Left and right ventricular collagen type I/III ratios and remodeling post-myocardial infarction.

BACKGROUND: Types I and III collagen have different physical properties, and an increase of type I/III ratio can have a deleterious impact on myocardial compliance and left and right ventricular diastolic function. Post-myocardial infarction, these changes in collagen types may be relevant to the remodeling process and the development of heart failure. METHODS AND RESULTS: In the rat coronary ligation heart failure model, we studied the time course of changes in types I and III and total collagen levels over 10 weeks postinfarction. Collagen types were separately quantified in the left (LV) and right ventricles (RV) by computerized morphometry and standard immunohistochemistry techniques, and also by hydroxyproline analysis, and these were correlated with hemodynamic changes. Compared with sham-operated rats, total collagen level increased 2.5- to 2.9-fold and 1.7- to 2.9-fold in the noninfarcted areas (NIAs) of the LV and RV, respectively, over the 10-week period and showed a good relation with changes in hydroxyproline content (r2 = 0.62; P < .0001). In the NIAs of both the LV and RV, type III collagen level showed a transient twofold increase at 2 weeks, which declined to normal at 4 weeks. Type I collagen level increased twofold at 4 weeks in the NIA of the LV and remained elevated at 10 weeks. In the RV, type I collagen level increased 2.7-fold to a peak at 4 weeks and declined gradually to 1.7 times baseline at 10 weeks. The patterns of change in type I collagen level in the RV correlated with the changes in LV end-diastolic pressure (r = 0.73; P < .0001) and RV weight to body weight ratio (r = 0.73; P < .0001). CONCLUSION: There is a relative greater increase of type I collagen level in the NIA and RV postinfarction, and this may lead to left and right ventricular dysfunction. Separate mechanisms might be involved in the induction of the different types of collagen deposition, with type I collagen levels apparently closely correlating with hemodynamic stress.

Influence of gene polymorphisms of the renin-angiotensin system on clinical outcome in heart failure among the Chinese.

BACKGROUND: An association between the DD allele of the angiotensin-converting enzyme gene and a poorer outcome in patients with heart failure has been found in whites. The DD allele frequency is lower in Chinese, but the M235T variant of the angiotensinogen gene is more common in Chinese than whites; it is not known to what extent polymorphisms of the renin-angiotensin system affect clinical status or prognosis in Chinese patients with heart failure. METHODS: We assessed the relations among polymorphism of the angiotensin-converting enzyme gene, angiotensinogen M235T (AGT) gene, and angiotensin type I receptor A1166C gene with left ventricular systolic function, left and right ventricular diastolic function, serum angiotensin-converting enzyme, plasma aldosterone and atrial natriuretic peptide levels at presentation, and clinical outcome at 1 year (survival, hospital admissions) in a cohort of Chinese patients with typical systolic heart failure (n = 82). RESULTS: We confirmed the low prevalence of the angiotensin-converting DD and the angiotensin type I receptor CC genotypes, and high prevalence of the AGT TT genotype in Chinese subjects compared with whites. There was no relation between the various gene polymorphisms and survival at 1 year assessed by multiple regression or Cox regression survival analysis. The AC variant of the angiotensin type I receptor gene was associated with morbidity over a 1-year period (hospital admissions) and increased baseline aldosterone levels, but none of the other polymorphisms correlated with systolic or diastolic function, aldosterone or atrial natriuretic peptide levels. By multiple regression for effects on mortality rate, only atrial natriuretic peptide and age were significant. CONCLUSIONS: In Chinese patients with heart failure, polymorphisms of the renin-angiotensin system do not appear to be related to survival or severity, probably because of the different prevalence of these genotypes in the Chinese. Thus this study illustrates that large interethnic differences in the frequencies of genotype polymorphisms of the renin-angiotensin system exist and results from one ethnic group cannot be extrapolated to another.

Diastolic dysfunction and natriuretic peptides in systolic heart failure. Higher ANP and BNP levels are associated with the restrictive filling pattern.

BACKGROUND: Left ventricular diastolic dysfunction is common in patients with systolic heart failure and the restrictive type of filling pattern appears to be associated with increased cardiac mortality. Both artrial and brain (or ventricular) natriuretic peptides are also proven markers of the severity of heart failure. The aim of this study was to determine in a large cohort of patients with systolic heart failure whether diastolic abnormalities, and in particular the restrictive filling pattern of transmitral flow velocity, correlate with plasma atrial and brain natriuretic peptide levels. METHODS: Sixty-eight consecutive patients with symptomatic systolic heart failure (ejection fraction < 0.5) underwent two-dimensional Doppler echocardiography of left ventricular systolic and diastolic function, together with measurement of atrial and brain natriuretic peptides. RESULTS: The restrictive filling pattern was present in 62%, the abnormal relaxation pattern in 31% and only 7% were normal. Atrial and brain natriuretic peptide (ANP/BNP) levels were significantly higher in the restrictive compared to the abnormal relaxation group (ANP: 202.2 +/- 31.7 vs 102.5 +/- 22.1 pg.ml-1, P = 0.012; BNP: 277.8 +/- 27.7 vs 162.4 +/- 21.9 pg.ml-1, P = 0.002). In addition, a restrictive filling pattern was associated with lower ejection fractions (P = 0.026), higher pulmonary artery systolic pressure (P < 0.001), larger left atrial size (P = 0.044), and were more likely to be in New York Heart Association class III or IV than those with an abnormal relaxation pattern (P = 0.007). Both atrial and brain natriuretic peptides correlated inversely with ejection fraction (P < 0.001), fractional shortening (P < 0.001), and positively with pulmonary artery pressure (P = 0.004 and 0.001 respectively). There were no significant correlations between single diastolic parameters and atrial or brain natriuretic peptide levels for the total patient group except between mitral peak A wave velocity and brain natriuretic peptides (r = -0.3, P = 0.01). For those with abnormal relaxation pattern mitral, valve E-wave deceleration time correlated significantly with both atrial and brain natriuretic peptide levels (P < 0.01). CONCLUSIONS: This study confirms that the restrictive filling pattern of transmitral flow velocity is a marker of more severe heart failure, as indicated by its association with higher atrial and brain natriuretic peptide levels, lower ejection fraction and higher pulmonary artery pressure. Thus, this easily obtained Doppler-derived marker of diastolic dysfunction is useful for identifying those patients with more severe heart failure.

Effect of low dose beta blockers on atrial and ventricular (B type) natriuretic factor in heart failure: a double blind, randomised comparison of metoprolol and a third generation vasodilating beta blocker.

OBJECTIVES: This study examines the acute effects of two differing beta adrenergic blocking agents (metoprolol and a third generation vasodilating beta blocker) on plasma concentrations of atrial natriuretic factor (ANF), brain (ventricular) natriuretic factor (BNF), and haemodynamic variables in patients with heart failure. SETTING: University teaching hospital. METHODS: 20 patients with impaired left ventricular systolic function [ejection fraction 32 (SEM 2.3)%] were randomised in a double blind manner to receive either oral metoprolol 6.25 mg twice daily or celiprolol 25 mg daily. Haemodynamic variables were evaluated by Swan-Ganz pulmonary artery catheter over 24 hours. ANF and BNF concentrations were measured at baseline, 5 h, and 24 h by radioimmunoassay. RESULTS: At baseline ANF and BNF concentrations were considerably raised compared to the normal range. Treatment with metoprolol caused ANF to rise further to 147% of the basal level at 5 h (P = 0.017) and 112% at 24 h (P = 0.029). This was associated with a small but non-significant rise in pulmonary capillary wedge pressure. Cardiac output and systemic vascular resistance were unchanged at 24 h. In contrast, after celiprolol ANF fell to 90% of basal levels at 5 h and to 74% of basal level at 24 h (P = 0.019), associated with a small but non-significant fall in pulmonary capillary wedge pressure [-3.3 (2.7) mm Hg] and systemic vascular resistance, and rise in cardiac output from 3.2 (0.2) to 4.0 (0.4) l/min (P = 0.04). BNF concentrations rose to 112% of baseline at 5 h (P = 0.09) after metoprolol but fell slightly, to 91% of baseline values, after celiprolol (NS). CONCLUSIONS: Metoprolol, even in very low doses (6.25 mg), produced a rise in ANF and BNF, although minimal haemodynamic changes were detected. In contrast, a vasodilating beta blocker was associated with a significant fall in ANF and BNF and a small rise in cardiac output. This study confirms both the advantages of vasodilating beta blockers over metoprolol for initial treatment of heart failure and the usefulness of ANF and BNF measurements for the assessment of drug effects in heart failure compared to traditional haemodynamic measurements.