Heart failure, aging, and renal synthesis of dopamine.

The present study evaluates renal dopaminergic activity in 23 patients with heart failure (HF), 10 age-matched controls, and 10 young subjects during normal-salt (NS) intake and after 8 days of low-salt (LS) intake (patients with HF and age-matched controls only). LS intake produced a marked reduction in urine volume in patients with HF but failed to affect urine volume in age-matched controls. Urinary sodium and fractional excretion of sodium were markedly reduced by LS intake in patients with HF and age-matched controls. Daily urinary excretion of L-3,4-dihydroxyphenylalanine (L-dopa) and dopamine was lower in patients with HF than in age-matched controls. LS intake failed to alter L-dopa and dopamine urinary excretion in control subjects. In patients with HF, LS intake produced a significant decrease in urinary L-dopa excretion, but failed to alter the urinary excretion of dopamine. No significant differences were observed in urinary L-dopa, dopamine, and dopamine metabolite levels between aged controls and young healthy subjects. Urinary dopamine-L-dopa ratios in patients with HF on LS intake (24.5 +/- 7.1) were significantly greater than those with NS intake (11.6 +/- 1.3). Urinary dopamine-L-dopa ratios in old control subjects (LS, 9.7 +/- 1.3; NS, 9.3 +/- 1.1) did not differ from those in young healthy subjects (9.2 +/- 0.8). LS intake produced a marked increase in plasma aldosterone levels in both patients with HF (84.6 +/- 14.4 to 148.2 +/- 20.4 pg/mL; P = 0.0008) and controls (102.1 +/- 13.4 to 151.6 +/- 15.7 pg/mL; P < 0.04). Plasma norepinephrine levels were not significantly affected by LS intake in controls (5.1 +/- 1.62 to 6.3 +/- 1.6 pmol/mL; P = 0.22), but were significantly increased in patients with HF (5.8 +/- 0.8 to 7.1 +/- 0.9 pmol/mL; P = 0.04). In conclusion, patients with HF are endowed with an enhanced ability to take up (or decarboxylate) filtered L-dopa, which might counterbalance the reduced renal delivery of L-dopa, contributing to a relative preservation of dopamine synthesis. This may result as a compensatory mechanism, activated by stimuli leading to sodium reabsorption. Age seems to have no influence on renal dopamine production.

[Neuro-hormonal mechanisms in heart failure -- from physiopathology to treatment]. / Mecanismos neuro-hormonais na insuficiência cardíaca--da fisiopatologia ao tratamento.

This review updates some recent advances of a new and exciting developments in basic and clinical cardiology: a) the role, in the congestive heart failure (CHF), of the neurohumoral systems (NHS) which act to maintain circulatory homeostatic equilibrium, and b) the therapeutic implications of such a role. Six NHS, acting in CHF, have presently been identified: three of them induce vasoconstriction and sodium retention (sympathetic nervous systems, renin-angiotensin-aldosterone system and arginine-vasopressine system); the remaining three offset or balance the former ones, acting, therefore as "counterregulators" (prostaglandins--PGE2 and PGI2--, dopaminergic system and atrial natriuretic factor). Each one of these NHS influences the "compensatory" mechanisms of heart failure, acting on the target-organs both by direct effects and by interaction with other NHS; consequently, in heart failure, all the NHS are stimulated with the respective increase in the plasma levels of their active agents. In asymptomatic stages of ventricular dysfunction the stimulation of the vasodilator-and-natriuretic systems appears to be predominant and able to maintain circulatory equilibrium. However, as the heart dysfunction increases and becomes symptomatic, the vasoconstrictor and sodium-retaining forces appear to predominate; this phenomenon becomes increasingly apparent as the functional class becomes more advanced. The hyperstimulation of these last systems has an extremely important role in the pathophysiology and clinical manifestations of congestive heart failure, as well as in its prognosis. Therefore, the attempts to correct these neurohormonal imbalance in patients with heart failure has a sound rational basis, not only to improve the symptoms and the exercise capacity but also to increase the survival of these patients. At the present time, amongst the potential pharmacological interventions acting on NHS in CHF, the blockade of the RAA system with ACE-inhibitors is generally accepted as the most feasible, the safest and the most effective therapeutic tool. In fact, its application has broadened from an earlier use in severe CHF to other symptomatic stages of cardiac failure, including the milder forms. In addition, preliminary data strongly suggest its unique usefulness in asymptomatic phase of ventricular dysfunction. Looking back at the medical therapy of heart failure, in can be concluded that we are starting a new era. Throughout 200 years (since the introduction of digitalis) the therapeutic goal in CHF has been the improvement of symptoms. With the developments of the present decade, a new and exciting goal is being offered to these patients, called by Packer "the second frontier", that is, the prolongation of their lives.

Neurohormonal activation, the renal dopaminergic system and sodium handling in patients with severe heart failure under vasodilator therapy.

The benefits of tailoring therapy with vasodilators in patients with severe heart failure are well documented, but this may lead to neurohormonal activation and sodium retention. Renal dopamine has local natriuretic actions and interacts with other hormones involved in renal sodium handling. The aim of the present work was to determine the effects of arterial underfilling induced by vasodilator therapy on renal sodium handling, neurohormonal activation and the activity of the renal dopaminergic system in patients with severe heart failure. For this purpose we monitored haemodynamic parameters, plasma levels of type B natriuretic peptide (BNP), catecholamines, aldosterone, renin activity (PRA), sodium and creatinine, and urinary excretion of sodium, creatinine, L-DOPA, dopamine and its metabolites, before initiation of sodium nitroprusside therapy and every 6 h thereafter (for 42 h), and again after 5 days of angiotensin-converting enzyme (ACE) inhibition, in 10 male patients with severe heart failure. The results of nitroprusside therapy were a marked increase in cardiac index and a substantial decrease in systemic vascular resistance index. Plasma levels of BNP decreased significantly, while PRA, noradrenaline and aldosterone showed marked increases, resulting in a substantial reduction in urinary sodium excretion. Creatinine clearance was not affected. Urinary dopamine and dopamine metabolites increased in response to nitroprusside therapy. After 5 days of ACE inhibition, urinary sodium returned to baseline values, while urinary dopamine was markedly reduced. These results suggest that the renal dopaminergic system is activated in patients with severe heart failure by stimuli leading to sodium renal reabsorption.

Clinical significance of brain natriuretic peptide in patients with postmyocardial infarction.

BACKGROUND: Risk stratification after acute myocardial infarction (AMI) includes the evaluation of left ventricular (LV) function. Natriuretic peptides, and particularly brain natriuretic peptide (BNP), emerged as a potential marker of ventricular function and prognosis after AMI. HYPOTHESIS: Brain natriuretic peptide levels are related to ventricular function, either systolic or isolated diastolic, and can give prognostic information in patients surviving AMI. METHODS: In all, 101 patients were enrolled. An echocardiographic (M-mode, two-dimensional, and pulsed Doppler) evaluation was performed and blood samples for BNP measurement were obtained. Clinical events were recorded during 12 months of follow-up. RESULTS: A negative correlation between BNP and LV ejection fraction was observed (r = -0.38; p < 0.001). The BNP levels were higher among patients with LV systolic dysfunction than in patients with isolated diastolic dysfunction (339.1 +/- 249.9 vs. 168.0 +/- 110.5 pg/ml, p = 0.001). The latter had higher levels of BNP than those with normal LV function (68.3 +/- 72.6 pg/ml, p < 0.001). The BNP accuracy to detect LV systolic dysfunction was good (area under the ROC curve [AUC] = 0.83) and increased when isolated diastolic dysfunction was also considered (AUC = 0.87). Brain natriuretic peptide had a very good accuracy in the prediction of death (AUC = 0.95) and the development of heart failure (AUC = 0.90). CONCLUSION: These results extend previous evidence relating BNP to systolic function after AMI. Furthermore, a relationship between BNP levels and diastolic function was found. Brain natriuretic peptide had a very good performance in detecting the occurrence of an adverse event. We conclude that BNP can detect high-risk patients and help select patients for more aggressive approaches.

Evaluation of brain natriuretic peptide in the diagnosis of heart failure.

A diagnosis of heart failure (HF) can be difficult, especially in patients with mild symptomatology. The purpose of this study was to evaluate the significance of brain natriuretic peptide (BNP) in the diagnosis of HF with systolic or isolated diastolic ventricular dysfunction. One hundred patients and 9 controls were included in the study. Eighty-five patients were diagnosed with HF, based on clinical and echocardiographic findings. BNP levels were accurate for the diagnosis of HF, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.92. In addition, BNP levels showed an excellent accuracy for the diagnosis of isolated diastolic HF (AUC = 0.89). These data suggest that the measurement of BNP levels may be helpful in the diagnosis of HF and in selecting patients for further evaluation. Furthermore, BNP measurement can play an important role in the diagnosis of isolated diastolic HF.

Renal dopaminergic mechanisms in renal parenchymal diseases, hypertension, and heart failure.

The recovery of renal function in renal transplant recipients is accompanied by an enhanced ability to synthesize dopamine (DA), which may contribute to maintain sodium homeostasis. Patients suffering from chronic renal parenchymal disease, a well-recognized form of salt sensitive (SS) hypertension, have a reduced ability to produce DA that correlates well with deterioration of renal function. In patients afflicted with IgA nephropathy, but normal renal function, urinary excretion of DA correlated positively with BP responses to changes from 200 to 20 mmol/day salt intake. In black salt resistant (SR) normotensives (NT) and SR hypertensives, under low salt intake (40 mmol/day), but not SS-NT and SS-HT, the saline infusion induced increments of DA and DOPAC urinary excretion correlated significantly with increments of sodium urinary excretion and sodium fractional excretion. Patients afflicted with heart failure (HF) have a reduced delivery of L-DOPA to the kidney, accompanied by an increase in DA/L-DOPA urinary ratios. This suggests that HF patients have an increased ability to take up or decarboxylate L-DOPA. Sodium restriction resulted in a significant decrease in urinary L-DOPA, DA and DOPAC in HF patients, suggesting that the system responds to sodium. It is concluded that activity of renal dopaminergic system may be altered in SS subjects, despite the level of their BP, and an enhanced delivery of L-DOPA to the kidney may be beneficial in edema formation states.

Predictors of prognosis in patients with stable mild to moderate heart failure.

BACKGROUND: A number of prognostic indexes have been developed to predict the outcome of patients with severe heart failure (HF). In patients with mild to moderate HF, however, there is no consensus regarding the usefulness of such indexes. The goal of this study is to determine the prognostic value of selected clinical variables in the latter group of patients. METHODS AND RESULTS: We prospectively evaluated the prognostic value of the functional capacity evaluation, the ventricular function, biochemical metabolic indicators, and brain natriuretic peptide (BNP) levels in 139 consecutive patients with mild to moderate HF. A clinical and echocardiographic examination (M-mode, 2D and pulsed Doppler of the mitral inflow); a 6-minute walk test; and a determination of serum sodium, uric acid, and BNP levels were performed. Death by any cause was predefined as the study end-point. Variables found to be related with survival in a univariate Cox regression analysis were NYHA class; ischemic origin for HF; left ventricular ejection fraction; deceleration time of the E wave; and 6-minute walk distance, serum sodium, uric acid, and BNP levels. In a multivariate analysis, ischemic origin of HF, 6-minute walk distance, deceleration time of the E wave, and BNP levels were found to be independent prognostic factors. The clustering of the independent prognostic factors was associated with the worse prognosis. CONCLUSIONS: These results suggest that the noninvasive evaluation used in this study and in our population of patients with mild to moderate HF allows the identification of individuals with the worst prognosis. The selected variables might prove to be very helpful in stratifying HF patients and identifying those that might benefit the most from a HF management program.

Renal synthesis of dopamine in asymptomatic post-infarction left ventricular systolic dysfunction.

Left ventricular systolic dysfunction (LVSD) following acute myocardial infarction (AMI), by decreasing renal blood flow, may interfere with renal L-DOPA availability and, consequently, dopamine synthesis. Dopamine of renal origin exerts local natriuretic effects. We studied 17 post-AMI patients with asymptomatic LVSD (ejection fraction < 40%) and 14 without (ejection fraction > or = 40%), measuring 24-h urinary excretions of L-DOPA, dopamine and its metabolites, and plasma levels of the amines, amine derivatives and type-B natriuretic peptide (BNP). Baseline characteristics were well balanced between the two groups. No differences were observed in urinary volume and sodium and creatinine excretions. The group with asymptomatic LVSD presented lower urinary excretion of L-DOPA (66.8 +/- 10.1 versus 115.3 +/- 21.9 nmol x day(-1), P = 0.04), whereas plasma levels of L-DOPA were identical in both groups. Urinary dopamine was similar in the two groups (1124.2 +/- 172.4 versus 1049.0 +/- 146.4 nmol x day(-1), P = 0.86), resulting in higher urinary dopamine/L-DOPA ratios in patients with asymptomatic LVSD (20.4 +/- 3.0 versus 9.9 +/- 0.8, P < 0.001). Plasma levels of BNP were higher in the asymptomatic LVSD group (348.5 +/- 47.3 versus 146.8 +/- 21.9 microg x ml(-1), P = 0.003). Ejection fraction was negatively correlated with both plasma levels of BNP and urinary dopamine/L-DOPA ratios. Renal dopamine production is well preserved in patients with asymptomatic LVSD and increased neurohumoral activation, despite reduced urinary excretion of its precursor. This suggests that renal uptake and/or decarboxylation of L-DOPA is enhanced in this condition, as a compensatory mechanism, contributing to preservation of urinary sodium excretion.

Brain natriuretic peptide as a marker of cardiac involvement in hypertension.

Hypertensive patients with heart abnormalities have increased risk of cardiovascular events. Brain natriuretic peptide is a natriuretic peptide mainly of ventricular origin produced in response to pressure and stretch. We hypothesise that brain natriuretic peptide could be a useful marker of cardiac remodelling in hypertensive patients. We studied 36 consecutive community mild-to-moderate hypertensive patients and 11 well-matched normotensive controls with respect to clinical characteristics, brain natriuretic peptide, creatinine and echocardiography parameters (M-mode, 2-D arid transmitral pulsed Doppler). Brain natriuretic peptide levels were significantly higher in hypertensive patients than in controls [36.54 (IQR: 38.61) vs. 10.30 (IQR: 13.20) pg ml(-1), p<0.0001] and it was correlated with left ventricular mass index. Hypertensive patients with impairment of diastolic filling had significantly higher brain natriuretic peptide concentrations than patients with no abnormalities on echocardiography [61.16 (45.38) vs. 31.27 (18.10) pg ml(-1), p=0.001]. Multivariate analysis showed that only diastolic dysfunction and left ventricular mass index were significantly and independently related with brain natriuretic peptide concentrations in this population. In conclusion, impairment of diastolic function and left ventricular mass index are related to brain natriuretic peptide levels, thus giving the insight that this peptide can be a marker of ventricular remodelling in hypertensive patients.

Predictors of myocardial dysfunction in human immunodeficiency virus-infected patients.

BACKGROUND: Some of the most frequent manifestations of heart involvement in human immunodeficiency virus (HIV) infection include right and left ventricular dysfunction. The pathogenesis remains obscure. METHODS AND RESULTS: This prospective clinical and echocardiographic study involved 181 patients at all stages of HIV infection. We tested a set of clinical variables using a backward logistic regression model to assess their ability to independently predict the presence of ventricular dysfunction. The presence of pulmonary infections (all etiologies mixed) was the only variable independently associated with isolated right ventricular dysfunction (odds ratio = 4.08; P = .02). Signs suggestive of pulmonary arterial hypertension were present in 71% of the patients with right ventricular dilation. History of previous opportunistic infections (all etiologies mixed) (odds ratio = 10.9; P = .0026) and time since the diagnosis of acquired immunodeficiency syndrome more than 12 months (odds ratio = 6.6; P = .03) were the only two independent predictors of left ventricular dysfunction. CONCLUSIONS: Isolated right ventricular dysfunction may be secondary to pulmonary hypertension caused by repetitive pulmonary infections and not to primary myocardial disease. The aggressive treatment of opportunistic infections may become an important element of heart failure prophylaxis in HIV infection because they may be associated with left ventricular dysfunction.

[The importance of the endothelium in heart failure]. / Importância do endotélio na insuficiência cardíaca.

The endothelium is involved in cardiac and vascular dysfunction characteristic of heart failure. Vascular dysfunction has been related either to an impaired endothelium dependent vasodilation of both capacitance and resistance vessels, or to an increase in the plasmatic levels of endothelium derived contracting factors, such as endothelin-1. While the former seems to respond favourably to ACE-inhibitors, physical training and L-arginine; the latter will soon be treatable with endothelin-1 A e B receptor antagonists or with inhibitors of its converting enzyme. Cardiac dysfunction may be explained not only by the loss of the positive inotropic effect induced by low concentrations of nitric oxide (produced by the constitutive NO-synthase in the normal endothelium), but also by the negative inotropic effect induced by the high concentrations of nitric oxide, produced as a consequence of the stimulation of the inducible NO-synthase. It is therefore conceivable that cardiac dysfunction would also improve with the administration of drugs presently used to correct endothelium dependent vasodilatation disturbances.

Angiotensin-converting enzyme inhibitors in heart failure: physicians' prescribing behavior.

BACKGROUND: Several studies document an underuse of angiotensin-converting enzyme inhibitors (ACEIs) in heart failure (HF) patients, despite their proven efficacy and good tolerability. Also, there is some evidence that the doses used in clinical practice are far lower than those used in clinical trials. METHODS AND RESULTS: To identify patterns of ACEI use in HF patients this study examined data collected on admission day regarding demographic, clinical, and medical care characteristics of 355 patients hospitalized because of decompensated HF who were treated with and without ACEIs. Additionally, measures of in-hospital outcome were compared among the two groups. Fifty-eight point six percent of patients were receiving ACEIs at admission and 80.6% were treated with ACEIs during hospitalization. The average ACEI does was low. No differences were observed in age and measures of severity of HF between ACEI-prescribed and nonprescribed patients. Patterns that could explain ACEI underuse included female sex, lower systolic blood pressure, worse renal function, left ventricular diastolic dysfunction, use of alternate drugs (eg, spironolactone), and overall less intense medical management. Patterns associated with the use of lower doses of ACEIs included older age, higher New York Heart Association functional class, and lower systolic blood pressure. In-hospital death rates were significantly higher for patients not treated with ACEIs. CONCLUSIONS: This study suggests that many patients eligible for ACEI treatment were deprived of the advantages of these drugs because of erroneous clinical strategies. Nevertheless, the patterns of ACEI use were similar to those reported by other studies. Clinical trials conducted to determine the risk/benefit ratio of ACEI use in patients with renal dysfunction and the utility of ACEIs in diastolic HF, as well as programs to educate care providers on proper use of ACEIs in HF patients, are strongly recommended.

Evaluation of the sympathetic nervous system using heart rate variability and plasma hormones in hypertensive patients treated with cilazapril and atenolol.

In a double-blind placebo-controlled parallel study, we assessed basal and post-therapeutic sympathetic activity both in supine and standing positions in mildly to moderately hypertensive patients by two different methods: frequency domain indices of heart rate variability (HRV) and plasma levels of both noradrenaline (NA) and its metabolite, 3,4-dihydroxyphenylglycol (DOPEG). Patients were evaluated on placebo and after 8 weeks of treatment with either cilazapril, 2.5-5 mg/day (13 patients) or atenolol, 50-100 mg/day (14 patients). Twenty-four-hour blood pressure was similarly reduced (p < 0.01) by both cilazapril and atenolol. Heart rate decreased with atenolol by 14 beats per min (p < 0.001) but did not change with cilazapril. When compared to the placebo, cilazapril did not modify sympathetic activity indices of HRV but did significantly reduce NA and DOPEG levels in both the supine and standing (p < 0.05) positions. As expected, atenolol reduced (p < 0.05) sympathetic activity indices of HRV but did not modify NA levels in either position. Moreover, while on placebo, patients showed no significant correlations between values of NA or DOPEG, nor in any of the HRV indices. We conclude that: (1) the antihypertensive effects of cilazapril and atenolol are similar, but in these patients, sympathetic activity indices showed divergent results both before and after therapy; (2) this may be due to different aspects of sympathetic activators, assessed independently by different methods, and (3) these discrepancies must be taken into account when evaluating autonomous nervous system parameters.

Influence of non-steroidal anti-inflammatory drugs on renal function and 24h ambulatory blood pressure-reducing effects of enalapril and nifedipine gastrointestinal therapeutic system in hypertensive patients.

OBJECTIVE: To evaluate the influence of non-steroidal anti-inflammatory drugs (NSAIDs; aspirin and indomethacin) on the renal and antihypertensive effects of enalapril and nifedipine gastrointestinal therapeutic system (GITS) in patients with essential hypertension. DESIGN AND METHODS: In a crossover study, 18 patients on an unrestricted-salt diet were randomly assigned to receive either enalapril (20-40 mg/day) or nifedipine-GITS (30-60 mg/day) for 4-8 weeks, followed by aspirin (100 mg/day for 2 weeks) and then indomethacin (75 mg/day for 1 week). Blood pressure was measured by 24h ambulatory monitoring. RESULTS: Enalapril and nifedipine-GITS significantly reduced blood pressure compared with placebo. Aspirin did not alter the antihypertensive effect of either drug. Indomethacin attenuated (by 45%) the antihypertensive effect of enalapril throughout the 24h period of evaluation, but did not interfere with the effect of nifedipine. Furthermore, indomethacin significantly reduced the fractional excretion of sodium and plasma levels of prostaglandins in a similar way when added to either the enalapril or the nifedipine regimen. CONCLUSIONS: Vasodilatory prostaglandins are probably involved in the antihypertensive effects of enalapril but not of nifedipine, and this interaction seems to be independent of any indomethacin-induced decrease in renal sodium excretion. Nifedipine may be an appropriate drug to treat hypertensive patients requiring concomitant therapy with NSAID.

Phonomechanocardiographic parameters in patients with atrial septal defect.

The purpose of the present study was to noninvasively evaluate left (LV) systolic and diastolic function in patients with atrial septal defect (ASD) using the phonomechanocardiogram. We studied 40 patients with atrial septal defect, 16 males and 24 females, ages ranging from 6 to 56 years (mean 21.1 years), consecutively observed before surgery in our institution, during a four year period. We measured the systolic time intervals (Q-A2c, Q-S1, ICT, PEP, LVETc, PEP/LVET), the Apex Cardiographic (ACG) diastolic parameters A2-Oc and A/H and the hemodynamic variables Qp/Qs, Pulmonary Vascular Resistance (PVR) and Left Ventricular End Diastolic Pressure (LVEDP). We compared the data with 74 normal individuals using the Student t-test and linear regression analysis. We found significant Q-S1 lengthening (81.2 +/- 16.4 ms, p < 0.001); PEP, ICT and A2-Oc were significantly reduced (101.2 +/- 21.7 ms, p < 0.001, 20.0 +/- 5.3 ms, p < 0.05 and 117.1 +/- 26.3 ms, p < 0.001, respectively) and A/H was significantly increased (17.4 +/- 12.1%, p < 0.005). Except for the case of Q-S1, where there was a weak positive linear correlation with Qp/Qs (r = 0.37), we found no correlation between the other parameters and Qp/Qs or PVR. Sixty-seven percent of the patients had Q-S1 prolongation and a Q-S1 > 76.2 ms identified left-right shunts > 2 with a positive predictive value of 82%; 62% of the patients had a reduced A2-Oc and a A2-Oc < 110 ms identified shunts > 2 with a positive predictive value of 90%.(ABSTRACT TRUNCATED AT 250 WORDS)