David M. Systrom

Sildenafil Improves Exercise Capacity and Quality of Life in Patients With Systolic Heart Failure and Secondary Pulmonary Hypertension

Background— Patients with systolic heart failure (HF) who develop secondary pulmonary hypertension (PH) have reduced exercise capacity and increased mortality compared with HF patients without PH. We tested the hypothesis that sildenafil, an effective therapy for pulmonary arterial hypertension, would lower pulmonary vascular resistance and improve exercise capacity in patients with HF complicated by PH. Methods and Results— Thirty-four patients with symptomatic HF and PH were randomized to 12 weeks of treatment with sildenafil (25 to 75 mg orally 3 times daily) or placebo. Patients underwent cardiopulmonary exercise testing before and after treatment. The change in peak &OV0312;o2 from baseline, the primary end point, was greater in the sildenafil group (1.8±0.7 mL · kg−1 · min−1) than in the placebo group (−0.27 mL · kg−1 · min−1; P=0.02). Sildenafil reduced pulmonary vascular resistance and increased cardiac output with exercise (P<0.05 versus placebo for both) without altering pulmonary capillary wedge or mean arterial pressure, heart rate, or systemic vascular resistance. The ability of sildenafil treatment to augment peak &OV0312;o2 correlated directly with baseline resting pulmonary vascular resistance (r=0.74, P=0.002) and indirectly with baseline resting right ventricular ejection fraction (r=−0.64, P=0.01). Sildenafil treatment also was associated with improvement in 6-minute walk distance (29 m versus placebo; P=0.047) and Minnesota Living With Heart Failure score (−14 versus placebo; P=0.01). Subjects in the sildenafil group experienced fewer hospitalizations for HF and a higher incidence of headache than those in the placebo group without incurring excess serious adverse events. Conclusions— Phosphodiesterase 5 inhibition with sildenafil improves exercise capacity and quality of life in patients with systolic HF with secondary PH.

Sildenafil Improves Exercise Hemodynamics and Oxygen Uptake in Patients With Systolic Heart Failure

Background— Heart failure (HF) is frequently associated with dysregulation of nitric oxide–mediated pulmonary vascular tone. Sildenafil, a type 5 phosphodiesterase inhibitor, lowers pulmonary vascular resistance in pulmonary hypertension by augmenting intracellular levels of the nitric oxide second messenger, cyclic GMP. We tested the hypothesis that a single oral dose of sildenafil (50 mg) would improve exercise capacity and exercise hemodynamics in patients with chronic systolic HF through pulmonary vasodilation. Methods and Results— Thirteen patients with New York Heart Association class III HF underwent assessment of right heart hemodynamics, gas exchange, and first-pass radionuclide ventriculography at rest and with cycle ergometry before and 60 minutes after administration of 50 mg of oral sildenafil. Sildenafil reduced resting pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance, and increased resting and exercise cardiac index (P<0.05 for all) without altering mean arterial pressure, heart rate, or pulmonary capillary wedge pressure. Sildenafil reduced exercise pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular resistance/systemic vascular resistance ratio, which indicates a selective pulmonary vasodilator effect with exercise. Peak &OV0312;o2 increased (15±9%) and ventilatory response to CO2 output (&OV0312;e/&OV0312;co2 slope) decreased (16±5%) after sildenafil treatment. Improvements in right heart hemodynamics and exercise capacity were confined to patients with secondary pulmonary hypertension (rest pulmonary arterial pressure >25 mm Hg). Conclusions— The present study shows that in patients with systolic HF, type 5 phosphodiesterase inhibition with sildenafil improves peak &OV0312;o2, reduces &OV0312;e/&OV0312;co2 slope, and acts as a selective pulmonary vasodilator during rest and exercise in patients with HF and pulmonary hypertension.

Exercise-Induced Pulmonary Arterial Hypertension

Background— The clinical relevance of exercise-induced pulmonary arterial hypertension (PAH) is uncertain, and its existence has never been well studied by direct measurements of central hemodynamics. Using invasive cardiopulmonary exercise testing, we hypothesized that exercise-induced PAH represents a symptomatic stage of PAH, physiologically intermediate between resting pulmonary arterial hypertension and normal. Methods and Results— A total of 406 consecutive clinically indicated cardiopulmonary exercise tests with radial and pulmonary arterial catheters and radionuclide ventriculographic scanning were analyzed. The invasive hemodynamic phenotype of exercise-induced PAH (n=78) was compared with resting PAH (n=15) and normals (n=16). Log-log plots of mean pulmonary artery pressure versus oxygen uptake (&OV0312;o2) were obtained, and a “join-point” for a least residual sum of squares for 2 straight-line segments (slopes m1, m2) was determined; m2m1=“takeoff” pattern. At maximum exercise, &OV0312;o2 (55.8±20.3% versus 66.5±16.3% versus 91.7±13.7% predicted) was lowest in resting PAH, intermediate in exercise-induced PAH, and highest in normals, whereas mean pulmonary artery pressure (48.4±11.1 versus 36.6±5.7 versus 27.4+3.7 mm Hg) and pulmonary vascular resistance (294±158 versus 161±60 versus 62±20 dyne · s · cm−5, respectively; P<0.05) followed an opposite pattern. An exercise-induced PAH plateau (n=32) was associated with lower &OV0312;o2max (60.6±15.1% versus 72.0±16.1% predicted) and maximum cardiac output (78.2±17.1% versus 87.8±18.3% predicted) and a higher resting pulmonary vascular resistance (247±101 versus 199±56 dyne · s · cm−5; P<0.05) than takeoff (n=40). The plateau pattern was most common in resting PAH, and the takeoff pattern was present in nearly all normals. Conclusions— Exercise-induced PAH is an early, mild, and clinically relevant phase of the PAH spectrum.

Metabolic Signatures of Exercise in Human Plasma

Measurement by mass spectrometry of 200 blood metabolites reveals that individuals who are more fit respond more effectively to exercise, as shown by larger exercise-induced increase in glycerol. What Happens When You Run the Boston Marathon? We used to call it toil; now, we call it exercise. The human body has evolved to perform physical labor, and modern sedentary lifestyles are at odds with this evolutionary mandate. This disconnect makes it all the more imperative that we understand the physiology of how the body converts fuel to work. Lewis and colleagues have moved us toward that goal by comprehensively surveying blood metabolites in people of varying fitness levels before and during exercise. Through the use of a high-sensitivity mass spectrometry method, they have characterized these exercise-induced metabolic changes in unprecedented detail. The authors measured 200 blood metabolites in groups of people before, during, and after exercise on a treadmill. They found that the elevated glycolysis, lipolysis, and amino acid catabolism that occur in skeletal muscle cells during use are reflected in a rise in marker metabolites of these processes in blood. Also appearing in the blood after exercise were niacinamide, which enhances insulin release and improves glycemic control, and allantoin, an indicator of oxidative stress. Even when other variables were controlled for, the people who were more fit—as measured by their maximum oxygen use—exhibited more lipolysis during exercise (98% increase) than did the less fit (48% increase) participants or those who developed heart ischemia upon exertion (18% increase). Even more striking was the increase in lipolysis (1128%) in runners after they finished the Boston Marathon, a 26.2-mile run through the winding roads of Boston and its environs. From these data, the authors could not tell whether the more well-conditioned individuals were fitter because their metabolism used fat more effectively or whether, once attaining fitness, these able-bodied metabolic systems were better at burning fat. A mechanistic clue is provided by a final experiment in which the authors show that a combination of six of the metabolites elevated by exercise reflects an increase in glucose utilization and lipid metabolism in skeletal muscle cells, whereas none of the individual elevated molecules signal this effect. Thus, a cost of our sedentary lives may be to deoptimize the operation of the complicated system that is human metabolism. Sorting out how this backsliding occurs and how to restore the vigor of our metabolism will be facilitated by the findings and tools reported here. Exercise provides numerous salutary effects, but our understanding of how these occur is limited. To gain a clearer picture of exercise-induced metabolic responses, we have developed comprehensive plasma metabolite signatures by using mass spectrometry to measure >200 metabolites before and after exercise. We identified plasma indicators of glycogenolysis (glucose-6-phosphate), tricarboxylic acid cycle span 2 expansion (succinate, malate, and fumarate), and lipolysis (glycerol), as well as modulators of insulin sensitivity (niacinamide) and fatty acid oxidation (pantothenic acid). Metabolites that were highly correlated with fitness parameters were found in subjects undergoing acute exercise testing and marathon running and in 302 subjects from a longitudinal cohort study. Exercise-induced increases in glycerol were strongly related to fitness levels in normal individuals and were attenuated in subjects with myocardial ischemia. A combination of metabolites that increased in plasma in response to exercise (glycerol, niacinamide, glucose-6-phosphate, pantothenate, and succinate) up-regulated the expression of nur77, a transcriptional regulator of glucose utilization and lipid metabolism genes in skeletal muscle in vitro. Plasma metabolic profiles obtained during exercise provide signatures of exercise performance and cardiovascular disease susceptibility, in addition to highlighting molecular pathways that may modulate the salutary effects of exercise.

Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training

Non‐technical summary  MicroRNA (miRNA) molecules are essential intracellular mediators of numerous biological processes including angiogenesis, inflammation, and mitochondrial metabolism. Recently, it has been shown that miRNAs are secreted into the bloodstream and that circulating miRNAs (c‐miRNAs) may serve important endocrine functions. This study examined plasma profiles of specific c‐miRNAs in healthy competitive athletes at rest and during exhaustive exercise testing, before and after a 90 day period of exercise training. In this setting, we observed four distinct patterns of c‐miRNA response to exercise: (1) c‐miRNAs up‐regulated by acute exhaustive exercise before and after sustained exercise training, (2) c‐miRNAs responsive to acute exhaustive exercise before but not after sustained exercise training, (3) c‐miRNAs responsive only to sustained exercise training, and (4) non‐responsive c‐miRNAs. These findings set the stage for further work aimed at defining the role of c‐miRNAs as fitness biomarkers and physiological mediators of exercise‐induced cardiovascular adaptation.

Pulmonary Vascular Response Patterns During Exercise in Left Ventricular Systolic Dysfunction Predict Exercise Capacity and Outcomes

Background— Elevated resting pulmonary arterial pressure (PAP) in patients with left ventricular systolic dysfunction (LVSD) purports a poor prognosis. However, PAP response patterns to exercise in LVSD and their relationship to functional capacity and outcomes have not been characterized. Methods and Results— Sixty consecutive patients with LVSD (age 60±12 years, left ventricular ejection fraction 0.31±0.07, mean±SD) and 19 controls underwent maximum incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring. During low-level exercise (30 W), LVSD subjects, compared with controls, had greater augmentation in mean PAPs (15±1 versus 5±1 mm Hg), transpulmonary gradients (5±1 versus 1±1 mm Hg), and effective pulmonary artery elastance (0.05±0.02 versus −0.03±0.01 mm Hg/mL, P<0.0001 for all). A linear increment in PAP relative to work (0.28±0.12 mm Hg/W) was observed in 65% of LVSD patients, which exceeded that observed in controls (0.07±0.02 mm Hg/W, P<0.0001). Exercise capacity and survival was worse in patients with a PAP/watt slope above the median than in patients with a lower slope. In the remaining 35% of LVSD patients, exercise induced a steep initial increment in PAP (0.41±0.16 mm Hg/W) followed by a plateau. The plateau pattern, compared with a linear pattern, was associated with reduced peak VO2 (10.6±2.6 versus 13.1±4.0 mL · kg−1 · min−1, P=0.005), lower right ventricular stroke work index augmentation with exercise (5.7±3.8 versus 9.7±5.0 g/m2, P=0.002), and increased mortality (hazard ratio 8.1, 95% CI 2.7 to 23.8, P<0.001). Conclusions— A steep increment in PAP during exercise and failure to augment PAP throughout exercise are associated with decreased exercise capacity and survival in patients with LVSD, and may therefore represent therapeutic targets. Clinical Trial Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00309790.

Determinants of Ventilatory Efficiency in Heart Failure The Role of Right Ventricular Performance and Pulmonary Vascular Tone

Background— Ventilatory efficiency, right ventricular (RV) function, and secondary pulmonary hypertension are each prognostic indicators in patients with heart failure due to left ventricular systolic dysfunction, but the relationships among these variables have not been comprehensively investigated. In this study, we hypothesized that inefficient ventilation during exercise, as defined by an abnormally steep relationship between ventilation and carbon dioxide output (Ve/Vco2 slope), may be a marker of secondary pulmonary hypertension and RV dysfunction in heart failure. Methods and Results— A cohort of patients with systolic heart failure (mean±SD age, 58±13 years; left ventricular ejection fraction, 0.27±0.05; peak oxygen uptake, 11.2±3.2 mL kg−1 min−1) underwent incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring and first-pass radionuclide ventriculography before and after 12 weeks of treatment with sildenafil, a selective pulmonary vasodilator, or placebo. Ve/Vco2 slope was positively related to rest and exercise pulmonary vascular resistance ( R =0.39 and R =0.60, respectively) and rest pulmonary capillary wedge pressure ( R =0.49, P <0.005 for all) and weakly indirectly related to peak exercise RV ejection fraction ( R =−0.29, P =0.03). Over the 12-week study period, Ve/Vco2 slope fell 8±3% ( P =0.02) with sildenafil and was unchanged with placebo. Changes in Ve/Vco2 slope correlated with changes in exercise pulmonary vascular resistance ( R =0.69, P <0.001) and rest and exercise RV ejection fraction ( R =−0.58 and −0.40, respectively, both P <0.05). Conclusions— In patients with systolic heart failure and secondary pulmonary hypertension, ventilatory efficiency is closely related to RV function and pulmonary vascular tone during exercise. Received April 13, 2008; accepted September 25, 2008.Background—Ventilatory efficiency, right ventricular (RV) function, and secondary pulmonary hypertension are each prognostic indicators in patients with heart failure due to left ventricular systolic dysfunction, but the relationships among these variables have not been comprehensively investigated. In this study, we hypothesized that inefficient ventilation during exercise, as defined by an abnormally steep relationship between ventilation and carbon dioxide output (Ve/Vco2 slope), may be a marker of secondary pulmonary hypertension and RV dysfunction in heart failure. Methods and Results—A cohort of patients with systolic heart failure (mean±SD age, 58±13 years; left ventricular ejection fraction, 0.27±0.05; peak oxygen uptake, 11.2±3.2 mL kg−1 min−1) underwent incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring and first-pass radionuclide ventriculography before and after 12 weeks of treatment with sildenafil, a selective pulmonary vasodilator, or placebo. Ve/Vco2 slope was positively related to rest and exercise pulmonary vascular resistance (R=0.39 and R=0.60, respectively) and rest pulmonary capillary wedge pressure (R=0.49, P<0.005 for all) and weakly indirectly related to peak exercise RV ejection fraction (R=−0.29, P=0.03). Over the 12-week study period, Ve/Vco2 slope fell 8±3% (P=0.02) with sildenafil and was unchanged with placebo. Changes in Ve/Vco2 slope correlated with changes in exercise pulmonary vascular resistance (R=0.69, P<0.001) and rest and exercise RV ejection fraction (R=−0.58 and −0.40, respectively, both P<0.05). Conclusions—In patients with systolic heart failure and secondary pulmonary hypertension, ventilatory efficiency is closely related to RV function and pulmonary vascular tone during exercise.

Sertraline Effects on Dyspnea in Patients With Obstructive Airways Disease

Dyspnea can have a debilitating effect on psychosocial and physical functioning in patients with chronic obstructive airways disease. Previous research has suggested that treatment of concomitant mood or anxiety symptoms can improve dyspnea and exercise intolerance among patients with respiratory disease. The authors report here on a case series of 7 patients with obstructive airways disease who reported improvements in dyspnea after sertraline 25-100 mg/day was added to their medication regimens. Four of the seven patients did not appear to meet syndromal criteria for a mood or anxiety disorder. Subjective improvements in dyspnea may have been related to relief of mood or anxiety symptoms or to direct effects on central respiratory systems. Controlled studies are needed to clarify the potential antidyspneic effects of sertraline.

Exercise Oscillatory Ventilation in Systolic Heart Failure An Indicator of Impaired Hemodynamic Response to Exercise

Background— Exercise oscillatory ventilation (EOV) is a noninvasive parameter that potently predicts outcomes in systolic heart failure (HF). However, mechanistic insights into EOV have been limited by the absence of studies relating EOV to invasive hemodynamic measurements and blood gases performed during exercise. Methods and Results— Fifty-six patients with systolic HF (mean±SEM age, 59±2 years; left ventricular ejection fraction, 30±1%) and 19 age-matched control subjects were studied with incremental cardiopulmonary exercise testing. Fick cardiac outputs, filling pressures, and arterial blood gases were measured at 1-minute intervals during exercise. We detected EOV in 45% of HF (HF+EOV) patients and in none of the control subjects. The HF+EOV group did not differ from the HF patients without EOV (HF−EOV) in age, sex, body mass index, left ventricular ejection fraction, or origin of HF. Univariate predictors of the presence of EOV in HF, among measurements performed during exercise, included higher right atrial pressure and pulmonary capillary wedge pressure and lower cardiac index (CI) but not Paco2 or Pao2. Multivariate logistic regression identified that low exercise CI is the strongest predictor of EOV (odds ratio, 1.39 for each 1.0-L · min−1 · m−2 decrement in CI; 95% confidence interval, 1.14–1.70; P =0.001). Among HF patients with EOV, exercise CI was inversely related to EOV cycle length ( R =−0.71) and amplitude ( R =−0.60; both P <0.001). In 11 HF+EOV subjects treated with 12 weeks of sildenafil, EOV cycle length and amplitude decreased proportionately to increases in CI. Conclusion— Exercise oscillatory ventilation is closely related to reduced CI and elevated filling pressures during exercise and may be an important surrogate for exercise-induced hemodynamic impairment in HF patients. Clinical Trial Registration— URL: . Unique identifier: [NCT00309790][1]. # Clinical Perspective {#article-title-46} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00309790&atom=%2Fcirculationaha%2F124%2F13%2F1442.atomBackground— Exercise oscillatory ventilation (EOV) is a noninvasive parameter that potently predicts outcomes in systolic heart failure (HF). However, mechanistic insights into EOV have been limited by the absence of studies relating EOV to invasive hemodynamic measurements and blood gases performed during exercise. Methods and Results— Fifty-six patients with systolic HF (mean±SEM age, 59±2 years; left ventricular ejection fraction, 30±1%) and 19 age-matched control subjects were studied with incremental cardiopulmonary exercise testing. Fick cardiac outputs, filling pressures, and arterial blood gases were measured at 1-minute intervals during exercise. We detected EOV in 45% of HF (HF+EOV) patients and in none of the control subjects. The HF+EOV group did not differ from the HF patients without EOV (HF−EOV) in age, sex, body mass index, left ventricular ejection fraction, or origin of HF. Univariate predictors of the presence of EOV in HF, among measurements performed during exercise, included higher right atrial pressure and pulmonary capillary wedge pressure and lower cardiac index (CI) but not PaCO2 or PaO2. Multivariate logistic regression identified that low exercise CI is the strongest predictor of EOV (odds ratio, 1.39 for each 1.0-L · min−1 · m−2 decrement in CI; 95% confidence interval, 1.14–1.70; P=0.001). Among HF patients with EOV, exercise CI was inversely related to EOV cycle length (R=−0.71) and amplitude (R=−0.60; both P<0.001). In 11 HF+EOV subjects treated with 12 weeks of sildenafil, EOV cycle length and amplitude decreased proportionately to increases in CI. Conclusion— Exercise oscillatory ventilation is closely related to reduced CI and elevated filling pressures during exercise and may be an important surrogate for exercise-induced hemodynamic impairment in HF patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00309790.

Determinants of Ventilatory Efficiency in Heart FailureCLINICAL PERSPECTIVE

Background— Ventilatory efficiency, right ventricular (RV) function, and secondary pulmonary hypertension are each prognostic indicators in patients with heart failure due to left ventricular systolic dysfunction, but the relationships among these variables have not been comprehensively investigated. In this study, we hypothesized that inefficient ventilation during exercise, as defined by an abnormally steep relationship between ventilation and carbon dioxide output (Ve/Vco2 slope), may be a marker of secondary pulmonary hypertension and RV dysfunction in heart failure. Methods and Results— A cohort of patients with systolic heart failure (mean±SD age, 58±13 years; left ventricular ejection fraction, 0.27±0.05; peak oxygen uptake, 11.2±3.2 mL kg−1 min−1) underwent incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring and first-pass radionuclide ventriculography before and after 12 weeks of treatment with sildenafil, a selective pulmonary vasodilator, or placebo. Ve/Vco2 slope was positively related to rest and exercise pulmonary vascular resistance ( R =0.39 and R =0.60, respectively) and rest pulmonary capillary wedge pressure ( R =0.49, P <0.005 for all) and weakly indirectly related to peak exercise RV ejection fraction ( R =−0.29, P =0.03). Over the 12-week study period, Ve/Vco2 slope fell 8±3% ( P =0.02) with sildenafil and was unchanged with placebo. Changes in Ve/Vco2 slope correlated with changes in exercise pulmonary vascular resistance ( R =0.69, P <0.001) and rest and exercise RV ejection fraction ( R =−0.58 and −0.40, respectively, both P <0.05). Conclusions— In patients with systolic heart failure and secondary pulmonary hypertension, ventilatory efficiency is closely related to RV function and pulmonary vascular tone during exercise. Received April 13, 2008; accepted September 25, 2008.Background—Ventilatory efficiency, right ventricular (RV) function, and secondary pulmonary hypertension are each prognostic indicators in patients with heart failure due to left ventricular systolic dysfunction, but the relationships among these variables have not been comprehensively investigated. In this study, we hypothesized that inefficient ventilation during exercise, as defined by an abnormally steep relationship between ventilation and carbon dioxide output (Ve/Vco2 slope), may be a marker of secondary pulmonary hypertension and RV dysfunction in heart failure. Methods and Results—A cohort of patients with systolic heart failure (mean±SD age, 58±13 years; left ventricular ejection fraction, 0.27±0.05; peak oxygen uptake, 11.2±3.2 mL kg−1 min−1) underwent incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring and first-pass radionuclide ventriculography before and after 12 weeks of treatment with sildenafil, a selective pulmonary vasodilator, or placebo. Ve/Vco2 slope was positively related to rest and exercise pulmonary vascular resistance (R=0.39 and R=0.60, respectively) and rest pulmonary capillary wedge pressure (R=0.49, P<0.005 for all) and weakly indirectly related to peak exercise RV ejection fraction (R=−0.29, P=0.03). Over the 12-week study period, Ve/Vco2 slope fell 8±3% (P=0.02) with sildenafil and was unchanged with placebo. Changes in Ve/Vco2 slope correlated with changes in exercise pulmonary vascular resistance (R=0.69, P<0.001) and rest and exercise RV ejection fraction (R=−0.58 and −0.40, respectively, both P<0.05). Conclusions—In patients with systolic heart failure and secondary pulmonary hypertension, ventilatory efficiency is closely related to RV function and pulmonary vascular tone during exercise.