Aaron S. Eisman

Association of Fitness in Young Adulthood With Survival and Cardiovascular Risk: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

IMPORTANCE Although cardiorespiratory fitness (CRF) is prognostic in older adults, the effect of CRF during early adulthood on long-term cardiovascular structure, function, and prognosis is less clear. OBJECTIVE To examine whether CRF in young adults is associated with long-term clinical outcome and subclinical cardiovascular disease (CVD). DESIGN, SETTING, AND PARTICIPANTS Prospective study of 4872 US adults aged 18 to 30 years who underwent treadmill exercise testing at a baseline study visit from March 25, 1985, to June 7, 1986, and 2472 individuals who underwent a second treadmill test 7 years later. Median follow-up was 26.9 years, with assessment of obesity, left ventricular mass and strain, coronary artery calcification (CAC), and vital status and incident CVD. Follow-up was complete on August 31, 2011, and data were analyzed from recruitment through the end of follow-up. MAIN OUTCOMES AND MEASURES The presence of CAC was assessed by computed tomography at years 15 (2000-2001), 20 (2005-2006), and 25 (2010-2011), and left ventricular mass was assessed at years 5 (1990-1991) and 25 (with global longitudinal strain). Incident CVD and all-cause mortality were adjudicated. RESULTS Of the 4872 individuals, 273 (5.6%) died and 193 (4.0%) experienced CVD events during follow-up. After comprehensive adjustment, each additional minute of baseline exercise test duration was associated with a 15% lower hazard of death (hazard ratio [HR], 0.85; 95% CI, 0.80-0.91; P < .001) and a 12% lower hazard of CVD (HR, 0.88; 95% CI, 0.81-0.96; P = .002). Higher levels of baseline CRF were associated with significantly lower left ventricular mass index (β = -0.24; 95% CI, -0.45 to -0.03; P = .02) and significantly better lobal longitudinal strain (β = -0.09; 95% CI, -0.14 to -0.05; P < .001) at year 25. Fitness was not associated with CAC. A 1-minute reduction in fitness by year 7 was associated with 21% and 20% increased hazards of death (HR, 1.21; 95% CI, 1.07-1.37; P = .002) and CVD (HR, 1.20; 95% CI, 1.06-1.37; P = .006), respectively, along with a more impaired strain (β = 0.15; 95% CI, 0.08-0.23; P < .001). No association between change in fitness and CAC was found. CONCLUSIONS AND RELEVANCE Higher levels of fitness at baseline and improvement in fitness early in adulthood are favorably associated with lower risks for CVD and mortality. Fitness and changes in fitness are associated with myocardial hypertrophy and dysfunction but not CAC. Regular efforts to ascertain and improve CRF in young adulthood may play a critical role in promoting cardiovascular health and interrupting early CVD pathogenesis.

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.

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.

Pulmonary vascular response patterns during exercise in interstitial lung disease

When overt pulmonary hypertension arises in interstitial lung disease (ILD), it contributes to exercise intolerance. We sought to determine the functional significance of abnormal pulmonary arterial pressure (PAP) responses to exercise in ILD. 27 ILD patients and 11 age-matched controls underwent invasive cardiopulmonary exercise testing (iCPET). Mean PAP (mPAP) was indexed to cardiac output (Q´T) during exercise, with a mPAP–Q´T slope ≥3 mmHg·min·L−1 defined as an abnormal pulmonary vascular response. All control subjects had mPAP–Q´T slopes <3 mmHg·min·L−1 (mean±sem 1.5±0.1 mmHg·min·L−1). 15 ILD patients had mPAP–Q´T slopes ≥3 mmHg·min·L−1 (4.1±0.2 mmHg·min·L−1) and were labelled as having ILD plus pulmonary vascular dysfunction (PVD). Subjects without pulmonary hypertension and with mPAP–Q´T slopes <3 mmHg·min·L−1 (1.9±0. 2 mmHg·min·L−1) were labelled as ILD minus PVD (n=12). ILD+PVD and ILD−PVD patients did not differ in terms of age, sex, body mass index, pulmonary function testing or degree of exercise oxygen desaturation. Peak oxygen consumption was lower in ILD+PVD than in ILD−PVD (13.0±0.9 versus 17±1.1 mL·kg−1·min−1, p=0.012) and controls (19.8±1.7 mL·kg−1·min−1, p=0.003). ILD+PVD patients had increased dead space volume (VD)/tidal volume (VT) and minute ventilation/carbon dioxide production at the anaerobic threshold. In ILD, mPAP–Q´T slope ≥3 mmHg·min·L−1 is associated with lower peak oxygen consumption, increased VD/VT and inefficient ventilation. While noninvasive parameters were unable to predict those with abnormal pulmonary vascular responses to exercise, iCPET-derived mPAP–Q´T slope may aid in identifying physiologically significant, early pulmonary vascular disease in ILD. PAP responses to exercise may help to refine resting phenotypes related to pulmonary vascular dysfunction in ILD http://ow.ly/M0nMa

Exercise intolerance in heart failure with preserved ejection fraction: Diagnosing and ranking Its causes using personalized O2pathway analysis

Background: Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with a pressing shortage of therapies. Exercise intolerance is a cardinal symptom of HFpEF, yet its pathophysiology remains uncertain. Methods: We investigated the mechanism of exercise intolerance in 134 patients referred for cardiopulmonary exercise testing: 79 with HFpEF and 55 controls. We performed cardiopulmonary exercise testing with invasive monitoring to measure hemodynamics, blood gases, and gas exchange during exercise. We used these measurements to quantify 6 steps of oxygen transport and utilization (the O2 pathway) in each patient with HFpEF, identifying the defective steps that impair each one’s exercise capacity (peak Vo2). We then quantified the functional significance of each O2 pathway defect by calculating the improvement in exercise capacity a patient could expect from correcting the defect. Results: Peak Vo2 was reduced by 34±2% (mean±SEM, P<0.001) in HFpEF compared with controls of similar age, sex, and body mass index. The vast majority (97%) of patients with HFpEF harbored defects at multiple steps of the O2 pathway, the identity and magnitude of which varied widely. Two of these steps, cardiac output and skeletal muscle O2 diffusion, were impaired relative to controls by an average of 27±3% and 36±2%, respectively (P<0.001 for both). Due to interactions between a given patient’s defects, the predicted benefit of correcting any single one was often minor; on average, correcting a patient’s cardiac output led to a 7±0.5% predicted improvement in exercise intolerance, whereas correcting a patient’s muscle diffusion capacity led to a 27±1% improvement. At the individual level, the impact of any given O2 pathway defect on a patient’s exercise capacity was strongly influenced by comorbid defects. Conclusions: Systematic analysis of the O2 pathway in HFpEF showed that exercise capacity was undermined by multiple defects, including reductions in cardiac output and skeletal muscle diffusion capacity. An important source of disease heterogeneity stemmed from variation in each patient’s personal profile of defects. Personalized O2 pathway analysis could identify patients most likely to benefit from treating a specific defect; however, the system properties of O2 transport favor treating multiple defects at once, as with exercise training.

Native myocardial T1 as a biomarker of cardiac structure in non-ischemic cardiomyopathy

Diffuse myocardial fibrosis is involved in the pathology of nonischemic cardiomyopathy (NIC). Recently, the application of native (noncontrast) myocardial T1 measurement has been proposed as a method for characterizing diffuse interstitial fibrosis. To determine the association of native T1 with myocardial structure and function, we prospectively studied 39 patients with NIC (defined as left ventricular ejection fraction (LVEF) ≤ 50% without cardiac magnetic resonance (CMR) evidence of previous infarction) and 27 subjects with normal LVEF without known overt cardiovascular disease. T1, T2, and extracellular volume fraction (ECV) were determined over 16 segments across the base, mid, and apical left ventricular (LV). NIC participants (57 ± 15 years) were predominantly men (74%), with a mean LVEF 34 ± 10%. Subjects with NIC had a greater native T1 (1,131 ± 51 vs 1,069 ± 29 ms; p <0.0001), a greater ECV (0.28 ± 0.04 vs 0.25 ± 0.02, p = 0.002), and a longer myocardial T2 (52 ± 8 vs 47 ± 5 ms; p = 0.02). After multivariate adjustment, a lower global native T1 time in NIC was associated with a greater LVEF (β = -0.59, p = 0.0003), greater right ventricular ejection fraction (β = -0.47, p = 0.006), and smaller left atrial volume index (β = 0.51, p = 0.001). The regional distribution of native myocardial T1 was similar in patients with and without NIC. In NIC, native myocardial T1 is elevated in all myocardial segments, suggesting a global (not regional) abnormality of myocardial tissue composition. In conclusion, native T1 may represent a rapid, noncontrast alternative to ECV for delineating myocardial tissue remodeling in NIC.

Impaired right ventricular reserve predicts adverse cardiac outcomes in adults with congenital right heart disease

Objective The prevalence of heart failure (HF) among adult patients with congenital heart disease (ACHD) is rising. Right ventricle (RV) exercise reserve and its relationship to outcomes have not been characterised. We aim to evaluate the prognostic impact of impaired RV reserve in an ACHD population referred for cardiopulmonary exercise testing (CPET). Methods This retrospective study evaluates patients with ACHD who underwent CPET (n=147) with first-pass radionuclide ventriculography at a single tertiary care centre. RV reserve was categorised as normal, mild to moderately or severely impaired. The primary composite clinical outcome included clinical right HF, arrhythmia, transplantation or death. Results Patients were median age 41±13 years, 50% were female and median follow-up was 1.1 (IQR: 0.7–2.0) years. Exercise RV reserve was impaired in 103 patients (70%), of whom 32% were asymptomatic. Resting RV systolic function poorly predicted RV reserve, with 52% of patients with severe impairment having a qualitatively normal echocardiographic assessment. The severely impaired reserve group had lower peak oxygen consumption (VO2)(17.2 vs 22.5 mL/kg/min, p<0.0001) compared with the normal reserve group, and was more likely to develop the composite outcome (48% vs 9%, log-rank p<0.001). Severely impaired RV reserve predicted event-free survival after adjusting for peak VO2, age, sex, RV pathology, QRS duration, New York Heart Association class, resting RV ejection fraction and RV dilation by echocardiography or MRI (HR 3.7, 95% CI 1.1 to 13.0, p=0.039). Conclusion Impaired RV reserve, occurred in asymptomatic patients, was not well predicted by resting systolic function assessment, and strongly predicted adverse cardiovascular outcomes.

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.

Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection FractionCLINICAL PERSPECTIVE

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.