trandolapril and Hypertrophy--Left-Ventricular

Cardiac hypertrophy due to a chronic mechanical overload puts into play a biologic cascade, including a trigger (the mechanical stretch), a transmitter (very likely to be the phosphoinositol pathway), and the final target (which is the DNA). The permanent changes in genetic expression resulting from the activation of this cascade allows the heart to produce normal active tension at a lower cost in terms of energy expenditure. The process is reversible, providing the treatment reduces the real load on the heart--i.e., not only the peripheral resistances but also the aortic impedance--during a period of time that has to be several times the half-life of cardiac proteins, and also that the treatment has an effect on the detrimental consequences of cardiac hypertrophy, namely, the systolic and diastolic dysfunction and the incidence of arrhythmias. In this report semisenescent spontaneously hypertensive rats were treated for 3 months with the converting enzyme inhibitor trandolapril. The treatment had a rather modest effect on blood pressure but resulted in a pronounced reduction in cardiac hypertrophy and in cardiac fibrosis, an improved coronary reserve, and attenuated both the effects of anoxia on the left ventricular diastolic compliance and the incidence of ventricular arrhythmias.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Humans; Hypertrophy, Left Ventricular; Hypoxia; Indoles; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Ventricular Function, Left

Knowledge of predictors of diabetes mellitus (DM) development in patients with coronary artery disease (CAD) who use antihypertensive therapy could contribute to decreasing this adverse metabolic consequence. This is particularly relevant because the standard of care, beta blockers combined with diuretics, may contribute to adverse metabolic risk. The INternational VErapamil SR-trandolapril STudy compared a calcium antagonist-based (verapamil SR) and a beta-blocker-based (atenolol) strategy with trandolapril and/or hydrochlorothiazide added to control blood pressure (BP) in patients with CAD. The 16,176 patients without DM at entry were investigated with regard to newly diagnosed DM during follow-up. Newly diagnosed DM was less frequent in the verapamil SR versus atenolol strategy (7.0% vs 8.2%, hazard ratio 0.85, 95% confidence interval 0.76 to 0.95, p <0.01). Characteristics associated with risk for newly diagnosed DM included United States residence, left ventricular hypertrophy, previous stroke/transient ischemic attack, Hispanic ethnicity, coronary revascularization, hypercholesterolemia, greater body mass index, and higher follow-up systolic BP. Addition of trandolapril to verapamil SR decreased DM risk and addition of hydrochlorothiazide to atenolol increased risk. In conclusion, clinical findings associated with more severe vascular disease and Hispanic ethnicity identify a group at high risk for developing DM, whereas lower on-treatment BP and treatment with verapamil SR-trandolapril attenuated this risk.

Topics: Adrenergic beta-Antagonists; Aged; Antihypertensive Agents; Atenolol; Body Mass Index; Calcium Channel Blockers; Coronary Artery Disease; Diabetes Mellitus; Drug Therapy, Combination; Female; Follow-Up Studies; Hispanic or Latino; Humans; Hydrochlorothiazide; Hypercholesterolemia; Hypertrophy, Left Ventricular; Indoles; Ischemic Attack, Transient; Male; Myocardial Revascularization; Residence Characteristics; Risk Factors; Stroke; Systole; Verapamil

It has been reported that treatment with an angiotensin-converting enzyme (ACE) inhibitor is not adequate to suppress aldosterone, and we previously demonstrated that adding spironolactone to an ACE inhibitor may have beneficial effects on left ventricular hypertrophy (LVH) in selected patients with essential hypertension (EH). We have extended our previous short-term study, and addressed the relative long-term clinical effects of spironolactone and an ACE inhibitor in patients with EH who have LVH. Twenty patients with EH and concomitant LVH participated in this study. Subjects were treated with either an ACE inhibitor alone (group 1: 10 patients) or an ACE inhibitor plus spironolactone at the dose of 25 mg (group 2: 10 patients) for 60 weeks. The baseline clinical and echocardiographic characteristics of the two groups were similar. Final values of blood pressure were also similar between the two groups. The LV mass index (LVMI) decreased significantly in both groups, but the extent of reduction was significantly greater in group 2 at 60 weeks. The early peak to atrial peak filling velosities ratio (E/A ratio) was significantly increased to a similar extent in both groups. Serum procollagen type III amino-terminal peptide (PIIINP) was significantly decreased in group 2, but not in group 1. In group 2, there was a statistically significant correlation between the changes in LVMI and PIIINP. In conclusion, adding spironolactone to therapy with an ACE inhibitor for 60 weeks may have beneficial effects in patients with EH and concomitant LVH. Our study strongly suggests the possibility that attenuation of the effects of cardiac aldosterone in patients with EH by treatment with spironolactone and an ACE inhibitor may become a new goal for the prevention and regression of cardiac hypertrophy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Flow Velocity; Blood Pressure; Coronary Circulation; Diastole; Drug Therapy, Combination; Echocardiography; Enalapril; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Indoles; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Procollagen; Spironolactone

We recently demonstrated that spironolactone may have beneficial effects on left ventricular hypertrophy in selected patients with essential hypertension undergoing treatment with an angiotensin-converting enzyme (ACE) inhibitor. To clarify the possible mechanisms by which spironolactone improves cardiac hypertrophy, we investigated the change in serum procollagen type III amino-terminal peptide (PIIINP) in 11 patients with essential hypertension treated with spironolactone and an ACE inhibitor for 24 weeks. Both blood pressure and serum PIIINP levels were significantly decreased by treatment. There was a statistical significant correlation between the changes in LVMI and those in PIIINP. The reduction in PIIINP was significant in patients whose initial serum PIIINP levels were above the normal range. Before treatment, there were no statistically significant correlations between serum PIIINP levels and either LVMI, blood pressure, or plasma aldosterone concentration. Essential hypertensive patients matched in terms of duration of therapy, blood pressure and LVMI and treated with an ACE inhibitor alone showed no change in serum PIIINP levels. In conclusion, the results of the present study demonstrate that patients with essential hypertension and high serum levels of PIIINP are particularly responsive to MR blockade in terms of left ventricular hypertrophy. Moreover, these results suggest that spironolactone limits cardiac collagen turnover in such patients. Larger studies may provide definitive evidence for the involvement of aldosterone in left ventricular hypertrophy in patients with abnormally high PIIINP levels.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Diuretics; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Indoles; Male; Middle Aged; Peptide Fragments; Procollagen; Spironolactone; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Enalapril; Exercise; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Indoles; Male

Baseline echocardiography was performed on 25 patients with essential hypertension and a supine diastolic blood pressure of 95 to 114 mm Hg while receiving placebo. Once-daily trandolapril was then titrated from 1 to 4 mg. After 3 months of therapy, supine diastolic blood pressure decreased by 7.5% (p < 0.0001). Left ventricular hypertrophy regressed as evidenced by a 23.2% (p < 0.0001) decrease in left ventricular mass index at 3 months and a 12.4% (p < 0.05) reduction of relative wall thickness at 6 months. Although afterload decreased by 12.4% (p < 0.05) at 3 months, left ventricular systolic function remained unchanged, whereas left ventricular contractility, which was assessed from the load-independent relationship of end-systolic wall stress to velocity of circumferential fiber shortening, improved. Left ventricular diastolic function (E/A ratio) improved in 15 of 25 patients with low baseline values from 0.96 +/- 0.14 to 1.18 +/- 0.25 (mean +/- SD, p < 0.0002) at 3 months. We conclude that trandolapril effectively reduces left ventricular hypertrophy and improves diastolic function in patients with hypertension while systolic function is preserved.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Echocardiography, Doppler; Female; Heart; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Indoles; Male; Middle Aged

In models of hypertension and of renal failure, pharmacological blockade of the ET(A) receptor has been shown to cause some inconsistent lowering of blood pressure (BP) and lesser left ventricular hypertrophy (LVH). The effects of ET(A) receptor blockade (ET(A)-RB) on vascular remodeling and their potential relation to BP lowering, have not been clarified.. The experimental study in male Sprague-Dawley rats was designed to compare four experimental groups: (1) sham-operated controls (sham); (2) untreated rats with one-clip-two-kidney (1C-2K) renovascular hypertension; (3) 1C-2K rats treated with the ACE inhibitor (ACE-i) trandolapril (0.3 mg/kg b.w./day), and (4) 1C-2K rats treated with the ET(A)-RB LU-135252 (50 mg/kg b.w./day). BP was measured weekly by tail plethysmography. After 3 weeks, animals were sacrificed and cardiac, aortic and mesenteric artery morphology was evaluated using morphometric and stereological techniques.. Systolic BP was significantly higher in 1C-2K rats compared to sham. BP was not significantly affected by ET(A)-RB, but was significantly lowered by the ACE-i. Despite no significant change in BP, ET(A)-RB treatment led to a significantly less volume density of the cardiac interstitium (sham 1.40 +/- 0.18, 1C-2K 2.66 +/- 0.56, 1C-2K + ACE-i 1.88 +/- 0.38, 1C-2K + ET(A)-RB 2.15 +/- 0.37%). In contrast, ET(A)-RB had no significant effect on left ventricular/body weight ratio (sham 2.85 +/- 0.26, 1C-2K 2.96 +/- 0.33, 1C-2K + ACE-i 2.54 +/- 0.22 and 1C-2K + ET(A)-RB 3.15 +/- 0.44 mg/g) or on wall thickness of intramyocardial arteries.. The ET(A)-RB LU-135252 ameliorated the development of myocardial fibrosis in a short-term hyperreninemic normal salt model of experimental hypertension nearly as effectively as an ACE-i. This effect of LU-135252 is independent of systemic BP. In contrast to findings in other models, ET(A) receptor blockade had no significant effect on LVH or vascular remodeling. Only the ACE-i but not the ET(A)-RB prevented structural changes of small intramyocardial arteries and of the aorta.

Topics: Animals; Aorta; Blood Pressure; Coronary Vessels; Endomyocardial Fibrosis; Endothelin A Receptor Antagonists; Hypertension, Renovascular; Hypertrophy, Left Ventricular; Indoles; Male; Mesenteric Arteries; Phenylpropionates; Pyrimidines; Rats; Rats, Sprague-Dawley

Trandolapril was given to male Wistar rats with aortic banding at 10 AM or 10 PM for 6 weeks to examine the influence of dosing time on the development of left ventricular mass (LVM). Aortic banding increased the LVM compared with the sham-operated animals (P<0.01). Trandolapril (1 mg/kg) at 10 AM reduced LVM (1.74+/-0.04 [S.E.M.] mg/g) more than the dosing at 10 PM (1.92+/-0.04 mg/g, P<0.05), suggesting that trandolapril has a dosing time-dependent effect in the prevention of cardiac hypertrophy in rats with aortic banding.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Cardiomegaly; Dose-Response Relationship, Drug; Hypertrophy, Left Ventricular; Indoles; Male; Rats; Rats, Wistar; Time Factors

We quantified the repolarization time (so-called QT interval) in a rat, an animal species that does not show a well-characterized T wave on surface ECG. We used spontaneously hypertensive rats (SHR) and converting enzyme inhibition to demonstrate a reversible increase in QT interval in pressure-overloaded hearts in the absence of ischemia. An implanted telemetry system recording ECG data in freely moving rats was used to automatically calculate the RR interval. The QT duration was manually determined by use of a calibrated gauge, and a time-frequency domain analysis was used to evaluate heart rate variability. Left ventricular mass was sequentially assessed by echocardiography. Before treatment, 12-month-old SHR had higher left ventricular mass, QT and RR intervals, and unchanged heart rate variability compared with age-matched Wistar rats. A 2-month converting enzyme inhibition treatment with trandolapril reduces systolic blood pressure, left ventricular mass, and QT interval. The RR interval and heart rate variability remains unchanged. There is a positive correlation between the QT interval and left ventricular mass. The SHR is suitable for longitudinal studies on the QT interval. Thus, the detection of the QT interval reflects the phenotypic changes that occur during mechanical overload and, on the basis of these criteria, allows an in vivo determination of the adaptational process.

Topics: Age Factors; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Echocardiography; Electrocardiography; Electrocardiography, Ambulatory; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Indoles; Observer Variation; Rats; Rats, Inbred SHR; Rats, Wistar; Regression Analysis; Reproducibility of Results; Species Specificity

Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmia and multiple electrophysiologic abnormalities that normalize with regression of hypertrophy. For patients who have hypertension, treatment with angiotensin-converting enzyme (ACE) inhibitors produces regression of hypertrophy and a reduction in ventricular arrhythmia. It is unclear whether the reduction in ventricular arrhythmia associated with ACE inhibitor therapy is due to regression of hypertrophy alone, a direct antiarrhythmic effect of ACE inhibition, or both. We performed electrophysiologic studies in normal cats and cats with fixed left ventricular hypertrophy before and after acute intravenous administration of trandolopril. Trandolopril produced a small, consistent prolongation of monophasic action potential duration in normal and hypertrophied ventricles although this prolongation did not reach statistical significance. Trandolopril had no significant effect on effective refractory period, inducibility of arrhythmia, or ventricular fibrillation threshold in normal or hypertrophied ventricles. These data suggest that the reduction in arrhythmia associated with ACE inhibitors is not caused by a direct electrophysiologic effect but is more likely caused by regression of hypertrophy.

Topics: Action Potentials; Angiotensin-Converting Enzyme Inhibitors; Animals; Cats; Heart Conduction System; Heart Ventricles; Hypertrophy, Left Ventricular; Indoles; Ventricular Function

Although severe arrhythmias are still a major problem in patients with left ventricular hypertrophy (LVH), the relationship between ventricular remodeling and its regression or prevention, and the prevalence of ventricular premature beats (VPB) or more sustained arrhythmias are still poorly explored in hypertensive heart disease.. Holter monitoring was used to quantify supraventricular premature beats and VPB and heart rate (HR) in middle-aged spontaneously hypertensive rats (SHR) and Wistar rats treated for 3 months with trandolapril (ACE inhibitor, 0.3 mg/kg per day). Hypertrophy and fibrosis were morphometrically determined. Statistical analysis was performed with the use of simple regression and multivariate data analysis (cluster and correspondence analysis). SHR have higher cardiac mass and fibrosis, more VPB, and a decreased HR. Cluster analysis demonstrated that trandolapril was only effective in SHR. Trandolapril significantly reduced cardiac hypertrophy, fibrosis, and VPB incidence and increased the HR. Simple regression analysis showed that VPB incidence correlated to both hypertrophy and fibrosis. Correspondence analysis evidenced a strong correlation between hypertrophy, fibrosis, and VPB, but only for severe hypertrophy, and the correlation disappeared for moderate hypertrophy.. After trandolapril treatment, the regression of VPB incidence not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved including the myocardial phenotype and new calcium metabolism. Our model of Holter monitoring in conscious middle-aged SHR and multivariate data analysis might be useful in correlating myocardial structural modifications and ectopic activity.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Complexes, Premature; Electrocardiography, Ambulatory; Endomyocardial Fibrosis; Hypertension; Hypertrophy, Left Ventricular; Incidence; Indoles; Male; Multivariate Analysis; Prevalence; Rats; Rats, Inbred SHR; Rats, Wistar

The effects of trandolapril, a converting enzyme inhibitor (CEI), on left ventricular (LV) diastolic stiffness and coronary vascular resistance (CVR), were studied with an isolated heart preparation in 15-month-old spontaneously hypertensive rats (SHR). The hypertensive animals were treated for 3 months with trandolapril (0.3 mg/kg/day) (SHRT), and compared with untreated age-matched Wistar-Kyoto rats (WKY) and SHR. Trandolapril treatment resulted in 15% diminution in blood pressure (BP). In contrast, it completely normalized left ventricular (LV) weight. Untreated SHR, as compared with WKY, had a dilated LV and increased diastolic tissue stiffness. Trandolapril had no effect on either chamber or tissue stiffness. Five-minute anoxia resulted in the same dramatic increase in chamber stiffness in every experimental group. During anoxia, as during normoxia, tissue stiffness was still greater in SHR than in WKY. A major effect of CEI was to normalize the tissue stiffness of SHR under anoxia. Coronary vascular resistance (CVR) was increased in SHR as compared with WKY. Trandolapril improves CVR and significantly shifts the coronary pressure flow curve to the dilatory side. Both collagen concentration (approximately 2 mg/g) and the content in slow V3 myosin isoform, used as biologic markers of cardiac senescence, were the same in the three experimental groups, but higher than in young hearts. Trandolapril had no effect on these parameters. In semisenescent SHR, despite having rather slight effect on arterial pressure, trandolapril completely normalized LV weight. In addition, collagen content and its physiologic counterpart, tissue stiffness, were unaffected by 3-month treatment with trandolapril. Nevertheless, the anoxia-induced increase in LV tissue stiffness was improved by trandolapril in parallel with reduction in LV hypertrophy (LVH).

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Coronary Vessels; Disease Models, Animal; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Hypoxia; In Vitro Techniques; Indoles; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vascular Resistance

In 15 patients with untreated mild to moderate essential hypertension and left ventricular hypertrophy, we assessed blood pressure, echocardiographic left ventricular mass index, brachial artery compliance (pulsed doppler flowmetry), and calculated forearm vascular resistance (strain gauge plethysmography) before, during (6 and 12 months) and after (1 month washout period) 1 year of satisfactory (blood pressure < or = 140/90 mm Hg) antihypertensive therapy with the angiotensin-converting enzyme inhibitor trandolapril (2.0 mg orally once daily). During the antihypertensive effective treatment, we observed a significant reduction of systolic and diastolic blood pressures, left ventricular mass index, and forearm vascular resistance at both 6 and 12 months. In addition, brachial artery compliance was significantly increased. After washout, systolic (156 +/- 3 mm Hg) and diastolic (102 +/- 1 mm Hg) blood pressures returned to levels comparable to baseline. However, left ventricular mass index (132 +/- 4; p < 0.01) and brachial artery compliance (1.53 +/- 0.01; p < 0.01) were still different from baseline. These results demonstrate that chronic antihypertensive treatment with trandolapril is associated with a stable regression of cardiac and vascular abnormalities, which is partially unrelated to the blood pressure lowering effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteries; Brachial Artery; Compliance; Forearm; Heart; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Indoles