstream transmission to PAP in a close to one-for-one mm Hg fashion. Multipoint PAP-flow relationships are usually described by a linear approximation, but present with a slight curvilinearity, which is explained by resistive vessel distensibility. When mPAP is expressed as a function of oxygen uptake or workload, plateau patterns may be observed in patients with systolic heart failure who cannot further increase .Q at the highest levels of exercise. Exercise has to be dynamic to avoid the increase in systemic vascular resistance and abrupt changes in intrathoracic pressure that occur with resistive exercise and can lead to unpredictable effects on the pulmonary circulation. Postexercise measurements are unreliable because of the rapid return of pulmonary vascular pressures and flows to the baseline resting state. Recent studies suggest that exercise-induced increase in PAP to a mean higher than 30 mm Hg may be associated with dyspnea-fatigue symptomatology.

Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction The Role of Abnormal Peripheral Oxygen Extraction

Background—Exercise capacity as measured by peak oxygen uptake (VO2) is similarly impaired in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). However, characterization of how each component of VO2 changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o2 extraction (arterio-mixed venous o2 content difference, [C(a-v)o2]) during exercise significantly contributes to impaired exercise capacity in HFpEF. Methods and Results—We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring on 104 patients with symptomatic NYHA II to IV heart failure (HFpEF, n=48, peak VO2=13.9±0.5 mL kg−1 min−1, mean±SEM, and HFrEF, n=56, peak VO2=12.1±0.5 mL kg−1 min−1) and 24 control subjects (peak VO2 27.0±1.7 mL kg−1 min−1). Peak exercise C(a-v)o2 was lower in HFpEF compared with HFrEF (11.5±0.27 versus 13.5±0.34 mL/dL, respectively, P<0.0001), despite no differences in age, hemoglobin level, peak respiratory exchange ratio, CaO2, or cardiac filling pressures. Peak C(a-v)o2 and peak heart rate emerged as the leading predictors of peak VO2 in HFpEF. Impaired peripheral o2 extraction was the predominant limiting factor to exercise capacity in 40% of patients with HFpEF and was closely related to elevated systemic blood pressure during exercise (r=0.49, P=0.0005). Conclusions—In the first study to directly measure C(a-v)o2 throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o2 was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o2 extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.

Exercise Oscillatory Ventilation in Heart Failure

Irregular breathing characterized by cyclic variation of ventilation with a period of approximately 1 min has been recognized in patients with heart failure for almost two centuries. Periodic breathing during exercise is a noninvasive parameter that is easily recognizable during submaximal cardiopulmonary exercise testing. Recent studies have established that periodic breathing during exercise not only signals significant impairment in resting and exercise hemodynamic parameters but also potently predicts adverse events in heart failure patients. This article reviews the mechanistic basis of periodic breathing and the clinical utility of discerning patterns of irregular breathing in patients with heart failure.

Pulmonary Vascular Distensibility Predicts Pulmonary Hypertension Severity, Exercise Capacity, and Survival in Heart Failure.

Background—Pulmonary vascular (PV) distensibility, defined as the percent increase in pulmonary vessel diameter per mm Hg increase in pressure, permits the pulmonary vessels to increase in size to accommodate increased blood flow. We hypothesized that PV distensibility is abnormally low in patients with heart failure (HF) and serves as an important determinant of right ventricular performance and exercise capacity. Methods and Results—Patients with HF with preserved ejection fraction (n=48), HF with reduced ejection fraction (n=55), pulmonary arterial hypertension without left heart failure (n=18), and control subjects (n=30) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and first-pass radionuclide ventriculography. PV distensibility was derived from 1257 matched measurements (mean±SD, 8.3±2.8 per subject) of pulmonary arterial pressure, pulmonary arterial wedge pressure and cardiac output. PV distensibility was lowest in the pulmonary arterial hypertension group (0.40±0.24% per mm Hg) and intermediate in the HF with preserved ejection fraction and HF with reduced ejection fraction groups (0.92±0.39 and 0.84±0.33% per mm Hg, respectively) compared to the control group (1.39±0.32% per mm Hg, P<0.0001 for all three). PV distensibility was associated with change in right ventricular ejection fraction (RVEF, &rgr;=0.39, P<0.0001) with exercise and was an independent predictor of peak VO2. PV distensibility also predicted cardiovascular mortality independent of peak VO2 in HF patients (n=103; Cox hazard ratio, 0.30; 95% confidence interval, 0.10–0.93; P=0.036). In a subset of patients with HF with reduced ejection fraction (n=26), 12 weeks of treatment with the pulmonary vasodilator sildenafil or placebo led to a 24.6% increase in PV distensibility (P=0.015) in the sildenafil group only. Conclusions—PV distensibility is reduced in patients with HF and pulmonary arterial hypertension and is closely related to RV systolic function during exercise, maximal exercise capacity, and survival. Furthermore, PV distensibility is modifiable with selective pulmonary vasodilator therapy and may represent an important target for therapy in selected HF patients with pulmonary hypertension. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00309790.

Effect of Phosphodiesterase Inhibition on Insulin Resistance in Obese Individuals

Background Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (cGMP) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase‐5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals. Methods and Results We conducted a randomized, double‐blinded, placebo‐controlled trial of adults age 18 to 50 years with obesity and elevated fasting insulin levels (≥10 μU/mL). Participants were randomized to tadalafil 20 mg daily or placebo for 3 months. Oral glucose tolerance tests were performed, and the effect of tadalafil on IR was examined. A total of 53 participants (mean age, 33 years; body mass index [BMI], 38 kg/m2) were analyzed, 25 randomized to tadalafil and 28 to placebo. In the overall sample, measures of IR did not differ between tadalafil and placebo groups at 3 months. However, in individuals with severe obesity (BMI ≥36.2 kg/m2), tadalafil use was associated with improved IR (homeostatic model assessment for IR), compared to placebo (P=0.02, respectively). Furthermore, one measure of β‐cell compensation for IR (oral disposition index) improved with tadalafil in the overall sample (P=0.009) and in the subgroup with severe obesity (P=0.01). Conclusion Results of this pilot study did not show improvements in IR with tadalafil, compared to placebo. However, tadalafil may have favorable effects on β‐cell compensation, particularly in individuals with severe obesity. Future studies evaluating the potential metabolic benefits of cGMP modulation in obesity are warranted. Clinical Trial Registration URL: ClinicalTrials.gov. Unique Identifier: NCT01444651.

Prolonged Mean VO2 Response Time in Systolic Heart Failure: An Indicator of Impaired Right Ventricular-Pulmonary Vascular Function

Background— In patients with left ventricular systolic dysfunction (LVSD), the rate at which oxygen uptake (VO2) increases on initiation of exercise is inadequate to match metabolic demands. To gain mechanistic insights into delayed VO2 kinetics in LVSD, we simultaneously assessed hemodynamic measurements, ventilatory parameters, and peripheral oxygen usage during exercise. Methods and Results— Forty-two patients with symptomatic LVSD (age, 59±2 years [mean±SEM]; LV ejection fraction, 30±1%) and 17 controls (LV ejection fraction, 68±1%) underwent maximum upright cycle ergometry cardiopulmonary exercise testing. Hemodynamic monitoring and first-pass radionuclide ventriculography were performed at rest and during exercise. VO2 kinetics were quantified by mean response time (MRT), which was significantly longer in patients with LVSD compared with controls (64±3 versus 45±5 s; P =0.004). In LVSD patients, MRT was associated with higher biventricular filling pressures and reduced cardiac output during early exercise. LVSD patients with MRT ≥60 s, compared with LVSD subjects with MRT <60 s, demonstrated greater impairment in right ventricular-pulmonary vascular function during exercise as evidenced by lower right ventricular ejection fraction (35±2 versus 45±2%; P =0.03), steeper increment in transpulmonary gradient relative to cardiac output (3.7 versus 2.2 mm Hg/L; P <0.001), and increased ventilatory dead-space fraction (17±1 versus 12±2%; P =0.03). In contrast, MRT was not associated with LV ejection fraction (rest, exercise), PaO2, hemoglobin, or resting pulmonary function test results. Conclusions— Delayed oxygen uptake on initiation of exercise (ie, MRT ≥60 s) in LVSD is closely related to impaired right ventricular-pulmonary vascular function and may represent an important surrogate for inability to augment RV performance during physical activity in patients with heart failure.Background—In patients with left ventricular systolic dysfunction (LVSD), the rate at which oxygen uptake (VO2) increases on initiation of exercise is inadequate to match metabolic demands. To gain mechanistic insights into delayed VO2 kinetics in LVSD, we simultaneously assessed hemodynamic measurements, ventilatory parameters, and peripheral oxygen usage during exercise. Methods and Results—Forty-two patients with symptomatic LVSD (age, 59±2 years [mean±SEM]; LV ejection fraction, 30±1%) and 17 controls (LV ejection fraction, 68±1%) underwent maximum upright cycle ergometry cardiopulmonary exercise testing. Hemodynamic monitoring and first-pass radionuclide ventriculography were performed at rest and during exercise. VO2 kinetics were quantified by mean response time (MRT), which was significantly longer in patients with LVSD compared with controls (64±3 versus 45±5 s; P=0.004). In LVSD patients, MRT was associated with higher biventricular filling pressures and reduced cardiac output during early exercise. LVSD patients with MRT ≥60 s, compared with LVSD subjects with MRT <60 s, demonstrated greater impairment in right ventricular-pulmonary vascular function during exercise as evidenced by lower right ventricular ejection fraction (35±2 versus 45±2%; P=0.03), steeper increment in transpulmonary gradient relative to cardiac output (3.7 versus 2.2 mm Hg/L; P<0.001), and increased ventilatory dead-space fraction (17±1 versus 12±2%; P=0.03). In contrast, MRT was not associated with LV ejection fraction (rest, exercise), PaO2, hemoglobin, or resting pulmonary function test results. Conclusions—Delayed oxygen uptake on initiation of exercise (ie, MRT ≥60 s) in LVSD is closely related to impaired right ventricular-pulmonary vascular function and may represent an important surrogate for inability to augment RV performance during physical activity in patients with heart failure.

Prolonged Mean Vo2 Response Time in Systolic Heart FailureClinical Perspective

Background— In patients with left ventricular systolic dysfunction (LVSD), the rate at which oxygen uptake (VO2) increases on initiation of exercise is inadequate to match metabolic demands. To gain mechanistic insights into delayed VO2 kinetics in LVSD, we simultaneously assessed hemodynamic measurements, ventilatory parameters, and peripheral oxygen usage during exercise. Methods and Results— Forty-two patients with symptomatic LVSD (age, 59±2 years [mean±SEM]; LV ejection fraction, 30±1%) and 17 controls (LV ejection fraction, 68±1%) underwent maximum upright cycle ergometry cardiopulmonary exercise testing. Hemodynamic monitoring and first-pass radionuclide ventriculography were performed at rest and during exercise. VO2 kinetics were quantified by mean response time (MRT), which was significantly longer in patients with LVSD compared with controls (64±3 versus 45±5 s; P =0.004). In LVSD patients, MRT was associated with higher biventricular filling pressures and reduced cardiac output during early exercise. LVSD patients with MRT ≥60 s, compared with LVSD subjects with MRT <60 s, demonstrated greater impairment in right ventricular-pulmonary vascular function during exercise as evidenced by lower right ventricular ejection fraction (35±2 versus 45±2%; P =0.03), steeper increment in transpulmonary gradient relative to cardiac output (3.7 versus 2.2 mm Hg/L; P <0.001), and increased ventilatory dead-space fraction (17±1 versus 12±2%; P =0.03). In contrast, MRT was not associated with LV ejection fraction (rest, exercise), PaO2, hemoglobin, or resting pulmonary function test results. Conclusions— Delayed oxygen uptake on initiation of exercise (ie, MRT ≥60 s) in LVSD is closely related to impaired right ventricular-pulmonary vascular function and may represent an important surrogate for inability to augment RV performance during physical activity in patients with heart failure.Background—In patients with left ventricular systolic dysfunction (LVSD), the rate at which oxygen uptake (VO2) increases on initiation of exercise is inadequate to match metabolic demands. To gain mechanistic insights into delayed VO2 kinetics in LVSD, we simultaneously assessed hemodynamic measurements, ventilatory parameters, and peripheral oxygen usage during exercise. Methods and Results—Forty-two patients with symptomatic LVSD (age, 59±2 years [mean±SEM]; LV ejection fraction, 30±1%) and 17 controls (LV ejection fraction, 68±1%) underwent maximum upright cycle ergometry cardiopulmonary exercise testing. Hemodynamic monitoring and first-pass radionuclide ventriculography were performed at rest and during exercise. VO2 kinetics were quantified by mean response time (MRT), which was significantly longer in patients with LVSD compared with controls (64±3 versus 45±5 s; P=0.004). In LVSD patients, MRT was associated with higher biventricular filling pressures and reduced cardiac output during early exercise. LVSD patients with MRT ≥60 s, compared with LVSD subjects with MRT <60 s, demonstrated greater impairment in right ventricular-pulmonary vascular function during exercise as evidenced by lower right ventricular ejection fraction (35±2 versus 45±2%; P=0.03), steeper increment in transpulmonary gradient relative to cardiac output (3.7 versus 2.2 mm Hg/L; P<0.001), and increased ventilatory dead-space fraction (17±1 versus 12±2%; P=0.03). In contrast, MRT was not associated with LV ejection fraction (rest, exercise), PaO2, hemoglobin, or resting pulmonary function test results. Conclusions—Delayed oxygen uptake on initiation of exercise (ie, MRT ≥60 s) in LVSD is closely related to impaired right ventricular-pulmonary vascular function and may represent an important surrogate for inability to augment RV performance during physical activity in patients with heart failure.

Exercise oscillatory ventilation: Mechanisms and prognostic significance

Alteration in breathing patterns characterized by cyclic variation of ventilation during rest and during exercise has been recognized in patients with advanced heart failure (HF) for nearly two centuries. Periodic breathing (PB) during exercise is known as exercise oscillatory ventilation (EOV) and is characterized by the periods of hyperpnea and hypopnea without interposed apnea. EOV is a non-invasive parameter detected during submaximal cardiopulmonary exercise testing. Presence of EOV during exercise in HF patients indicates significant impairment in resting and exercise hemodynamic parameters. EOV is also an independent risk factor for poor prognosis in HF patients both with reduced and preserved ejection fraction irrespective of other gas exchange variables. Circulatory delay, increased chemosensitivity, pulmonary congestion and increased ergoreflex signaling have been proposed as the mechanisms underlying the generation of EOV in HF patients. There is no proven treatment of EOV but its reversal has been noted with phosphodiesterase inhibitors, exercise training and acetazolamide in relatively small studies. In this review, we discuss the mechanistic basis of PB during exercise and the clinical implications of recognizing PB patterns in patients with HF.

METABOLIC COST OF UNLOADED VERSUS RAMP EXERCISE: MECHANISMS OF EXERCISE INTOLERANCE IN HEART FAILURE PRESERVED EJECTION FRACTION

Exercise intolerance is a cardinal symptom of heart failure with preserved ejection (HFpEF). Mechanisms contributing to exercise intolerance in HFpEF remain incompletely understood. We performed cycle ergometry cardiopulmonary exercise testing in 31 HFpEF patients and 33 controls. Aerobic

Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection FractionCLINICAL PERSPECTIVE: The Role of Abnormal Peripheral Oxygen Extraction

Background—Exercise capacity as measured by peak oxygen uptake (VO2) is similarly impaired in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). However, characterization of how each component of VO2 changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o2 extraction (arterio-mixed venous o2 content difference, [C(a-v)o2]) during exercise significantly contributes to impaired exercise capacity in HFpEF. Methods and Results—We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring on 104 patients with symptomatic NYHA II to IV heart failure (HFpEF, n=48, peak VO2=13.9±0.5 mL kg−1 min−1, mean±SEM, and HFrEF, n=56, peak VO2=12.1±0.5 mL kg−1 min−1) and 24 control subjects (peak VO2 27.0±1.7 mL kg−1 min−1). Peak exercise C(a-v)o2 was lower in HFpEF compared with HFrEF (11.5±0.27 versus 13.5±0.34 mL/dL, respectively, P<0.0001), despite no differences in age, hemoglobin level, peak respiratory exchange ratio, CaO2, or cardiac filling pressures. Peak C(a-v)o2 and peak heart rate emerged as the leading predictors of peak VO2 in HFpEF. Impaired peripheral o2 extraction was the predominant limiting factor to exercise capacity in 40% of patients with HFpEF and was closely related to elevated systemic blood pressure during exercise (r=0.49, P=0.0005). Conclusions—In the first study to directly measure C(a-v)o2 throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o2 was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o2 extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.