Transition from asymptomatic left ventricular dysfunction to congestive heart failure.

One of the main goals of modern management and care of heart failure is to prevent the disease to progress toward congestion and death. The achievement of such an objective may, in fact, guarantee a sufficient quality of life and reduce the exposure of patients to the most common life-threatening complications associated with the congestive stage of the disease. Early identification of left ventricular dysfunction as well as a better knowledge of the mechanisms that favor the progression to more advanced stages of heart failure are fundamental requirements for the proper treatment of asymptomatic heart failure and for preventing the transition to symptomatic and more severe heart failure. The authors reviewed the literature on this topic, with emphasis on a series of studies they performed, to characterize the pathophysiologic profile of mild heart failure and the mechanisms that are possibly involved in the progression to congestive heart failure.

Blood levels of erythropoietin in congestive heart failure and correlation with clinical, hemodynamic, and hormonal profiles.

Plasma levels of erythropoietin (mU/ml) were measured in patients with congestive heart failure (CHF) (n = 108) and in a control group of normal subjects (n = 45). In normal subjects, plasma levels of erythropoietin were 1.9 +/- 0.2. In patients with CHF, plasma levels of erythropoietin increased progressively according to New York Heart Association (NYHA) class (I: 1.4 +/- 0.2, n = 28; II: 5.4 +/- 0.8, n = 27; III: 9.6 +/- 2, n = 32; IV: 34 +/- 8, n = 21; F = 57.7, p < 0.001) and were significantly higher in NYHA classes II, III, and IV than in normal subjects. Plasma erythropoietin significantly decreased (from 43 +/- 14 to 12 +/- 3 mU/ml, p < 0.01) in patients with severe CHF (n = 9) when enalapril (20 mg/day administered orally) was added to long-term treatment for 3 weeks. Finally, in a subgroup of patients with NYHA class IV CHF (n = 9) and high plasma erythropoietin levels (37 +/- 9 mU/ml), packed red blood cell volume, assessed by the iodine-125-albumin dilution method, was higher than that in normal subjects (n = 11) (2,616 +/- 235 vs 2,028 +/- 119 ml, p < 0.05). The present study demonstrates that plasma erythropoietin levels are elevated in a large cohort of patients with CHF of varying etiology, and that this increase is related to the progression of the disease. The increase in circulating erythropoietin is associated with augmented packed red blood cell volume in patients with severe CHF. These results suggest a participation of erythropoietin in the complex neurohormonal response that occurs in CHF.

Abnormalities of sodium handling and of cardiovascular adaptations during high salt diet in patients with mild heart failure.

BACKGROUND: Sodium retention and hormonal activation are fundamental hallmarks in congestive heart failure. The present study was designed to assess the ability of patients with asymptomatic to mildly symptomatic heart failure and no signs or symptoms of congestion to excrete ingested sodium and to identify possible early abnormalities of hormonal and hemodynamic mechanisms related to sodium handling. METHODS AND RESULTS: The effects of a high salt diet (250 mEq/day for 6 days) on hemodynamics, salt-regulating hormones, and renal excretory response were investigated in a balanced study in 12 untreated patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (NYHA class I-II, ejection fraction < 50%) (HF) and in 12 normal subjects, who had been previously maintained a 100 mEq/day NaCl diet. In normal subjects, high salt diet was associated with significant increases of echocardiographically measured left ventricular end-diastolic volume, ejection fraction, and stroke volume (all P < .001) and with a reduction of total peripheral resistance (P < .001). In addition, plasma atrial natriuretic factor (ANF) levels increased (P < .05), and plasma renin activity and aldosterone concentrations fell (both P < .001) in normals in response to salt excess. In HF patients, both left ventricular end-diastolic and end-systolic volumes increased in response to high salt diet, whereas ejection fraction and stroke volume failed to increase, and total peripheral resistance did not change during high salt diet. In addition, plasma ANF levels did not rise in HF in response to salt loading, whereas plasma renin activity and aldosterone concentrations were as much suppressed as in normals. Although urinary sodium excretions were not significantly different in the two groups, there was a small but systematic reduction of daily sodium excretion in HF, which resulted in a significantly higher cumulative sodium balance in HF than in normals during the high salt diet period (P < .001). CONCLUSIONS: These results show a reduced ability to excrete a sodium load and early abnormalities of cardiac and hemodynamic adaptations to salt excess in patients with mild heart failure and no signs or symptoms of congestion.

Hormonal profile in mild heart failure.

Neurohormonal activation is a fundamental component in the pathophysiology of congestive heart failure. In fact it represents a mechanism consecutive to cardiac dysfunction that favours the development of congestion and of further heart failure through vasoconstriction and water and salt retention. The time of onset and the mechanisms responsible for neurohormonal activation in heart failure are not defined. This brief article reviews this topic and summarizes the findings of studies that investigated the dynamic adaptations of hormonal mechanisms in the milder or initial stages of heart failure. An early characterization and detection of the abnormalities of the hormonal responses to salt or volume changes may be useful for a better comprehension and the treatment of the initial stage of the disease.

Angiotensin converting enzyme inhibition restores cardiac and hormonal responses to volume overload in patients with dilated cardiomyopathy and mild heart failure.

BACKGROUND: Angiotensin converting enzyme (ACE) inhibition exerts a favorable effect on the response to exercise in heart failure. This study was planned to define the influence of ACE inhibition on the adaptation to volume overload. METHODS AND RESULTS: We studied the hemodynamic, hormonal, and renal responses to acute volume expansion (sodium chloride, 0.9%, 0.25 ml.kg-1.min-1 for 2 hours) in patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (New York Heart Association class I or II, ejection fraction < or = 50%). The patients were studied without any pretreatment (n = 14) or after 1 week of treatment with the oral ACE inhibitor quinapril at a dosage of 10 mg/day (n = 11). Seven patients were studied during constant intravenous infusion with nitroglycerin (0.1 micrograms.kg-1.min-1). The study groups had similar hemodynamic and clinical characteristics and hormonal profile at baseline evaluation. In the untreated patients, volume expansion did not increase left ventricular end-diastolic volume measured by echocardiography and was associated with a reduction in ejection fraction (p < 0.05) and with a paradoxical increase in forearm vascular resistance (p < 0.05) estimated by plethysmography. In addition, plasma atrial natriuretic factor did not change, and plasma norepinephrine was increased by saline loading. In contrast, in the patients treated with quinapril, volume expansion induced an increase of both left ventricular volumes (p < 0.001) without changing ejection fraction and reduced forearm vascular resistance (p < 0.05). In addition, in this group, plasma atrial natriuretic factor levels increased (p < 0.05) and plasma norepinephrine did not change during volume overload. During nitroglycerin infusion, volume expansion was associated with peripheral vasodilatation, increases of left ventricular volumes, and no change in ejection fraction. In this group, however, plasma atrial natriuretic factor levels did not change in response to volume overload. CONCLUSIONS: We conclude that pretreatment with the ACE inhibitor quinapril significantly improves compromised responses to acute isotonic volume overload in patients with dilated cardiomyopathy and mild heart failure. The favorable influence of ACE inhibition on cardiovascular and hormonal responses to volume expansion seems to be related to the cardiac unloading produced by this treatment.

Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure.

To investigate whether the response of atrial natriuretic factor (ANF) to volume expansion is impaired in the early stages of dilated cardiomyopathy, the effects of saline load (SL; 0.25 ml/kg.min for 120 min) were assessed in 12 patients with dilated cardiomyopathy and asymptomatic to mildly symptomatic heart failure (HF) and in nine normal subjects (N). SL increased plasma ANF levels in N (from 14.3 +/- 2 to 19.5 +/- 3 and 26 +/- 4 pg/ml, at 60 and 120 min, respectively, P less than 0.001), but not in HF (from 42.9 +/- 9 to 45.9 +/- 9 and 43.9 +/- 8 pg/ml). Left ventricular end-diastolic volume (LVEDV) and stroke volume were increased (P less than 0.001) by SL in N but not in HF. Urinary sodium excretion (UNaV) increased in N more than in HF during SL, whereas forearm vascular resistance (FVR) did not change in N and increased in HF (P less than 0.001). In five HF patients SL was performed during ANF infusion (50 ng/kg, 5 ng/kg.min) that increased ANF levels from 37.1 +/- 10 to 146 +/- 22 pg/ml. In this group, SL raised both LVEDV (P less than 0.01) and ANF (P less than 0.05), whereas FVR did not rise. In addition, the UNaV increase and renin and aldosterone suppressions by SL were more marked than those observed in HF under control conditions. Thus, in patients with dilated cardiomyopathy and mild cardiac dysfunction, plasma ANF levels are not increased by volume expansion as observed in N. The lack of ANF response is related to the impaired cardiac adaptations. The absence of an adequate increase of ANF levels may contribute to the abnormal responses of HF patients to saline load.

Abnormal hormonal and renal responses to saline load in hypertensive patients with parental history of cardiovascular accidents.

BACKGROUND: Acute cardiac and cerebrovascular accidents are more frequent in hypertensive subjects with a family history of acute vascular accidents. The mechanisms underlying the susceptibility to vascular disease in these subjects are unknown. We investigated whether a parental history of premature heart attack or stroke in hypertensive subjects is associated with abnormalities of sodium handling. METHODS AND RESULTS: Patients with mild, uncomplicated essential hypertension were divided into two subgroups according to family history: a subgroup with a parental history of premature heart attack or stroke (FV+, n = 18) and a subgroup with a family history completely negative for vascular accidents (FV-, n = 14). The two subgroups were comparable with respect to age, weight, sex distribution, blood pressure, duration of hypertension, cardiovascular risk factors, renal function, and organ damage. Baseline plasma renin activity (PRA), concentrations of aldosterone (PA), atrial natriuretic factor (ANF), and norepinephrine, and urinary electrolyte excretion were also comparable in the two subgroups. Despite these similarities, the responses to an acute saline load, measured under controlled metabolic and experimental conditions, were different in the two subgroups. In the FV+ subgroup at 60 minutes of saline load, PRA fell by 1.0 +/- 0.2 ng/ml/hr and PA concentration by 89.4 +/- 26 pg/ml and ANF concentration increased by 38 +/- 9 pg/ml, whereas in the FV- subgroup the corresponding responses were -2.3 +/- 0.3 ng/ml/hr (p less than 0.005), -190 +/- 43 pg/ml (p less than 0.05), and 80 +/- 13 pg/ml (p less than 0.005), respectively. Urinary sodium excretion was delayed in the FV+ subgroup (270 +/- 67 mu eq/min at 60 minutes) compared with the FV- subgroup (555 +/- 157 mu eq/min at 60 minutes, p less than 0.05). At 120 minutes of saline load, significant (p less than 0.005) differences in PRA and ANF concentration were still observed. In a control group of eight normal subjects the responses to a saline load were comparable to those in the FV- subgroup but greater than those in the FV+ subgroup at 60 minutes. CONCLUSIONS: These results provide evidence that the hormonal and renal adjustments to an acute salt load are impaired in hypertensive patients with a parental history of vascular accidents. We speculate that abnormalities of sodium handling may represent markers of a more rapid development of vascular injury in human hypertension.

[The early hemodynamic and hormonal changes in patients with left ventricular dysfunction]. / Alterazioni emodinamiche ed ormonali precoci in pazienti con disfunzione ventricolare sinistra.

The aim of this study was to highlight a different hormonal and hemodynamic pattern in patients with mild cardiomyopathy. For this purpose, we studied subjects with mild heart failure (CHF; NYHA class I and II; post-ischemic and idiopathic) who underwent an isotonic saline load (SL) (0.22 ml/kg/min of 0.9% NaCl for 120 min). A second group of age- and sex-matched normal subjects (C) was studied as a control. Basal hormonal and hemodynamic values of the 2 groups differed only in atrial natriuretic factor (ANF), left ventricular end-diastolic diameter and ejection fraction (EF). There were, on the contrary, no differences in basal plasma renin activity (PRA) and plasma aldosterone (PA) values. After SL, in C, percent changes in EF, cardiac output and ANF values were significantly higher than in CHF while total peripheral resistances increased only in CHF but not in C. In both groups there were decrements of PRA and PA, but these responses were significantly higher in C than in CHF. In conclusion, our results show that hormonal, renal and hemodynamic responses to salt/volume load are compromised in the early asymptomatic phase of heart failure. These abnormalities may predict the progressive deterioration of cardiac function, and may indicate appropriate therapeutic interventions since the early phases of the disease.

[Hormonal control of the endocrine function of the heart]. / Controllo ormonale della funzione endocrina del cuore.

Previous studies demonstrate that high doses of angiotensin II (Ang II) increase the release of ANF from atrial cells but it is not known whether this is a direct effect of Ang II or due to the induced hemodynamic changes. We report the effects of low doses of Ang II (1, 2.5, 5, 10 ng/kg/min) in anesthetized, instrumented dogs after volume load (2.5% body weight) and converting enzyme inhibition. During Ang II infusion we found an increase in mean blood pressure (from 147 +/- 3 to 160 +/- 3 mmHg, p less than 0.05) and arterial ANF (from 32 +/- 6 to 80 +/- 23 fmol/ml, p less than 0.05), while left and right atrial pressures did not change significantly. In a second group of dogs (n = 4) that underwent a similar protocol with the infusion of vehicle alone we failed to find any statistical difference in the above mentioned parameters. The Ang II induced ANF release was not related to the hemodynamic changes. Changes in plasma ANF levels were, in turn, related to the effects of Ang II on hormones and kidney, thus suggesting a role for endogenous ANF. In a separate study we found an increase of ANF production (+129 +/- 18, +176 +/- 46, +210 +/- 66% basal value) from isolated atrial minces exposed to Ang II concentration of 1, 10, and 100 nM, respectively.

Systemic anaphylaxis induced by physical exertion: a case report.

Anaphylaxis is a systemic reaction which can be very dangerous in many patients. In addition to the most common antigens (drugs, venoms, foods), physical exercise can provoke anaphylaxis in the sensitized patients. The mechanism of this reaction is still unknown. In this report, we describe a case of exercise-induced anaphylaxis in a 25 year old female who had experienced two syncopal attacks during strong physical activity. On other occasions she had noticed that prolonged work would cause urticaria, pruritus and numbness. During hospitalization, on two occasions a treadmill stress test induced bronchial spasm, urticaria and hypotension. We believe that the association of urticaria and anaphylaxis would suggest the possible presence of a vasoactive substance released from the mast-cells and basophil leucocytes.

Hypocholesterolaemic activity of suloctidil: double-blind, crossover short-term and long-term treatment trial.

Two studies were carried out in patients with primary hyperlipidaemia to investigate the effect of suloctidil (200 mg 3-times daily) on serum cholesterol levels and other lipidaemic variables. The first study was a double-blind, crossover comparison of suloctidil and placebo in 23 patients. Patients were allocated at random to receive one or other treatment for 4 weeks, after a wash-out period of 4 weeks on placebo, and were then crossed over to the alternative medication for the following 4 weeks. Patients were kept on a controlled diet throughout the trial. In the second, long-term study, 28 patients were treated, after an initial washout period of 8 weeks on placebo, with suloctidil for periods of up to 1 year. As in the short-term trial, patients were maintained on a controlled diet. The results showed that suloctidil produced a statistically significant reduction in total serum cholesterol and serum triglycerides in the short-term and this reduction was maintained over the longer period of the second study. In addition, there was a concomitant and approximately proportional increase in HDL-cholesterol. Suloctidil was well tolerated and no serious side-effects were reported.

[Association between viral infection and pleuropericarditis: study of a case list of pleurisy and pericarditis]. / Associazione tra infezione virale e pleuro-pericarditi: studio di una casistica di pleuriti e pericarditi.

The Authors report a study on a group of 47 patients affected by serositis (pleuritis, pericarditis, pleuro-pericarditis) of suspected viral origin. Two serum samples were taken from each patient at different times and were tested with many viral antigens by the complement fixation technique. The discussion is carried out on the lines followed by the majority of people in giving importance to their viral etiology and the viruses involved as agents of serositis are reported. In the present study 18 patients (38%) showed a significant rise of antibodies for viral antigens and therefore their disease might be due to viral etiology: 5 influenza viruses, 1 parainfluenza, 1 coxsackie, 1 RSV, 3 mumps virus, 5 CMV, 1 adenovirus.