Inspiratory muscle training reduces sympathetic nervous activity and improves inspiratory muscle weakness and quality of life in patients with chronic heart failure: a clinical trial.

PURPOSE: To evaluate the effect of inspiratory muscle training (IMT) on cardiac autonomic modulation and on peripheral nerve sympathetic activity in patients with chronic heart failure (CHF). METHODS: Functional capacity, low-frequency (LF) and high-frequency (HF) components of heart rate variability, muscle sympathetic nerve activity inferred by microneurography, and quality of life were determined in 27 patients with CHF who had been sequentially allocated to 1 of 2 groups: (1) control group (with no intervention) and (2) IMT group. Inspiratory muscle training consisted of respiratory exercises, with inspiratory threshold loading of seven 30-minute sessions per week for a period of 12 weeks, with a monthly increase of 30% in maximal inspiratory pressure (PI(max)) at rest. Multivariate analysis was applied to detect differences between baseline and followup period. RESULTS: Inspiratory muscle training significantly increased PI(max) (59.2 ± 4.9 vs 87.5 ± 6.5 cmH(2)O, P = .001) and peak oxygen uptake (14.4 ± 0.7 vs 18.9 ± 0.8 mL·kg(-1)·min(-1), P = .002); decreased the peak ventilation (VE)/carbon dioxide production (VCO(2)) ratio (35.8 ± 0.8 vs 32.5 ± 0.4, P = .001) and the VE/VCO(2) slope (37.3 ± 1.1 vs 31.3 ± 1.1, P = .004); increased the HF component (49.3 ± 4.1 vs 58.4 ± 4.2 normalized units, P = .004) and decreased the LF component (50.7 ± 4.1 vs 41.6 ± 4.2 normalized units, P = .001) of heart rate variability; decreased muscle sympathetic nerve activity (37.1 ± 3 vs 29.5 ± 2.3 bursts per minute, P = .001); and improved quality of life. No significant changes were observed in the control group. CONCLUSION: Home-based IMT represents an important strategy to improve cardiac and peripheral autonomic controls, functional capacity, and quality of life in patients with CHF.

Comparison of enoxaparin and unfractionated heparin on thrombin generation in acute coronary syndromes without ST-segment elevation.

Recent clinical trials have demonstrated a better ability of low-molecular-weight heparin, compared to unfractionated heparin, in reducing ischemic cardiac events in patients with acute coronary syndromes without ST-segment elevation. No data are available concerning the in-vivo comparison of enoxaparin and unfractionated heparin on thrombin generation in patients with unstable angina or non-Q-wave myocardial infarction. We measured the plasma levels of prothrombin fragment 1+2 (a marker of prothrombin activation) and thrombin/antithrombin complex (a marker of thrombin generation) in 45 patients with non ST-elevation acute coronary syndromes who were randomized to receive enoxaparin, 3000 IU anti-Xa as an i. v. bolus, followed by 70 IU anti-Xa/Kg every 8 h for 3 days (23 pts. Group 1) or a bolus of 100 IU/kg of unfractionated heparin followed by infusion for 3 days titrated to maintain the aPTT between 70 and 90 s (22 pts, Group 2). Plasma levels of prothrombin fragment 1+2 reduced significantly at 3rd h of treatment in both groups (-42% in Group 1 and -45% in Group 2), reached the lowest plasma concentration at the 24th h and exhibited a slight increase at the 72nd h; no differences were observed between the two groups at any time points. Plasma thrombin/antithrombin complex levels had a similar behaviour: reduced markedly in both groups at the 3rd h (-52% in Group 1 and -46% in Group 2), remained lower during the first two days and slightly rose at 72nd h. No differences between the two groups in plasma levels of this marker were apparent during drug infusion. In Group 1 the aPTT did not show significant changes: in Group 2 the mean value of aPTT doubled the basal value at any time point of determination. Both enoxaparin and unfractionated heparin produced a marked and similar reduction of thrombin generation. Other unknown mechanisms might explain the different clinical effects of the two heparins.

Circulatory response to fluid overload removal by extracorporeal ultrafiltration in refractory congestive heart failure.

OBJECTIVES: The goal of this study was to investigate the hemodynamic and circulatory adjustments to extracorporeal ultrafiltration (UF) in refractory congestive heart failure (rCHF). BACKGROUND: In rCHF, UF allows clinical improvement and restores diuretic efficacy. However, in the course of a UF session, patients are exposed to rapid variations of body fluid composition so that, as fluid is withdrawn from the intravascular compartment, hypotension or even shock could occur. METHODS: In 24 patients with rCHF undergoing UF, we measured, after every liter of plasma water removed, hemodynamics, blood gas analysis (in both systemic and pulmonary arteries), plasma volume changes (PV) and plasma refilling rate (PRR). The PV and PRR were calculated by considering hematocrit and ultrafiltrate volume. RESULTS: In all patients, UF was performed safely, without side effects or hemodynamic instability (ultrafiltrate = 4,880 +/- 896 ml). Mean right atrial, pulmonary artery and wedge pressures progressively reduced during the procedure. Cardiac output increased at the end of the procedure and, to a greater extent, 24 h later, in relation to the increase of stroke volume. Heart rate and systemic vascular resistance did not increase, and other peripheral biochemical parameters did not worsen during UF. Intravascular volume remained stable throughout the entire duration of the procedure, indicating that a proportional volume of fluid was refilled from the congested parenchyma. CONCLUSIONS: In patients with rCHF, subtraction of plasma water by UF is associated with hemodynamic improvement. Fluid refilling from the overhydrated interstitium is the major compensatory mechanism for intravascular fluid removal, and hypotension does not occur when plasma refilling rate is adequate to prevent hypovolemia.

Cardiac and renal dysfunction in chronic heart failure: relation to neurohumoral activation and prognosis.

BACKGROUND: In chronic heart failure (CHF), cardiac dysfunction is considered the major determinant of neurohumoral activation but the role of renal impairment has not been defined. We investigated the relationship between both cardiac and renal dysfunction and neurohumoral activation, and their possible influence on prognosis. METHODS: Hemodynamics, renal function, plasma neurohormones, and long-term follow-up were evaluated in 148 CHF patients, grouped according to systolic volume index (SVI) and serum creatinine (CRE) values: SVI > 28 mL/m2 and CRE < 1.5 mg/dL (group I, n = 55), SVI < 28 mL/m2 and CRE < 1.5 mg/dL (group II, n = 37), SVI > 28 mL/m2 and CRE > 1.5 mg/dL (group III, n = 25), SVI < 28 mL/m2 and CRE > 1.5 mg/dL (group IV, n = 31). RESULTS: Neurohormones progressively increased from Group I through IV and correlated with both cardiac and renal function. The hemodynamic pattern was similar in patients with normal or abnormal renal function, whereas neurohormones were only moderately increased in the former group and markedly increased in the latter group. Long-term survival progressively decreased from Group I through IV and was significantly poorer in patients with renal dysfunction. CONCLUSIONS: Our study confirms that, in CHF, neurohumoral activation is strictly related to long-term survival and that many factors contribute to its development and progression; among these, cardiac and renal dysfunction seem to play a major role.

Lack of improvement of lung diffusing capacity following fluid withdrawal by ultrafiltration in chronic heart failure.

OBJECTIVES: We sought to investigate the possibility that lung diffusing capacity reduction observed in chronic heart failure is reversible in the short term. BACKGROUND: Mechanical properties of the lung usually ameliorate with antifailure treatment including drugs, ultrafiltration and heart transplantation, whereas lung diffusion rarely improves. METHODS: We studied the mechanical properties of the lung (pulmonary function tests with determination of alveolar volume, extravascular lung fluids and lung tissue), lung diffusion for carbon monoxide (DLco), including membrane diffusing capacity (Dm), pulmonary capillary blood volume (Vc) and pulmonary hemodynamics, in 28 patients with stable chronic heart failure, before a single session of extracorporeal ultrafiltration (3,973 +/- 2200 ml) and four days thereafter. Lung mechanics and diffusion were also evaluated in 18 normal subjects. RESULTS: Vital capacity, forced expiratory volume (1 s) and maximal voluntary ventilation were lower in patients when compared with normal subjects, and increased after ultrafiltration from 2.1 +/- 0.7 to 2.5 +/- 0.7(1)*, 1.7 +/- 0.5 to 2.0 +/- 0.6(1)* and 67 +/- 25 to 79 +/- 26 (1/min)*, respectively (* p < 0.02 vs. pre-ultrafiltration). Post-ultrafiltration alveolar volume was augmented, while lung tissue, body weight (approximately 6 kg), chest X-ray extravascular lung water score and pulmonary vascular pressure were reduced. Heart dimensions (echocardiography) remained unchanged. DLco, Dm and Vc were 29.0 +/- 5.0 ml/min/mm Hg, 47.0 +/- 11.0 ml/min/mm Hg, 102 +/- 20 ml in normal subjects and 17.1 +/- 4.0#, 24.1 +/- 6.5#, 113 +/- 38 and 17.0 +/- 5.0#, 24.8 +/- 7.9#, 100 +/- 39 in patients before and after ultrafiltration, respectively (# = p < 0.01 vs. controls). CONCLUSIONS: In chronic heart failure, ultrafiltration improves volumes and mechanical properties of the lung by reducing lung fluids. Diffusion is unaffected by ultrafiltration, suggesting that, in chronic heart failure, the alveolar-capillary membrane abnormalities are fluid-independent.

[Platelet activation in the early phases of acute myocardial infarction]. / Attivazione piastrinica nelle prime fasi dell'infarto miocardico acuto.

Myocardial infarction and thrombolysis are proven to be associated with platelet activation. However, the time relationship of platelet activation with the onset of symptoms and with thrombolysis, and the response to aspirin are not well defined. In this study we measured platelet activity in the early phase of myocardial infarction treated with either streptokinase or recombinant tissue-type plasminogen activator (rt-PA) and evaluated whether and to what extent it may be counteracted by aspirin. Fourty-one patients (mean age 57 +/- 6 years) received thrombolytic therapy after coronary occlusion: 1.5 million units of streptokinase (Group 1; 21 patients) or 100 mg of rt-PA (Group 2; 20 patients). Ten randomly selected patients in either group were given 500 mg aspirin i.v. prior to infusion of the thrombolytic compound and, then, 325 mg/die of aspirin orally. Beta-thromboglobulin (BTG), a marker of platelet activity, was determined at admission, after thrombolysis and in the subsequent 48 hours. At admission, BTG plasma levels averaged 125 +/- 31 IU/ml in Group 1 and 134 +/- 35 IU/ml in Group 2 (NS). Thrombolysis produced a similar increase in platelet activity in both groups, and maximal values were reached at the third hour (196 +/- 43 IU/ml in Group 1 and 192 +/- 39 in Group 2, p < 0.001 vs baseline and NS between groups). Levels of BTG were higher in streptokinase-treated group starting from 24 hours (p < 0.05). Differences in BTG levels between aspirin-treated and aspirin-untreated patients became significant at 48 hours after thrombolysis in both groups. An inverse correlation was found between time elapsed from onset of symptoms and BTG value on admission (r = -0.86, p < 0.001); in patients admitted within 2 hours after the beginning of symptoms, and having the higher BTG levels, thrombolysis did not induce a significant increase in platelet activity; this, on the contrary, was observed in patients admitted later. Platelet activation is greater early after myocardial infarction and is differently influenced by thrombolytic treatment, depending on the delay of the patient's admission. Streptokinase and rt-PA induce a similar increase in platelet activity which is more persistent after streptokinase; cycloxygenase inhibition with aspirin seems to influence platelet activity only starting from the second day.

[Intra- and extravascular volumes in congestive heart failure and their redistribution following extracorporeal ultrafiltration]. / Volumi intra ed extravascolari nello scompenso cardiaco congestizio refrattario e loro ridistribuzione a seguito di ultrafiltrazione extracorporea.

In advanced congestive heart failure with fluid retention, extracorporeal ultrafiltration (UF) causes persistent relief of edema or anasarca through hemodynamic and humoral changes that interrupt refractoriness to diuretics. The intra and extravascular fluid partition in congestive heart failure, as well as changes occurring in the two compartments following fluid withdrawal with UF, are unknown. In 8 congestive heart failure patients with severe fluid retention undergoing UF, we measured total (TBV), intrathoracic (ITBV) and pulmonary blood volumes (PBV), and extravascular lung water (EVLW). The intra and extravascular volumes were evaluated by a fiberoptic thermal dye dilution monitoring system, before, at the end of UF (3697 +/- 699 ml) and 24 hours later. Baseline data were compared with those of 10 subjects without heart failure undergoing coronary bypass surgery. In congestive heart failure patients, as compared with controls, TBV was normal, the intrathoracic blood content (ITBV, PBV and PBV/TBV ratio) was increased and EVLW was normal. UF did not induce significant changes in TBV and in EVLW, and reduced ITBV, PBV and PBV/TBV ratio, suggesting that a shift of fluid from the intra to the extrathoracic intravascular compartment occurred. Because both TBV and EVLW were not affected by the procedure, the largest proportion of fluid removed by UF derived from the systemic extravascular space. Both pulmonary wedge and right atrial pressures significantly decreased after UF, and cardiac output increased. In conclusion, congestive heart failure is associated with normal TBV and EVLW content and with intravascular intrathoracic hypervolemia and extrathoracic hypovolemia. UF induces hemodynamic improvement through a selective fluid removal from the extravascular systemic space without changes in both TBV and EVLW.

[Mechanisms facilitating oxygen delivery during exercise in patients with chronic heart failure]. / Meccanismi di facilitazione della cessione di ossigeno durante esercizio nel paziente con scompenso cardiaco cronico]

The aim of the study was to estimate the relative importance of the Bohr effect and redistribution of blood from the non-exercising tissues on the arterial-venous oxygen content differences across the exercising extremities and the central circulation in patients with chronic heart failure; the relationship among femoral vein, systemic and pulmonary artery oxygen partial pressure and hemoglobin saturation was determined. It has been reported that the maximal reduction in femoral vein pO2 precedes peak oxygen consumption and lactic acidosis threshold in patients with chronic heart failure and normal subjects during exercise. The increase in oxygen consumption at work rates above lactic acidosis threshold, therefore, must be accounted for by increase in blood flow in the exercising muscles and right-ward shift on the oxyhemoglobin dissociation curve. Since the total cardiac output increase is blunted in patients with chronic heart failure, diversion of blood flow from non-exercising to exercising tissues may account for some of the increase in muscle blood flow. Ten patients with chronic heart failure performed a progressively increasing leg cycle ergometer exercise test up to maximal effort while measuring ventilation and gas concentration for computation of oxygen uptake and carbon dioxide production, breath-by-breath. Blood samples were obtained, simultaneously, from systemic and pulmonary arteries and femoral vein at rest and every minute during exercise to peak oxygen consumption. At comparable levels of exercise, femoral vein pO2, hemoglobin saturation and oxygen content were lower than in the pulmonary artery. PCO2 and lactate concentration increased steeply in femoral vein and pulmonary artery blood above lactic acidosis threshold (due to lactic acid build-up and buffering), but more steeply in femoral vein blood. These increases allowed femoral vein oxyhemoglobin to dissociate without a further decrease in femoral vein pO2 (Bohr effect). The lowest femoral vein pO2 (16.6 +/- 3.9 mmHg) was measured at 66 +/- 22% of peak VO2 and before the lowest oxyhemoglobin saturation was reached. Artero-venous oxygen content difference was higher in the femoral vein than in the pulmonary artery; this difference became progressively smaller as oxygen consumption increased. "Ideal" oxygen consumption for a given cardiac output (oxygen consumption expected if all body tissues had maximized oxygen extraction) was always higher than the measured oxygen consumption; however the difference between the two was lost at peak exercise. This difference positively correlated with peak oxygen consumption and cardiac output increments at submaximal but not at maximal exercise. In conclusion, femoral vein pO2 reached its lowest value at a level of exercise at or below the lactic acidosis threshold. Further extraction of oxygen above the lactic acidosis threshold was accounted for by a right shift of the oxyhemoglobin dissociation curve. The positive correlation between increments of cardiac output vs "ideal" and measured oxygen consumption suggests a redistribution of blood flow from non-exercising to exercising regions of the body. Furthermore the positive correlation between exercise capacity and the difference between "ideal" and measured oxygen consumption suggests that patients with the poorer function have the greater capability to optimize blood flow redistribution during exercise.

[The influence of ACE inhibitors on urinary electrolyte secretion and the response to transitory hypovolemia in chronic heart failure]. / Influenza dell' ACE-inibizione sull'escrezione elettrolitica urinaria e sul suo adattamento all'ipovolemia transitoria nello scompenso cardiaco cronico.

Renin-angiotensin system promotes sodium and chloride retention, participates in the defense response to hypovolemia and, in congestive heart failure, contributes to edema formation and progression of the disease. We investigated whether ACE-inhibitors interfere with the action of the renin-angiotensin system on the nephron, and therefore with water and urinary electrolytes excretion. The interaction among renin-angiotensin system, diuretic treatment and urinary electrolytes was evaluated both during chronic treatment and in response to acute renin-angiotensin system activation as that observed after extracorporeal ultrafiltration-induced transient hypovolemia. Plasma renin activity and aldosterone, body fluid balance and urinary sodium, chloride and potassium concentrations were evaluated in 30 patients with congestive heart failure in NYHA II-III functional class, grouped according to whether long-term therapy did not include (Group I, n = 15) or included (Group II, n = 18) ACE-inhibitors. All parameters were evaluated at baseline and after a single session of extracorporeal ultrafiltration. At baseline, urinary output and urinary sodium and chloride concentrations were similar in the two groups, while urinary potassium concentration was lower in patients assuming ACE-inhibitors (Group II). Plasma renin activity was higher and aldosterone was lower in Group II than in Group I. After removal of similar amounts of plasma water by extracorporeal ultrafiltration, body weight decreased in both groups but the decrease was maintained in the following days only in Group II patients. A transient reduction (48 hours) of both plasma volume and urinary output was observed after ultrafiltration in both groups. Despite plasma renin activity and aldosterone increase, urinary electrolytes response to ultrafiltration was different in the two groups: sodium and chloride were reduced, and potassium did not change in Group 1 while, in Group II, sodium and chloride did not change and potassium excretion was significantly increased. In conclusion, chronic treatment with ACE-inhibitors does not enhance the excretion of sodium in congestive heart failure but just mitigates potassium loss. The role of these drugs becomes particularly relevant during acute renin-angiotensin system activation due to hypovolemia; in this setting ACE-inhibitors counteract sodium and chloride retention resulting in a potential hazard due to interference with the defence mechanisms toward hypovolemia, and an amplification of extracorporeal ultrafiltration efficacy by preventing edema recovery after its mechanical removal.

[Interrelation of plasma volume, fluid metabolism and neurohormonal activation after ultrafiltration in congestive heart failure]. / Interrelazione tra volume plasmatico, metabolismo idrico ed attivazione neurormonale dopo ultrafiltrazione nello scompenso cardiaco congestizio.

Ultrafiltration improves the clinical condition of patients with congestive heart failure (CHF) through a reduction of excessive body water. We investigated the relationships among intra and extravascular fluids, hemodynamics and neurohumoral pattern following plasma water subtraction. In 55 patients with CHF (35 in NYHA class IV, Group A, and 20 in NYHA class II-III, Group B), removal of 3242 +/- 201 ml and 1741 +/- 119 ml of plasma water acutely reduced plasma volume (calculated from hematocrit changes) by -20.7% and -12.9% in Group A and in Group B, respectively. Plasma volume returned to baseline values within 48 hours. Body weight and ventricular filling pressures also lowered and remained so for 2 days. After ultrafiltration urinary output increased and norepinephrine, renin activity and aldosterone plasma levels decreased in Group A, while a fall of diuresis and a rapid rise of plasma levels of the 3 hormones were observed in Group B. Two days after ultrafiltration the persistence of reduced body weight with recovery of plasma volume indicates a shift of fluid from the extravascular to the intravascular compartment. The different behaviour of hemodynamics, urinary output and neurohumoral pattern changes observed in the 2 groups after ultrafiltration, suggest that in severe heart failure (Group A) the physiological responses to intravascular volume depletion are unsettled while are preserved in less severe stages of the disease (Group B).