Cardiopulmonary exercise testing in patients with Cardiac Amyloidosis.

BACKGROUND: Cardiac involvement and dysfunction are common in patients presenting with AL and ATTR Amyloidosis. Cardiopulmonary exercise testing (CPET) performance is the gold standard to quantify functional capacity. PATIENTS AND METHODS: In this study, we evaluated CPET measurements in 41 patients with cardiac Amyloidosis and their correlation with current amyloid specific staging criteria. RESULTS: In both AL and ATTR cardiac Amyloidosis, percent predicted peak VO2 is significantly reduced and correlates with biomarker abnormalities. The association of cardiac biomarkers with peak VO2 is stronger for AL Amyloidosis (NT-proBNP (r = -0.57, P=0.006), Troponin (r = -0.70, p < 0.001) than ATTR (NT-proBNP (r = -0.4, P = 0.04) and Troponin (r = -0.57, P = 0.002) despite lower left ventricular mass in the former, suggesting that this may be further evidence for light chain toxicity in AL amyloidosis. CONCLUSION: Our findings suggest further evidence for AL toxicity.

Safety, Performance, and Efficacy of Cardiac Contractility Modulation Delivered by the 2-Lead Optimizer Smart System: The FIX-HF-5C2 Study.

BACKGROUND: Prior studies of cardiac contractility modulation (CCM) employed a 3-lead Optimizer system. A new 2-lead system eliminated the need for an atrial lead. This study tested the safety and effectiveness of this 2-lead system compared with the 3-lead system. METHODS: Patients with New York Heart Association III/IVa symptoms despite medical therapy, left ventricular ejection fraction 25% to 45%, and not eligible for cardiac resynchronization therapy could participate. All subjects received an Optimizer 2-lead implant. The primary end point was the estimated difference in the change of peak VO2 from baseline to 24 weeks between FIX-HF-5C2 (2-lead system) subjects relative to control subjects from the prior FIX-HF-5C (3-lead system) study. Changes in New York Heart Association were a secondary end point. The primary safety end point was a comparison of device-related adverse events between FIX-HF-5C2 and FIX-HF-5C subjects. RESULTS: Sixty subjects, 88% male, 66±9 years old with left ventricular ejection fraction 34±6% were included. Baseline characteristics were similar between FIX-HF-5C and FIX-HF-5C2 subjects except that 15% of FIX-HF-5C2 subjects had permanent atrial fibrillation versus 0% in FIX-HF-5C. CCM delivery did not differ significantly between 2- and 3-lead systems (19 892±3472 versus 19 583±4998 CCM signals/day, CI of difference [-1228 to 1847]). The change of peak VO2 from baseline to 24 weeks was 1.72 (95% Bayesian credible interval, 1.02-2.42) mL/kg per minute greater in the 2-lead device group versus controls. 83.1% of 2-lead subjects compared with 42.7% of controls experienced ≥1 class New York Heart Association improvement (P<0.001). There were decreased Optimizer-related adverse events with the 2-lead system compared with the 3-lead system (0% versus 8%; P=0.03). CONCLUSIONS: The 2-lead system effectively delivers comparable amount of CCM signals (including in subjects with atrial fibrillation) as the 3-lead system, is equally safe and improves peak VO2 and New York Heart Association. Device-related adverse effects are less with the 2-lead system. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03339310.

Resistance Training Reduces Skeletal Muscle Work Efficiency in Weight-Reduced and Non-Weight-Reduced Subjects.

OBJECTIVE: The objective of this study is to determine whether resistance training is similarly effective in reducing skeletal muscle efficiency and increasing strength in weight-reduced and maximal weight subjects. METHODS: This study examined the effects of supervised resistance exercise on skeletal muscle in 14 individuals with overweight and obesity sustaining a 10% or greater weight loss for over 6 months and a phenotypically similar group of 15 subjects who had not reduced weight and were weight stable at their maximal lifetime body weight. We assessed skeletal muscle work efficiency and fuel utilization (bicycle ergometry), strength (dynamometry), body composition (dual energy x-ray absorptiometry), and resting energy expenditure (indirect calorimetry) before and after 12 weeks of thrice-weekly resistance training. RESULTS: Non-weight-reduced subjects were significantly (10%-20%) stronger before and after the intervention than reduced-weight subjects and gained significantly more fat-free mass with a greater decline in percentage of body fat than weight-reduced subjects. Resistance training resulted in similar significant decreases (~10%) in skeletal muscle work efficiency at low-level exercise and ~10% to 20% increases in leg strength in both weight-reduced and non-weight-reduced subjects. CONCLUSIONS: Resistance training similarly increases muscle strength and decreases efficiency regardless of weight loss history. Increased resistance training could be an effective adjunct to reduced-weight maintenance therapy.

Triiodothyronine and leptin repletion in humans similarly reverse weight-loss-induced changes in skeletal muscle.

Subjects maintaining a ≥10% dietary weight loss exhibit decreased circulating concentrations of bioactive thyroid hormones and increased skeletal muscle work efficiency largely due to increased expression of more-efficient myosin heavy chain (MHC) isoforms (MHC I) and significantly mediated by the adipocyte-derived hormone leptin. The primary purpose of this study was to examine the effects of triiodothyronine (T3) repletion on energy homeostasis and skeletal muscle physiology in weight-reduced subjects and to compare these results with the effects of leptin repletion. Nine healthy in-patients with obesity were studied at usual weight (Wtinitial) and following a 10% dietary weight loss while receiving 5 wk of a placebo (Wt-10%placebo) or T3 (Wt-10%T3) in a single-blind crossover design. Primary outcome variables were skeletal muscle work efficiency and vastus lateralis muscle mRNA expression. These results were compared with the effects of leptin repletion in a population of 22 subjects, some of whom participated in a previous study. At Wt-10%placebo, skeletal muscle work efficiency and relative expression of the more-efficient/less-efficient MHC I/MHC II isoforms were significantly increased and the ratio of the less-efficient to the more-efficient sarco(endo)plasmic reticulum Ca2+-ATPase isoforms (SERCA1/SERCA2) was significantly decreased. These changes were largely reversed by T3 repletion to a degree similar to the changes that occurred with leptin repletion. These data support the hypothesis that the effects of leptin on energy expenditure in weight-reduced individuals are largely mediated by T3 and suggest that further study of the possible role of thyroid hormone repletion as adjunctive therapy to help sustain weight loss is needed.

A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation.

OBJECTIVES: This study sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%. BACKGROUND: CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period. METHODS: A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and ejection fraction ≥25% and ≤45% were randomized to continued medical therapy (control, n = 86) or CCM (treatment, n = 74, unblinded) for 24 weeks. Peak Vo2 (primary endpoint), Minnesota Living With Heart Failure questionnaire, NYHA functional class, and 6-min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%. RESULTS: The difference in peak Vo2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O2/kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p = 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p = 0.048). CONCLUSIONS: CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure; NCT01381172).

Effects of weight loss and leptin on skeletal muscle in human subjects.

Maintenance of a 10% or greater reduced body weight results in decreases in the energy cost of low levels of physical activity beyond those attributable to the altered body weight. These changes in nonresting energy expenditure are due mainly to increased skeletal muscle work efficiency following weight loss and are reversed by the administration of the adipocyte-derived hormone leptin. We have also shown previously that the maintenance of a reduced weight is accompanied by a decrease in ratio of glycolytic (phosphofructokinase) to oxidative (cytochrome c oxidase) activity in vastus lateralis muscle that would suggest an increase in the relative expression of the myosin heavy chain I (MHC I) isoform. We performed analyses of vastus lateralis muscle needle biopsy samples to determine whether maintenance of an altered body weight was associated with changes in skeletal muscle metabolic properties as well as mRNA expression of different isoforms of the MHC and sarcoplasmic endoplasmic reticular Ca(2+)-dependent ATPase (SERCA) in subjects studied before weight loss and then again after losing 10% of their initial weight and receiving twice daily injections of either placebo or replacement leptin in a single blind crossover design. We found that the maintenance of a reduced body weight was associated with significant increases in the relative gene expression of MHC I mRNA that was reversed by the administration of leptin as well as an increase in the expression of SERCA2 that was not significantly affected by leptin. Leptin administration also resulted in a significant increase in the expression of the less MHC IIx isoform compared with subjects receiving placebo. These findings are consistent with the leptin-reversible increase in skeletal muscle chemomechanical work efficiency and decrease in the ratio of glycolytic/oxidative enzyme activities observed in subjects following dietary weight loss.

Subgroup analysis of a randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure.

BACKGROUND: Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF ≤35% and narrow QRS randomized to optimal medical treatment (OMT) plus CCM (n = 215) versus OMT alone (n = 213) and found no significant effect on ventilatory anaerobic threshold (VAT), the study's primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM. METHODS AND RESULTS: The protocol specified that multiregression analysis would be used to determine if baseline EF, NYHA functional class, pVO(2), or etiology of heart failure influenced the impact of CCM on AT. Etiology and baseline pVO(2) did not affect efficacy. However, baseline NYHA functional class III and EF ≥25% were significant predictors of increased efficacy. In this subgroup (comprising 97 OMT and 109 CCM patients, ∼48% of the entire population) VAT increased by 0.10 ± 2.36 in CCM versus -0.54 ± 1.83 mL kg(-1) min(-1) in OMT (P = .03) and pVO(2) increased by 0.34 ± 3.11 in CCM versus -0.97 ± 2.31 (P = .001) at 24 weeks compared with baseline; 44% of CCM versus 23% of OMT subjects showed improvement of ≥1 class in NYHA functional class (P = .002), and 59% of CCM versus 42% of OMT subjects showed a ≥10-point reduction in Minnesota Living with Heart Failure Questionnaire (P = .01). All of these findings were similar to those seen at 50 weeks. CONCLUSIONS: The results of this retrospective hypothesis-generating analysis indicate that CCM significantly improves objective parameters of exercise tolerance in a subgroup of patients characterized by normal QRS duration, NYHA functional class III symptoms, and EF >25%.

A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure.

BACKGROUND: Cardiac contractility modulation (CCM) delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction. METHODS: We tested CCM in 428 New York Heart Association class III or IV, narrow QRS heart failure patients with ejection fraction (EF) ≤ 35% randomized to optimal medical therapy (OMT) plus CCM (n = 215) versus OMT alone (n = 213). Efficacy was assessed by ventilatory anaerobic threshold (VAT), primary end point, peak Vo2 (pVo2), and Minnesota Living with Heart Failure Questionnaire (MLWFQ) at 6 months. The primary safety end point was a test of noninferiority between groups at 12 months for the composite of all-cause mortality and hospitalizations (12.5% allowable delta). RESULTS: The groups were comparable for age (58 ± 13 vs 59 ± 12 years), EF (26% ± 7% vs 26% ± 7%), pVo2 (14.7 ± 2.9 vs 14.8 ± 3.2 mL kg⁻¹ min⁻¹), and other characteristics. While VAT did not improve at 6 months, CCM significantly improved pVo2 and MLWHFQ (by 0.65 mL kg⁻¹ min⁻¹ [P = .024] and -9.7 points [P < .0001], respectively) over OMT. Forty-eight percent of OMT and 52% of CCM patients experienced a safety end point, which satisfied the noniferiority criterion (P = .03). Post hoc, hypothesis-generating analysis identified a subgroup (characterized by baseline EF ≥ 25% and New York Heart Association class III symptoms) in which all parameters were improved by CCM. CONCLUSIONS: In the overall target population, CCM did not improve VAT (the primary end point) but did improve pVo2 and MLWHFQ. Cardiac contractility modulation did not have an adverse affect on hospitalizations or mortality within the prespecified boundaries. Further study is required to clarify the role of CCM as a treatment for medically refractory heart failure.

The ventilatory anaerobic threshold in heart failure: a multicenter evaluation of reliability.

BACKGROUND: The ventilatory threshold (VT) is usually determined by visual assessment of the point where the rate of elimination of carbon dioxide (VCO(2)) increases nonlinearly with respect to oxygen uptake (VO(2)) (the V-Slope method). We quantified the reliability of VT determination using data from a multicenter study in patients with heart failure. METHODS AND RESULTS: The Fix-Heart Failure-5 study of cardiac contractility modulation enrolled 428 patients from 50 centers in the United States. Cardiopulmonary exercise tests were performed at baseline and 12, 24, and 50 weeks after randomization, which provided 1679 tests. The VT was determined from each test in a core laboratory by 2 independent readers. VT could not be determined for 276 tests (16.4% indeterminate). Inter-observer variability (quantified by the 95% limits of agreement, LoA, expressed as a percent of the mean value) was 20.2% between the 2 readers, with a coefficient of variation (CV) of 7.3%. Intra-observer variability was assessed by resubmitting (blinded) 179 tests to the same readers; the LoA was 24.7% for reader 1 and 16.9% for reader 2, with CVs of 6.1 and 8.9%, respectively. Ninety-one tests were submitted to 2 additional readers at a second core lab. Inter-observer variability in the second lab was 26.7% with a CV of 9.6%. Inter-laboratory variability was 21.4%, with a CV of 7.7%. CONCLUSIONS: Inter-observer, intra-observer, and inter-site variation in determining the VT should be considered when using the VT as an end point in clinical trials of heart failure.

Effects of experimental weight perturbation on skeletal muscle work efficiency, fuel utilization, and biochemistry in human subjects.

Maintenance of a body weight 10% above or below that "customary" for lean or obese individuals results in respective increases or decreases in the energy expended in low levels of physical activity (nonresting energy expenditure, NREE). These changes are greater than can be accounted for by the altered body weight or composition and are due mainly to altered skeletal muscle work efficiency at low levels of power generation. We performed biochemical analysis of vastus lateralis muscle needle biopsy samples to determine whether maintenance of an altered body weight was associated with changes in skeletal muscle histomorphology. We found that the maintenance of a 10% reduced body weight was associated with significant declines in glycolytic (phosphofructokinase, PFK) enzyme activity and, in particular, in the ratio of glycolytic to oxidative (cytochrome c oxidase, COX) enzyme activity without significant changes in the activities of enzymes relevant to mitochondrial density, respiratory chain activity, or fuel transport; or in skeletal muscle fiber type or glycogen stores. The fractional change in the ratio of PFK/COX activity in subjects following weight loss was significantly correlated with changes in the systemic respiratory exchange ratio (RER) and measures of mechanical efficiency of skeletal muscle at low workloads (pedaling a bicycle to generate 10 or 25 W of power). Thus, predictable changes in systemic skeletal muscle biochemistry accompany the maintenance of an altered body weight and account for a significant portion of the variance in skeletal muscle work efficiency and fuel utilization at reduced body weight.

Chronotropic incompetence, beta-blockers, and functional capacity in advanced congestive heart failure: time to pace?

BACKGROUND: Chronotropic incompetence (CI) is often seen in subjects with chronic congestive heart failure (CHF). The prevalence of CI, its mechanisms and association with beta-blocker use as well as exercise capacity have not been clearly defined. METHODS AND RESULTS: Cardiopulmonary exercise tolerance testing data for 278 consecutive patients with systolic CHF was analyzed. CI, defined as the inability to reach 80% of maximally predicted heart rate was present in 128 of 278 subjects (46%). The prevalence of CI was highest in those with most impaired exercise capacity (72, 48, and 24% for subjects with a VO(2) of <14.0, 14.0-20.0, and >20.0 ml/kg/min respectively; p=0.001). While subjects with CI had lower peak exercise heart rate (114 vs. 152 bpm), and lower peak VO(2) (15.4 vs. 19.9 ml/kg/min), they were equally likely to be on chronic beta-blocker therapy (74% vs. 71%; p=0.51). Heart rate and norepinephrine (NE) levels were measured during exercise in a separate cohort of 24 subjects with CHF. There was no difference in beta-blocker dose between subjects with and without CI, however, exercise induced NE release and Chronotropic Responsiveness Index, a measure of post-synaptic beta-receptor sensitivity to NE, were lower in subjects with CI (1687+/-911 vs. 2593+/-1451 pg/ml p=0.08; CRI 12.7+/-5.7 vs. 22.1+/-4.7, p=0.002). CONCLUSIONS: CI occurs in >70% of subjects with advanced systolic CHF irrespective of beta-blocker use and is associated with a trend toward impaired NE release, post-synaptic beta-receptor desensitization and reduced exercise capacity.

Association of heart rate recovery and maximum oxygen consumption in patients with chronic congestive heart failure.

BACKGROUND: Peak oxygen consumption (peak VO2) is one of the strongest predictors of mortality in patients with congestive heart failure (CHF). In contrast to measurements of peak VO2, which requires analysis of expired gases, heart rate recovery, defined as maximum heart rate minus heart rate at 1 minute after exercise, is easily obtained. The current study was undertaken to determine the association between peak VO2 and heart rate recovery in patients with CHF. METHODS: Retrospective data on VO2 and heart rate recovery were analyzed in 296 patients with CHF secondary to left ventricular systolic dysfunction (left ventricular ejection fraction [LVEF] <50%) who had undergone cardiopulmonary exercise testing (CPET). Patients exercised on a treadmill using a graded work rate protocol with the work increasing to a symptom-limited maximum. Peak oxygen consumption was defined as the highest value of oxygen uptake attained in the final 20 seconds of exercise when the respiratory exchange ratio was >1.0. RESULTS: Heart rate recovery and peak VO2 correlated moderately (r = 0.47, p < 0.001). The degree of correlation was similar in patients receiving beta-blockers (r = 0.47, p < 0.001) and those not receiving beta-blockers (r = 0.49, p < 0.001). CONCLUSIONS: Although heart rate recovery and peak VO2 correlated moderately, from a clinical standpoint, this finding is probably not strong enough to use heart rate recovery in lieu of peak VO2. This modest correlation of two independent predictors of outcome may suggest their usefulness when combined in a multivariate score.

Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight.

Maintenance of a reduced body weight is accompanied by decreased energy expenditure that is due largely to increased skeletal muscle work efficiency. In addition, decreased sympathetic nervous system tone and circulating concentrations of leptin, thyroxine, and triiodothyronine act coordinately to favor weight regain. These "weight-reduced" phenotypes are similar to those of leptin-deficient humans and rodents. We examined metabolic, autonomic, and neuroendocrine phenotypes in 10 inpatient subjects (5 males, 5 females [3 never-obese, 7 obese]) under 3 sets of experimental conditions: (a) maintaining usual weight by ingesting a liquid formula diet; (b) maintaining a 10% reduced weight by ingesting a liquid formula diet; and (c) receiving twice-daily subcutaneous doses of leptin sufficient to restore 8 am circulating leptin concentrations to pre-weight-loss levels and remaining on the same liquid formula diet required to maintain a 10% reduced weight. During leptin administration, energy expenditure, skeletal muscle work efficiency, sympathetic nervous system tone, and circulating concentrations of thyroxine and triiodothyronine returned to pre-weight-loss levels. These responses suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency. Prevention of weight regain might be achievable by strategies relevant to reversing this leptin-insufficient state.

New predictors of outcome in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (PAH) is a rare disease with a poor prognosis. New therapies have improved the outcome of this condition; accordingly, the factors that determine outcome may have changed. We aimed to identify determinants of survival in a cohort of consecutive patients with PAH: which was idiopathic, familial, or associated with anorexigen use. We performed a retrospective cohort study of 84 consecutive patients with PAH who underwent initial evaluation at our center from January 1994 to June 2002. The primary outcome was death or lung transplantation. Survival at 1, 3, and 5 [corrected] years was 87%, 75%, and 61%, respectively. Multivariate analysis showed that being of African-American or Asian descent was associated with an increased risk of death. Warfarin use was associated with a reduced risk of death. Higher serum albumin and cardiac index and acute vasoreactivity were independently associated with improved survival. These data suggest that the determinants of outcome have changed. Race is identified as a new risk factor, which may be attributable to biologic or socioeconomic differences. Cardiac function and acute reactivity of the pulmonary vascular bed remain strong independent predictors of outcome.

Effects of experimental weight perturbation on skeletal muscle work efficiency in human subjects.

Maintenance of reduced or elevated body weight results in respective decreases or increases in energy expended in physical activity, defined as 24-h energy expenditure excluding resting energy expenditure and the thermic effect of feeding, beyond those attributable to weight change. We examined skeletal muscle work efficiency by graded cycle ergometry and, in some subjects, rates of gastrocnemius muscle ATP flux during exercise by magnetic resonance spectroscopy (MRS), in 30 subjects (15 males, 15 females) at initial weight and 10% below initial weight and in 8 subjects (7 males, 1 female) at initial weight and 10% above initial weight to determine whether changes in skeletal muscle work efficiency at altered body weight were correlated with changes in the energy expended in physical activity. At reduced weight, muscle work efficiency was increased in both cycle ergometry [mean (SD) change = +26.5 (26.7)%, P < 0.001] and MRS [ATP flux change = -15.2 (23.2)%, P = 0.044] studies. Weight gain resulted in decreased muscle work efficiency by ergometry [mean (SD) change = -17.8 (20.5)%, P = 0.043]. Changes in muscle efficiency at altered body weight accounted for 35% of the change in daily energy expended in physical activity.

Positron emission tomography, echo-doppler, and exercise studies of functional capacity in hypertensive heart disease.

BACKGROUND: This study examines the relationship between functional capacity, left ventricular diastolic function, and myocardial perfusion reserve (MPR) in patients with left ventricular hypertrophy (LVH). METHODS: We studied 16 patients with LVH and 10 controls. Functional capacity was assessed by cardiopulmonary exercise, MPR by positron emission tomography, and left ventricular diastolic function by echo-Doppler. RESULTS: Functional capacity and MPR were significantly lower in the patients. Functional capacity correlated positively with MPR and left ventricular diastolic function. CONCLUSIONS: Diminished functional capacity in patients with hypertension-induced LVH is related to the impairment in MPR and left ventricular diastolic function.