Maurizio Volterrani

Contribution of Muscle Afferents to the Hemodynamic, Autonomic, and Ventilatory Responses to Exercise in Patients With Chronic Heart Failure Effects of Physical Training

BACKGROUNDnA neural linkage between peripheral abnormalities and the exaggerated exercise responses in chronic heart failure (CHF) was postulated. We studied the ergoreceptors (afferents sensitive to skeletal muscle work) in CHF and whether training can affect their activity.nnnMETHODS AND RESULTSnIn 12 stable CHF patients (ejection fraction [EF] = 26.4%) and 10 control subjects (EF = 55.3%), we compared the responses to dynamic handgrip and during a 3-minute period of posthandgrip regional circulatory occlusion (PH-RCO). The ergoreflex contribution was quantified as the percentage responses to exercise maintained by PH-RCO compared with recovery without PH-RCO. Patients showed ergoreflex overactivation compared with control subjects in terms of ventilation (86.5% versus 54.5%), diastolic pressure (97.8% versus 53.5%), and leg vascular resistance (108.1% versus 48.9%) (all P < .05). The contribution of the ergoreflex to vagal withdrawal (high frequency of RR variability) and sympathetic activation (low frequency of RR, pressure variability) was evident in both groups. Nine control subjects and nine CHF patients participated in 6 weeks of forearm training. Training reduced the ergoreflex contributions more in CHF than in control subjects: diastolic pressure (-33.2% versus -4.6%), ventilation (-57.6% versus -24.6%), and leg vascular resistance (-59.9% versus -8.0%) (all P < .05).nnnCONCLUSIONSn(1) The ergoreflex role has a larger effect on the responses to exercise in CHF than in control subjects. (2) Training may reduce this exaggerated ergoreflex activity, thereby improving the responses to exercise.

Serum From Patients With Severe Heart Failure Downregulates eNOS and Is Proapoptotic Role of Tumor Necrosis Factor-α

BACKGROUNDnCytokine activation and endothelial dysfunction are typical phenomena of congestive heart failure (CHF). We tested the hypothesis that incubating human umbilical vein endothelial cells with serum from patients with CHF will downregulate endothelial constitutive nitric oxide synthase (eNOS) and induce apoptosis.nnnMETHODS AND RESULTSnWe studied 21 patients with severe CHF. Levels of tumor necrosis factor-alpha (TNF-alpha) and several neuroendocrine parameters were assessed. eNOS was measured by Western Blot analysis and apoptosis by optical microscopy and flow cytometry. We observed (1) eNOS downregulation (difference versus healthy subjects at 24 hours [P<0.05] and 48 hours [P<0.001]), (2) nuclear morphological changes typical of apoptosis; and (3) a high apoptotic rate with propidium iodide (increasing from 2.1+/-0.4% to 11.3+/-1.2% at 48 hours; P<0.001 versus healthy subjects) and annexin V. An anti-human TNF-alpha antibody did not completely counteract these effects. A strong correlation existed between eNOS downregulation and apoptosis (r = -0.89; P<0.001).nnnCONCLUSIONSnSerum from patients with severe CHF downregulates eNOS expression and increases apoptosis. High levels of TNF-alpha likely play a role, but they cannot be the only factor responsible.

Apoptosis in the skeletal muscle of patients with heart failure: investigation of clinical and biochemical changes

OBJECTIVE To investigate the contribution of apoptosis in the development of the skeletal myopathy in chronic heart failure. DESIGN The electrophoretic pattern of myosin heavy chains (MHC), fibre cross sectional area, number of in situ nick end labelling (TUNEL) positive apoptotic myocyte nuclei, and the tissue levels of caspase-3, Bcl-2, and ubiquitin were determined in biopsies taken from the vastus lateralis muscle. The study involved nine patients with severe chronic heart failure caused by ischaemic heart disease and hibernating myocardium and five controls. RESULTS In chronic heart failure patients the vastus lateralis showed a significant increase of MHC2a and MHC2b and a greater degree of fibre atrophy, as demonstrated by the decreased cross sectional area. There was also an increased number of TUNEL positive apoptotic myocyte nuclei. Tissue concentrations of Bcl-2 were decreased, while those of caspase-3 and ubiquitin were increased. Peak oxygen consumption (Vo 2) was negatively correlated with the number of TUNEL positive nuclei and the fibre cross sectional area. There was a correlation between the number of apoptotic nuclei and the fibre cross sectional area, but no correlation between myosin heavy chains and number of apoptotic nuclei. CONCLUSIONS Myocyte apoptosis occurs in the skeletal muscle of patients with chronic heart failure, and its magnitude is associated with the severity of exercise capacity limitation and the degree of muscle atrophy. Muscle atrophy contributes to the limitation of exercise capacity, together with the increased synthesis of fast, more fatiguable myosin heavy chains.

Estrogen acutely increases peripheral blood flow in postmenopausal women

PURPOSEnTo test the acute effect of estrogen on peripheral blood flow and vascular resistance in postmenopausal women.nnnPATIENTS AND METHODSnEleven normotensive, post-menopausal female volunteers (mean age 53 +/- 6 years) were studied. Six women were in natural menopause and 5 had had a hysterectomy (mean age of the menopause 49 +/- 3 years). We used a double-blind, randomized protocol to assess the acute response to sublingual estradiol-17 beta (1 mg) on the forearm resistance vessels, compared with sublingual placebo. Blood flow was measured by strain-gauge plethysmography, and mean peripheral vascular resistance was then calculated. Mean blood pressure was also measured.nnnRESULTSnThe mean blood flow induced by estradiol-17 beta after 40 minutes was significantly greater than that induced by placebo (3.9 +/- 0.5 mL/100 mL per minute versus 2.4 +/- 0.4 mL/100 mL per minute, respectively, P < 0.05). The forearm resistance was significantly reduced at 40 minutes after estradiol-17 beta compared with placebo (25.7 +/- 4.4 resistance units (RU) to 44.4 +/- 6.4 RU, respectively, P < 0.05). Mean blood pressure 40 minutes after the administration of estradiol-17 beta was no different when compared with placebo (91 +/- 1.5 mm Hg versus 90 +/- 2.5 mm Hg, respectively, P = NS).nnnCONCLUSIONSnThese results indicate that the acute administration of estradiol-17 beta affects blood flow in the peripheral vasculature in human subjects. The mechanism of this effect has not been determined, but it may explain some of the beneficial effects of estrogen on the vascular system and have future therapeutic potential in postmenopausal women.

Improved exercise tolerance after losartan and enalapril in heart failure: Correlation with changes in skeletal muscle myosin heavy chain composition

BACKGROUNDnIn congestive heart failure, fatigue-resistant, oxidative, slow type I fibers are decreased in leg skeletal muscle, contributing to exercise capacity (EC) limitation. The mechanisms by which ACE inhibitors and AII antagonists improve EC is still unclear. We tested the hypothesis that improvement in EC is related to changes in skeletal muscle composition toward type I fibers.nnnMETHODS AND RESULTSnEight patients with congestive heart failure, NYHA classes I through IV, were treated for 6 months with enalapril (E) 20 mg/d, and another 8 with losartan (L) 50 mg/d. EC was assessed with maximal cardiopulmonary exercise testing at baseline and after treatment. Myosin heavy chain (MHC) composition of the gastrocnemius was studied after electrophoretic separation of slow MHC1, fast oxidative MHC2a, and fast glycolytic MHC2b isoforms from needle microbiopsies obtained at baseline and after 6 months. EC improved in both groups. Peak V(O2) increased from 21.0+/-4.7 to 27.6+/-4.3 mL . kg-1 . min -1 (P=0.011) in the L group and from 17.5+/-5.0 to 25.0+/-5.5 mL . kg-1 . min -1 (P=0.014) in the E group. Similarly, ventilatory threshold changed from 15.0+/-4.0 to 19.9+/-4.9 mL (P=0. 049) with L and from 12.0+/-1.9 to 15.4+/-3.5 mL (P=0.039) with E. MCH1 increased from 61.2+/-11.2% to 75.4+/-7.6% with L (P=0.012) and from 60.6+/-13.1% to 80.1+/-10.9% (P=0.006) with E. Similarly, MHC2a decreased from 21.20+/-9.5% to 12.9+/-4.4% (P=0.05) with L and from 19.9+/-7.8% to 11.8+/-7.9% (P=0.06) with E. MHC2b changed from 17. 5+/-6.5% to 11.7+/-5.2% (P=0.07) with L and from 19.5+/-6.4% to 8. 1+/-4.6% (P=0.0015) with E. There was a significant correlation between net changes in MHC1 and absolute changes in peak V(O2) (r2=0.29, P=0.029) and a trend to significance for MHC2a and 2b.nnnCONCLUSIONSnSix months treatment with L and with E produces an improvement in EC of similar magnitude. These changes are accompanied by a reshift of MHCs of leg skeletal muscle toward the slow, more fatigue-resistant isoforms. Magnitude of MHC1 changes correlates with the net peak V(O2) gain, which suggests that improved EC may be caused by favorable biochemical changes occurring in the skeletal muscle.

Leg blood flow, metabolism and exercise capacity in chronic stable heart failure

OBJECTIVESnTo assess the metabolic state of skeletal muscle during exercise in patients with chronic heart failure (CHF) and relate this to exercise capacity.nnnBACKGROUNDnDuring exercise in CHF, there is little relation between exercise capacity and central haemodynamic function. Skeletal muscle and limb blood flow are abnormal in CHF. We investigated the relationship between leg blood flow, metabolism and exercise capacity and ventilation in 10 patients (average age 63.3 +/- 6.0 years; 3 female) with stable CHF.nnnMETHODSnPatients undertook maximal exercise testing. Peak oxygen consumption (VO2) and the slope of the relationship between ventilation and carbon dioxide production (VE/CO2 slope) were derived. During a supine cycle exercise test, cardiac output (CO) by Doppler echocardiography, femoral blood flow (FBF) by thermodilution, pulse and blood pressure were recorded, and radial arterial and femoral venous blood samples taken for catecholamine, lactate and potassium estimation every 3 min.nnnRESULTSnThe average peak VO2 was 19.7 (+/- 5.2; range 11.3-29.0) ml/kg/min. The proportion of CO to the right leg increased from 0.08 (+/- 0.03) to 0.22 (+/- 0.06) (P < 0.001) at 3 min, with no further significant change thereafter. There was a liner increase in leg VO2 reaching a plateau towards peak. At peak, femoral venous saturation was 22.79% +/- 7.20%. Venous lactate and potassium were higher than arterial (P < 0.001 for each comparison). There was no correlation between exercise performance and any of the measured metabolites either in absolute measurements, expressed as change from rest to peak exercise or as arterio-venous difference. The closest correlate of leg VO2 was leg hydrogen ion production, V[H+]. Change in femoral venous lactate from rest to peak exercise correlated with VE/VCO2 slope even when calculated from before the anaerobic threshold (r = -0.80; P = 0.025).nnnCONCLUSIONSnIn CHF, exercise capacity is not determined by individual haemodynamic events, and does not seem to be determined by the possible humoral signals we investigated. Ventilation is abnormal before anaerobic threshold, and predicts subsequent lactate rise, suggesting that skeletal muscle is the origin of excessive ventilation.

Ventilation-perfusion matching in chronic heart failure

BACKGROUNDnThe exercise limitation of patients with chronic heart failure is associated with an increased ventilatory response during exercise. This is thought to be due, at least in part, to excessive dead space ventilation.nnnMETHODSnTo assess ventilation perfusion matching, 20 patients with chronic heart failure and eight controls with asymptomatic left ventricular dysfunction underwent symptom limited treadmill exercise with arterial blood sampling. Metabolic gas exchange was determined by expired gas analysis. Fractional dead space ventilation and the alveolar arterial oxygen difference were derived.nnnRESULTSnThere was a fall in fractional dead space ventilation (0.43 to 0.28; P < 0.001), more marked in the controls (peak dead space fraction 0.19 (controls), 0.32 (patients); P = 0.002). There was a rise in alveolar arterial difference in all patients (1.59 to 2.55 kPa; P = 0.006) with no difference between patients and controls. Arterial carbon dioxide tension fell during exercise (4.89 to 4.63 kPa; P < 0.001), with no difference between patients and controls. There was no significant change in arterial oxygen tension.nnnCONCLUSIONSnThe fall in arterial carbon dioxide was the same in both patients and controls. The modest increase in alveolar-arterial oxygen difference tension was the same in both groups, which, coupled with the stable arterial oxygen tension makes it unlikely that a primary change in ventilation-perfusion matching is the cause of increased ventilatory response to exercise in chronic heart failure.

Physiological Basis for Contractile Dysfunction in Heart Failure

The purpose of this review is to enlighten the mechanisms of skeletal muscle dysfunction in heart failure. The muscle hypothesis suggests that chronic heart failure (CHF) symptoms, dyspnoea and fatigue are due to skeletal muscle alterations. Hyperventilation due to altered ergoreflex seems to be the cause of shortness of breath. Qualitative and quantitative changes occurring in the skeletal muscle, such as muscle wastage and shift from slow to fast fibers type, are likely to be responsible for fatigue. Mechanisms leading to muscle wastage in chronic heart failure, include cytokine-triggered skeletal muscle apoptosis, but also ubiquitin/proteasome and non-ubiquitin-dependent pathways. The regulation of fibre type involves the growth hormone/insulin-like growth factor 1/calcineurin/ transcriptional coactivator PGC1 cascade. The imbalance between protein synthesis and degradation plays an important role. Protein degradation can occur through ubiquitin-dependent and non-ubiquit-independent pathways. Systems controlling ubiquitin/ proteasome activation have been described. These are triggered by tumour necrosis factor and growth hormone/ insulin-like growth factor 1. However, an important role is played by apoptosis. In humans, and experimental models of heart failure, programmed cell death has been found in skeletal muscle and interstitial cells. Apoptosis is triggered by tumour necrosis factor and in vitro experiments have shown that it can be induced by its second messenger sphingosine. Apoptosis correlates with the severity of the heart failure syndrome. It involves activation of caspases 3 and 9 and mitochondrial cytochrome c release. Sarcomeric protein oxidation and its consequent contractile impairment can form another cause of skeletal muscle dysfunction in CHF.

Factors which alter the relationship between ventilation and carbon dioxide production during exercise in normal subjects.

AbstractThe slope of the linear relationship between ventilation n