Keri M. Shafer

Hemodynamic Responses to Rapid Saline Loading: The Impact of Age, Sex, and Heart Failure

Background— Hemodynamic assessment after volume challenge has been proposed as a way to identify heart failure with preserved ejection fraction. However, the normal hemodynamic response to a volume challenge and how age and sex affect this relationship remain unknown. Methods and Results— Sixty healthy subjects underwent right heart catheterization to measure age- and sex-related normative responses of pulmonary capillary wedge pressure and mean pulmonary arterial pressure to volume loading with rapid saline infusion (100–200 mL/min). Hemodynamic responses to saline infusion in heart failure with preserved ejection fraction (n=11) were then compared with those of healthy young (<50 years of age) and older (≥50 years of age) subjects. In healthy subjects, pulmonary capillary wedge pressure increased from 10±2 to 16±3 mm Hg after ~1 L and to 20±3 mm Hg after ~2 L of saline infusion. Older women displayed a steeper increase in pulmonary capillary wedge pressure relative to volume infused (16±4 mm Hg·L−1·m2) than the other 3 groups (P⩽0.019). Saline infusion resulted in a greater increase in mean pulmonary arterial pressure relative to cardiac output in women compared with men regardless of age. Subjects with heart failure with preserved ejection fraction exhibited a steeper increase in pulmonary capillary wedge pressure relative to infused volume (25±12 mm Hg·L−1·m2) than healthy young and older subjects (P⩽0.005). Conclusions— Filling pressures rise significantly with volume loading, even in healthy volunteers. Older women and patients with heart failure with preserved ejection fraction exhibit the largest increases in pulmonary capillary wedge pressure and mean pulmonary arterial pressure.Background— Hemodynamic assessment after volume challenge has been proposed as a way to identify heart failure with preserved ejection fraction. However, the normal hemodynamic response to a volume challenge and how age and sex affect this relationship remain unknown. Methods and Results— Sixty healthy subjects underwent right heart catheterization to measure age- and sex-related normative responses of pulmonary capillary wedge pressure and mean pulmonary arterial pressure to volume loading with rapid saline infusion (100–200 mL/min). Hemodynamic responses to saline infusion in heart failure with preserved ejection fraction (n=11) were then compared with those of healthy young (<50 years of age) and older (≥50 years of age) subjects. In healthy subjects, pulmonary capillary wedge pressure increased from 10±2 to 16±3 mm Hg after ~1 L and to 20±3 mm Hg after ~2 L of saline infusion. Older women displayed a steeper increase in pulmonary capillary wedge pressure relative to volume infused (16±4 mm Hg·L−1·m2) than the other 3 groups ( P ≤0.019). Saline infusion resulted in a greater increase in mean pulmonary arterial pressure relative to cardiac output in women compared with men regardless of age. Subjects with heart failure with preserved ejection fraction exhibited a steeper increase in pulmonary capillary wedge pressure relative to infused volume (25±12 mm Hg·L−1·m2) than healthy young and older subjects ( P ≤0.005). Conclusions— Filling pressures rise significantly with volume loading, even in healthy volunteers. Older women and patients with heart failure with preserved ejection fraction exhibit the largest increases in pulmonary capillary wedge pressure and mean pulmonary arterial pressure. # Clinical Perspective {#article-title-38}

The Importance of the Muscle and Ventilatory Blood Pumps During Exercise in Patients Without a Subpulmonary Ventricle (Fontan Operation)

OBJECTIVES The aim of this study was to determine the relative contribution of the muscle and ventilatory pumps to stroke volume in patients without a subpulmonic ventricle. BACKGROUND In patients with Fontan circulation, it is unclear how venous return is augmented to increase stroke volume and cardiac output during exercise. METHODS Cardiac output (acetylene rebreathing), heart rate (electrocardiography), oxygen uptake (Douglas bag technique), and ventilation were measured in 9 patients age 15.8 ± 6 years at 6.1 ± 1.8 years after Fontan operation and 8 matched controls. Data were obtained at rest, after 3 min of steady-state exercise (Ex) on a cycle ergometer at 50% of individual working capacity, during unloaded cycling at 0 W (muscle pump alone), during unloaded cycling with isocapnic hyperpnea (muscle and ventilatory pump), during Ex plus an inspiratory load of 12.8 ± 1.5 cm water, and during Ex plus an expiratory load of 12.8 ± 1.6 cm water. RESULTS In Fontan patients, the largest increases in stroke volume and stroke volume index were during zero-resistance cycling. An additional increase with submaximal exercise occurred in controls only. During Ex plus expiratory load, stroke volume indexes were reduced to baseline, non-exercise levels in Fontan patients, without significant changes in controls. CONCLUSIONS With Fontan circulation increases in cardiac output and stroke volume during Ex were due to the muscle pump, with a small additional contribution by the ventilatory pump. An increase in intrathoracic pressure played a deleterious role in Fontan circulation by decreasing systemic venous return and stroke volume.

Cardiovascular Effects of 1 Year of Alagebrium and Endurance Exercise Training in Healthy Older Individuals

Background—Lifelong exercise training maintains a youthful compliance of the left ventricle (LV), whereas a year of exercise training started later in life fails to reverse LV stiffening, possibly because of accumulation of irreversible advanced glycation end products. Alagebrium breaks advanced glycation end product crosslinks and improves LV stiffness in aged animals. However, it is unclear whether a strategy of exercise combined with alagebrium would improve LV stiffness in sedentary older humans. Methods and Results—Sixty-two healthy subjects were randomized into 4 groups: sedentary+placebo; sedentary+alagebrium (200 mg/d); exercise+placebo; and exercise+alagebrium. Subjects underwent right heart catheterization to define LV pressure–volume curves; secondary functional outcomes included cardiopulmonary exercise testing and arterial compliance. A total of 57 of 62 subjects (67±6 years; 37 f/20 m) completed 1 year of intervention followed by repeat measurements. Pulmonary capillary wedge pressure and LV end-diastolic volume were measured at baseline, during decreased and increased cardiac filling. LV stiffness was assessed by the slope of LV pressure–volume curve. After intervention, LV mass and end-diastolic volume increased and exercise capacity improved (by ≈8%) only in the exercise groups. Neither LV mass nor exercise capacity was affected by alagebrium. Exercise training had little impact on LV stiffness (training×time effect, P=0.46), whereas alagebrium showed a modest improvement in LV stiffness compared with placebo (medication×time effect, P=0.04). Conclusions—Alagebrium had no effect on hemodynamics, LV geometry, or exercise capacity in healthy, previously sedentary seniors. However, it did show a modestly favorable effect on age-associated LV stiffening. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01014572.

Effects of Age and Aerobic Fitness on Myocardial Lipid Content

Background—Aging and sedentary lifestyles lead to cardiac atrophy, ventricular stiffening, and impaired diastolic function. Both conditions are marked by increased adiposity, which can lead to ectopic fat deposition in nonadipocyte tissues including the myocardium. The effect of excess intramyocardial fat on cardiac function in nonobese individuals is unknown. Methods and Results—Cardiac lipid content was measured by magnetic resonance spectroscopy in 153 healthy nonobese subjects with varying fitness levels quantified by peak oxygen uptake during treadmill exercise. Cardiac function (echo) and left ventricular (LV) filling pressures (right heart catheterization) were measured under varying preloads. LV stiffness was calculated from a curve fit of the diastolic portion of the pressure–volume curve. The strongest clinical predictors of lipid content were body mass index (&bgr;=+0.03; 95% confidence interval, 0.001–0.06) and peak oxygen uptake (&bgr;=−0.02; 95% confidence interval, −0.03 to −0.009; R2=0.14; P<0.001). Subjects in the highest quintile had smaller LV end-diastolic volumes (68±13 versus 58±12 mL/m2; P<0.01) and decreased peak early mitral annular and increased peak late mitral inflow velocities. There were no differences in LV stiffness, but a leftward shift in the pressure–volume curve suggested a less distensible ventricle with increasing myocardial lipid levels. After adjusting for age, fitness, and body mass index, echocardiographic and morphometric differences among groups were attenuated and no longer significant. Conclusions—Body mass index and fitness levels are the strongest predictors of myocardial lipid content in nonobese humans. Cardiac lipid content is associated with decreased ventricular distensibility, and it may provide a causal mechanism linking changes in LV function related to age and fitness.

Exercise Oscillatory Ventilation in Patients With Fontan Physiology

Background—Exercise oscillatory ventilation (EOV) refers to regular oscillations in minute ventilation (VE) during exercise. Its presence correlates with heart failure severity and worse prognosis in adults with acquired heart failure. We evaluated the prevalence and predictive value of EOV in patients with single ventricle Fontan physiology. Methods and Results—We performed a cross-sectional analysis and prospective survival analysis of patients who had undergone a Fontan procedure and subsequent cardiopulmonary exercise test. Data were reviewed for baseline characteristics and incident mortality, heart transplant, or nonelective cardiovascular hospitalization. EOV was defined as regular oscillations for >60% of exercise duration with amplitude >15% of average VE. Survival analysis was performed using Cox regression. Among 253 subjects, EOV was present in 37.5%. Patients with EOV were younger (18.8±9.0 versus 21.7±10.1 years; P=0.02). EOV was associated with higher New York Heart Association functional class (P=0.02) and VE/VCO2 slope (36.8±6.9 versus 33.7±5.7; P=0.0002), but not with peak VO2 (59.7±14.3 versus 61.0±16.0% predicted; P=0.52) or noninvasive measures of cardiac function. The presence of EOV was associated with slightly lower mean cardiac index but other invasive hemodynamic variables were similar. During a median follow-up of 5.5 years, 22 patients underwent transplant or died (n=19 primary deaths, 3 transplants with 2 subsequent deaths). EOV was associated with increased risk of death or transplant (hazard ratio, 3.9; 95% confidence interval, 1.5–10.0; P=0.002) and also predicted the combined outcome of death, transplant, or nonelective cardiovascular hospitalization after adjusting for New York Heart Association functional class, peak VO2, and other covariates (multivariable hazard ratio, 2.0; 95% confidence interval, 1.2–3.6; P=0.01). Conclusions—EOV is common in the Fontan population and strongly predicts lower transplant-free survival.

Cardiovascular response to exercise training in the systemic right ventricle of adults with transposition of the great arteries

Patients with transposition of the great arteries (TGA) and systemic right ventricles have premature congestive heart failure; there is also a growing concern that athletes who perform extraordinary endurance exercise may injure the right ventricle. Therefore we felt it essential to determine whether exercise training might injure a systemic right ventricle which is loaded with every heartbeat. Previous studies have shown that short term exercise training is feasible in TGA patients, but its effect on ventricular function is unclear. We demonstrate that systemic right ventricular function is preserved (and may be improved) in TGA patients with exercise training programmes that are typical of recreational and sports participation, with no evidence of injury on biomarker assessment. Stroke volume reserve during exercise correlates with exercise training response in our TGA patients, identifying this as a marker of a systemic right ventricle (SRV) that may most tolerate (and possibly even be improved by) exercise training.

Decline in Peak Oxygen Consumption over Time Predicts Death or Transplantation in Adults with a Fontan Circulation

Background Peak oxygen consumption (pVO2) measured by cardiopulmonary exercise test (CPET) predicts mortality in adults with a Fontan circulation. The purpose of this study was to assess the additive prognostic value of change in pVO2 over time. Methods We analyzed a cohort of adults (≥18 years old) with a Fontan circulation who underwent at least 2 maximal CPETs separated by 6‐30 months at Boston Childrens Hospital between 2000 and 2015. Survival analysis was performed to determine whether changes in CPET variables, including pVO2 between consecutive tests, were associated with subsequent clinical events. The primary outcome was transplant‐free survival. Results The study included 130 patients with 287 CPET test pairs. Average age was 26.6 ± 9.5 years. Baseline pVO2 averaged 22.0 ± 5.7 mL/kg/min or 60.9% ± 13.7% predicted. In the cohort overall, there was no change in mean pVO2 between sequential CPETs. Eleven patients died and 2 underwent transplant. On average, pVO2 declined for patients who subsequently died or underwent transplant but remained stable among those who did not (−9.8% ± 14.6% vs 0.0 ± 13.0%, P < .01). Those with a decline in pVO2 between CPETs were at greater risk of death or transplantation (per 10% decrease in pVO2: HR = 2.0, 95% CI 1.2‐3.1, P = .004). Change in pVO2 remained a significant predictor of death or transplant after adjusting for pVO2 at first CPET (per 10% decline in pVO2: HR = 2.5, 95% CI 1.5‐4.2, P < .001). Conclusions A decline in pVO2 between consecutive CPETs predicts increased risk for death or transplant in adults with a Fontan circulation independent of baseline pVO2. These results support the additive clinical value of serial CPET in this population.

Purulent Pericarditis After Transbronchial Biopsy

A 28-year-old woman experienced hypotension and unresponsiveness. She had undergone bronchoscopy with needle biopsy 2 weeks before admission to evaluate hilar lymphadenopathy given suspicion of sarcoidosis. She had an elevated white blood cell count of 28,000/μL and a serum creatinine level of 4.0 mg/dL. Echocardiography showed a large pericardial effusion. Pericardiocentesis resulted in removal of 400 mL of yellow-green purulent material that grew Streptococcus milleri, Prevotella, Veillonella, and Peptostreptococcus species. Pericardiectomy and mediastinal washout were performed. Subsequently, her condition rapidly improved. She returned home after 26 days of admission. At 12-month follow-up, the patient had made a full recovery.

A Randomized Trial Comparing Cardiac Rehabilitation to Standard of Care for Adults With Congenital Heart Disease

Background: Cardiac rehabilitation (CR) improves exercise capacity and quality of life while reducing mortality in adults with acquired heart disease. Cardiac rehabilitation has not been extensively studied in adults with congenital heart disease (CHD). Methods: We performed a prospective, randomized controlled trial (NCT01822769) of a 12-week clinical CR program compared with standard of care (SOC). Participants were ≥16 years old, had moderate or severe CHD, had O2 saturation ≥92%, and had peak O2 consumption ( V ̇ O 2 pk ) < 80% predicted. We assessed exercise capacity, physical activity, quality of life, self-reported health status, and other variables at baseline and after 12 weeks. The prespecified primary end point was change in V ̇ O 2 pk . Results: We analyzed data on 28 participants (aged 41.1 ± 12.1 years, 50% male), 13 randomized to CR and 15 to SOC. V ̇ O 2 pk averaged 16.8 ± 3.8 mL/kg/min, peak work rate = 95 ± 28 W, and median Minnesota Living with Heart Failure Questionnaire (MLHFQ) score = 27 (interquartile range: 11-44). Cardiac rehabilitation participants were older (48 ± 9 years vs 36 ± 12 years; P = .01), but there were no significant between-group differences in other variables. There were no adverse events related to CR. V ̇ O 2 pk increased in the CR group compared with SOC (+2.2 mL/kg/min, 95% confidence interval: 0.7-3.7; P = .002, age-adjusted +2.7 mL/kg/min; P = .004); there was a nonsignificant improvement in work rate (+8.1 W; P = .13). Among the 25 participants with baseline MLHFQ > 5, there was a clinically important >5-point improvement in 72.7% and 28.6% of CR and SOC participants, respectively (P = .047). Cardiac rehabilitation was also associated with improved self-assessment of overall health (P < .04). Conclusions: Cardiac rehabilitation is safe and is associated with improvement in aerobic capacity and self-reported health status compared with SOC in adults with CHD.

Association of Albuminuria With Major Adverse Outcomes in Adults With Congenital Heart Disease: Results From the Boston Adult Congenital Heart Biobank

Importance Albuminuria is associated with adverse outcomes in diverse groups of patients, but the importance of albuminuria in the emerging population of increasingly complex adults with congenital heart disease (ACHD) remains unknown. Objective To assess the prevalence, risk factors, and prognostic implications of albuminuria in ACHD. Design, Setting, and Participants This prospective study assessed a cohort of ambulatory patients aged 18 years and older who were examined at an ACHD referral center and enrolled in the Boston ACHD Biobank between May 17, 2012, to August 5, 2016. Albuminuria was defined as an urine albumin-to-creatinine (ACR) ratio of 30 mg/g or more. Main Outcomes and Measures Death or nonelective cardiovascular hospitalization, defined as overnight admission for heart failure, arrhythmia, thromboembolic events, cerebral hemorrhage, and/or disease-specific events. Results We measured the ACR of 612 adult patients with CHD (mean [SD] age, 38.6 [13.4] years; 308 [50.3%] women). Albuminuria was present in 106 people (17.3%) and was associated with older age (patients with ACR <30 mg/g: mean [SD]: 37.5 [13.2] years; vs patients with ACR ≥30 mg/g: 43.8 [13.1] years; P < .001), presence of diabetes mellitus (ACR <30 mg/g: 13 of 506 [2.6%]; vs ≥30 mg/g: 11 of 106 [10.4%]; P < .001), lower estimated glomerular filtration rate (ACR <30 mg/g: median [interquartile range (IQR)]: 103.3 [90.0-116.4] mL/min/1.73 m2; ACR ≥30 mg/g: 99.1 [78.8-108.7] mL/min/1.73 m2; P = .002), and cyanosis (ACR <30 mg/g: 23 of 506 [5.1%]; vs ACR ≥30 mg/g: 21 of 106 [22.6%]; P < .001). After a mean (SD) follow-up time of 270 (288) days, 17 patients (2.5%) died, while 68 (11.1%) either died or experienced overnight inpatient admission. Albuminuria predicted outcome, with 30 of 106 patients with albuminuria (28.3%) affected vs 38 of 506 patients without albuminuria (7.5%; hazard ratio [HR], 3.0; 95% CI, 1.9-4.9; P < .001). Albuminuria was also associated with increased mortality (11 of 106 [10.4%]; vs 6 of 506 [1.2%] in patients with and without albuminuria, respectively; HR, 6.4; 95% CI, 2.4-17.3; P < .001). Albuminuria was associated with the outcomes only in patients with a biventricular circulation (HR, 4.5; 95% CI, 2.5-8.0) and not those with single-ventricle circulation (HR, 1.0; 95% CI, 0.4-2.8; P = 0.01 compared with biventricular circulation group). Among 133 patients (21.7%) in NYHA functional class 2, albuminuria was strongly associated with death or nonelective hospitalization. Conclusions and Relevance Albuminuria is common and is associated with increased risk for adverse outcome in patients with ACHD with biventricular circulation. Albuminuria appears especially useful in stratifying risk in patients categorized as NYHA functional class 2.