Abnormal heart rate recovery and deficient chronotropic response after submaximal exercise in young Marfan syndrome patients.

BACKGROUND: Marfan syndrome patients present important cardiac structural changes, ventricular dysfunction, and electrocardiographic changes. An abnormal heart rate response during or after exercise is an independent predictor of mortality and autonomic dysfunction. The aim of the present study was to compare heart rate recovery and chronotropic response obtained by cardiac reserve in patients with Marfan syndrome subjected to submaximal exercise. METHODS: A total of 12 patients on ß-blocker therapy and 13 off ß-blocker therapy were compared with 12 healthy controls. They were subjected to submaximal exercise with lactate measurements. The heart rate recovery was obtained in the first minute of recovery and corrected for cardiac reserve and peak lactate concentration. RESULTS: Peak heart rate (141±16 versus 155±17 versus 174±8 bpm; p=0.001), heart rate reserve (58.7±9.4 versus 67.6±14.3 versus 82.6±4.8 bpm; p=0.001), heart rate recovery (22±6 versus 22±8 versus 34±9 bpm; p=0.001), and heart rate recovery/lactate (3±1 versus 3±1 versus 5±1 bpm/mmol/L; p=0.003) were different between Marfan groups and controls, respectively. All the patients with Marfan syndrome had heart rate recovery values below the mean observed in the control group. The absolute values of heart rate recovery were strongly correlated with the heart rate reserve (r=0.76; p=0.001). CONCLUSION: Marfan syndrome patients have reduced heart rate recovery and chronotropic deficit after submaximal exercise, and the chronotropic deficit is a strong determinant of heart rate recovery. These changes are suggestive of autonomic dysfunction.

Heart Failure Impairs Muscle Blood Flow and Endurance Exercise Tolerance in COPD.

Heart failure, a prevalent and disabling co-morbidity of COPD, may impair cardiac output and muscle blood flow thereby contributing to exercise intolerance. To investigate the role of impaired central and peripheral hemodynamics in limiting exercise tolerance in COPD-heart failure overlap, cycle ergometer exercise tests at 20% and 80% peak work rate were performed by overlap (FEV1 = 56.9 ± 15.9% predicted, ejection fraction = 32.5 ± 6.9%; N = 16), FEV1-matched COPD (N = 16), ejection fraction-matched heart failure patients (N = 15) and controls (N = 12). Differences (Δ) in cardiac output (impedance cardiography) and vastus lateralis blood flow (indocyanine green) and deoxygenation (near-infrared spectroscopy) between work rates were expressed relative to concurrent changes in muscle metabolic demands (ΔO2 uptake). Overlap patients had approximately 30% lower endurance exercise tolerance than COPD and heart failure (p < 0.05). ΔBlood flow was closely proportional to Δcardiac output in all groups (r = 0.89-0.98; p < 0.01). Overlap showed the largest impairments in Δcardiac output/ΔO2 uptake and Δblood flow/ΔO2 uptake (p < 0.05). Systemic arterial oxygenation, however, was preserved in overlap compared to COPD. Blunted limb perfusion was related to greater muscle deoxygenation and lactate concentration in overlap (r = 0.78 and r = 0.73, respectively; p < 0.05). ΔBlood flow/ΔO2 uptake was related to time to exercise intolerance only in overlap and heart failure (p < 0.01). In conclusion, COPD and heart failure add to decrease exercising cardiac output and skeletal muscle perfusion to a greater extent than that expected by heart failure alone. Treatment strategies that increase muscle O2 delivery and/or decrease O2 demand may be particularly helpful to improve exercise tolerance in COPD patients presenting heart failure as co-morbidity.

Oxygen delivery-utilization mismatch in contracting locomotor muscle in COPD: peripheral factors.

Central cardiorespiratory and gas exchange limitations imposed by chronic obstructive pulmonary disease (COPD) impair ambulatory skeletal muscle oxygenation during whole body exercise. This investigation tested the hypothesis that peripheral factors per se contribute to impaired contracting lower limb muscle oxygenation in COPD patients. Submaximal neuromuscular electrical stimulation (NMES; 30, 40, and 50 mA at 50 Hz) of the quadriceps femoris was employed to evaluate contracting skeletal muscle oxygenation while minimizing the influence of COPD-related central cardiorespiratory constraints. Fractional O2 extraction was estimated by near-infrared spectroscopy (deoxyhemoglobin/myoglobin concentration; deoxy-[Hb/Mb]), and torque output was measured by isokinetic dynamometry in 15 nonhypoxemic patients with moderate-to-severe COPD (SpO2 = 94 ± 2%; FEV1 = 46.4 ± 10.1%; GOLD II and III) and in 10 age- and gender-matched sedentary controls. COPD patients had lower leg muscle mass than controls (LMM = 8.0 ± 0.7 kg vs. 8.9 ± 1.0 kg, respectively; P < 0.05) and produced relatively lower absolute and LMM-normalized torque across the range of NMES intensities (P < 0.05 for all). Despite producing less torque, COPD patients had similar deoxy-[Hb/Mb] amplitudes at 30 and 40 mA (P > 0.05 for both) and higher deoxy-[Hb/Mb] amplitude at 50 mA (P < 0.05). Further analysis indicated that COPD patients required greater fractional O2 extraction to produce torque (i.e., ↑Δdeoxy-[Hb/Mb]/torque) relative to controls (P < 0.05 for 40 and 50 mA) and as a function of NMES intensity (P < 0.05 for all). The present data obtained during submaximal NMES of small muscle mass indicate that peripheral abnormalities contribute mechanistically to impaired contracting skeletal muscle oxygenation in nonhypoxemic, moderate-to-severe COPD patients.

Modified BODE Index to Predict Mortality in Individuals With COPD: The Role of 4-Min Step Test.

BACKGROUND: The BODE (body mass index, air-flow obstruction, dyspnea, exercise capacity) index is a composite prognostic marker that predicts mortality in COPD. It includes body mass index, air-flow obstruction, dyspnea score, and exercise capacity by using the 6-min walk distance. However, a 30-m-long corridor is necessary to perform the test and this limits its use in clinical practice. Step tests may elicit distinct physiologic responses compared with the 6-min walk test but are easy to perform in the office setting. We sought to investigate whether a 4-min step test would be a suitable surrogate of the 6-min walk test, in a modified BODE step index (simplified BODE index), to predict mortality in COPD. METHODS: Individuals with COPD performed a self-paced 4-min step test, and the simplified BODE index was calculated by replacing the 6-min walk distance by the number of steps climbed. Cutoff values were determined by receiver operating characteristic curve analysis as follows: score 0 for >60 steps; score 1 for 50-60 steps; score 2 for 40-49 steps; and score 3 for <40 steps. RESULTS: A total of 186 individuals with COPD were enrolled from 2011 to 2016 (60% males; mean ± SD age, 65 ± 9 y; mean ± SD FEV1, 50 ± 17 L). There were 36 deaths among the study cohort. The simplified BODE index was a prognostic marker, independent of cardiovascular comorbidities and oxygen desaturation (HR 1.12, confidence interval (CI) [1.03-1.22]). Individuals with simplified BODE index scores ≥ 7 were at higher risk of death from any cause (P < .001, log-rank test). CONCLUSIONS: This was the first study, to our knowledge, to show that the 4-min step test as a surrogate of exercise capacity in the BODE index (simplified BODE index) is an independent predictor of mortality in COPD and may help to spread its use among practicing physicians.

Heart rate recovery improvement in patients following acute myocardial infarction: exercise training, ß-blocker therapy or both.

Heart rate recovery (HRR) is a strong mortality predictor. Exercise training (ET) and ß-blocker therapy have significant impact on the HRR of patients following myocardial infarction (MI). However, the combination of ET and ß-blocker therapy, as well as its effectiveness in patients with a more compromised HRR (≤12 bpm), has been under-studied. Male patients (n = 64) post-MI were divided: Training + ß-blocker (n = 19), Training (n = 15), ß-blocker (n = 11) and Control (n = 19). Participants performed an ergometric test before and after 3 months of intervention. HRR was obtained during 5 min of recovery and corrected by the cardiac reserve (HRRcorrCR ). Compared to pre-intervention, HRRcorrCR was significantly increased during the 1st and 2nd minutes of recovery in the Training + ß-blocker group (70·5% and 37·5%, respectively; P<0·05). A significant improvement, lasting from the 1st to the 4th minute of recovery, was also observed in the Training group (47%, 50%, 25% and 8·7%, respectively; P<0·05). In contrast, the ß-blocker group showed a reduction in HRRcorrCR during the 2nd and 3rd minutes of recovery (-21·2% and -16·3%, respectively; P<0·05). In addition, interventions involving ET (Training + ßb, Training) were significantly more effective in patients with a pre-intervention HRR ≤ 12 bpm than for patients with HRR > 12 bpm. Combination of ß-blocker therapy with ET does not compromise the effect of training and instead promotes HRR and aerobic capacity improvement. In addition, this combination is particularly beneficial for individuals presenting with a more compromised HRR. However, chronic administration of ß-blocker therapy alone did not promote improvement in HRR or aerobic capacity.

Hyperadditive ventilatory response arising from interaction between the carotid chemoreflex and the muscle mechanoreflex in healthy humans.

Physical exercise potentiates the carotid chemoreflex control of ventilation (VE). Hyperadditive neural interactions may partially mediate the potentiation. However, some neural interactions remain incompletely explored. As the potentiation occurs even during low-intensity exercise, we tested the hypothesis that the carotid chemoreflex and the muscle mechanoreflex could interact in a hyperadditive fashion. Fourteen young healthy subjects inhaled randomly, in separate visits, 12% O2 to stimulate the carotid chemoreflex and 21% O2 as control. A rebreathing circuit maintained isocapnia. During gases administration, subjects either remained at rest (i.e., normoxic and hypoxic rest) or the muscle mechanoreflex was stimulated via passive knee movement (i.e., normoxic and hypoxic movement). Surface muscle electrical activity did not increase during the passive movement, confirming the absence of active contractions. Hypoxic rest and normoxic movement similarly increased VE [change (mean ± SE) = 1.24 ± 0.72 vs. 0.73 ± 0.43 l/min, respectively; P = 0.46], but hypoxic rest only increased tidal volume (Vt), and normoxic movement only increased breathing frequency (BF). Hypoxic movement induced greater VE and mean inspiratory flow (Vt/Ti) increase than the sum of hypoxic rest and normoxic movement isolated responses (VE change: hypoxic movement = 3.72 ± 0.81 l/min vs. sum = 1.96 ± 0.83 l/min, P = 0.01; Vt/Ti change: hypoxic movement = 0.13 ± 0.03 l/s vs. sum = 0.06 ± 0.03 l/s, P = 0.02). Moreover, hypoxic movement increased both Vt and BF. Collectively, the results indicate that the carotid chemoreflex and the muscle mechanoreflex interacted, mediating a hyperadditive ventilatory response in healthy humans. NEW & NOTEWORTHY The main finding of this study was that concomitant carotid chemoreflex and muscle mechanoreflex stimulation provoked greater ventilation increase than the sum of ventilation increase induced by stimulation of each reflex in isolation, which, consequently, supports that the carotid chemoreflex and the muscle mechanoreflex interacted, mediating a hyperadditive ventilatory response in healthy humans.

Effects of heart failure on cerebral blood flow in COPD: Rest and exercise.

Cerebral blood flow (CBF) and oxygenation (COx) are generally well-preserved in COPD. It is unknown whether prevalent cardiovascular co-morbidities, such as heart failure, may impair CBF and COx responses to exertion. Eighteen males with moderate-to-severe COPD (8 with and 10 without overlapping heart failure) underwent a progressive exercise test with pre-frontal CBF and COx measurements (indocyanine green and near-infrared spectroscopy). Mean arterial pressure and cardiac output were lower from rest to exercise in overlap. Only COPD patients demonstrated an increase in arterialized PCO2 towards the end of progressive exercise. CBF index was consistently higher and increased further by ∼40% during exercise in COPD whereas a ∼10% reduction was observed in overlap. COx was lower in overlap despite preserved arterial oxygenation. In conclusion, heart failure introduces pronounced negative effects on CBF and COx in COPD which may be associated with clinically relevant outcomes, including dyspnea, exercise intolerance, cerebrovascular disease and cognitive impairment.

The dysfunction of ammonia in heart failure increases with an increase in the intensity of resistance exercise, even with the use of appropriate drug therapy.

BACKGROUND: Hyperammonemia during rest periods is a dysfunction in heart failure (HF). The low formation of ammonia during exercise reflects an inefficiency of purine metabolism. Hyperkalemia in response to physical exercise is common in HF and may contribute to a contractile inefficiency in type II fibers, leading to early fatigue. We tested the hypothesis that during resistance exercise of high intensity and low volume, this disorder of ammonia metabolism would be more intense, due to the hyperkalemia present in HF. METHODS: Alternating resistance exercise (RE) of low intensity and high volume, and high intensity and low volume, were applied to 18 patients with an interval of 7 days between them (functional class II-III New York Heart Association, FE = 33.5 ± 4%) and compared with 22 healthy controls matched for age and gender. Ammonia, potassium and lactate levels were assessed before and immediately after the RE. RESULTS: Significant differences: Deltas (control vs. HF) in 40% RE: lactate (mg/dl) 26.3 ± 10 vs. 37.7 ± 7; p < 0,001, ammonia (ug/dl) 92.5 ± 18 vs. 48.9 ± 9; p < 0.001. Deltas (control vs. HF) in 80%RE: lactate(mg/dl) 45.0 ± 12 vs. 54.1 ± 11; p < 0.05, ammonia(ug/dl) 133.5 ± 22 vs. 32.2 ± 7; p < 0.001, potassium (mEq/L) 1.6 ± 0.4 vs. 2.0 ± 0.8; p < 0.05. A negative correlation was found between the deltas of ammonia and potassium (r = -0.74, p < 0.001) in the HF group. CONCLUSIONS: We conclude that in HF, there is an inefficiency of purine metabolism that increases with increasing exercise intensity, but not with an increase of total volume. These findings suggest that hyperkalemia may play an important role in the disorders of purine metabolism.