Effect of Cilazapril on Ventricular Remodeling Assessed by Doppler-Echocardiographic Assessment and Cardiac Gene Expression

The purpose of this study is to determine whether the administration of the ACE inhibitor cilazapril can lessen the adverse effects of ventricular remodeling, including systolic and diastolic dysfunction, modulation of fetal gene expression, increase of collagen genes, and depression of the sarcoplasmic reticulum (SR) Ca²⁺ ATPase gene in a myocardial infarcted (MI) rat model. At 1 day after MI, the animals were randomly assigned to cilazapril treatment or no treatment. We performed Doppler-echocardiographic examinations and measured cardiac mRNA in rats at 1 month and 3 months after MI (each group n = 8). The weights of the right (RV) and left ventricles (LV) in 1- and 3-month MI rats were significantly larger than those of the control rats. Cilazapril significantly prevented the increase. The MI rats showed systolic dysfunction, as evidenced by decreased fractional shortening (control, 34 ± 3% vs. MI, 17 ± 3%; P <0.01) and ejection fraction measured by the modified Simpsons method (control, 61 ± 2% vs. MI, 36 ± 3%; P < 0.01) in rats at 1 month after operation. MI rats showed diastolic dysfunction, defined as increased peak early filling velocity, increased deceleration rate of the early filling wave, decreased late filling velocity, and an increase in the ratio of early filling to late filling velocity. Cilazapril significantly prevented systolic and diastolic dysfunction in rats after MI. The increases in -MHC, -skeletal actin, ANP, and collagen I and III mRNAs in the nonischemic LV and RV were significantly suppressed by treatment with cilazapril. Depressed SR Ca²⁺-ATPase mRNA (nonischemic LV, 0.7-fold, P < 0.05 vs. control; RV, 0.5-fold, P < 0.05 vs. control) at 3 months after MI was significantly restored to normal levels by cilazapril. Cilazapril improved the adverse remodeling process by attenuating the progression of systolic and diastolic dysfunction, and prevented abnormal cardiac gene expression following MI.     

Whole blood viscosity as a determinant of cardiac hypertrophy in systemic hypertension

The relationships among blood pressure (BP), blood viscosity and echocardiographic left ventricular (LV) muscle mass were evaluated in 24 patients with essential hypertension and in 13 normotensive control subjects. LV mass was greater in the hypertensive patients than in the control subjects (225 ± 69 vs 170 ± 31 g, p < 0.02) as was blood viscosity at a shear rate of 104 sec^?1 (4.7 ± 0.1 vs 4.3 ± 0.2 cp, p <0.005). Among the hypertensive patients, LV mass was most closely related to viscosity at 104 sec^?1 (r = 0.80, p < 0.001), whereas only weak correlations were found between LV mass and systolic or diastolic BP (r = 0.45, p < 0.05 for both). The 14 hypertensive patients with normal LV mass had viscosity similar to that in control subjects (4.5 ± 0.3 vs 4.3 ± 0.2 cp), whereas viscosity was consistently increased (5.0 ± 0.4 cp, p < 0.02) in hypertensive patients with LV hypertrophy. Thus, increased blood viscosity may be a determinant of or a response to hypertensive cardiac hypertrophy.     

Left Ventricular Untwisting in Restrictive and Pseudorestrictive Left Ventricular Filling: Novel Insights into Diastology

Background: Conceptually, an ideal therapeutic agent should target the underlying mechanisms that cause left ventricular (LV) diastolic dysfunction. The objective of our study was to gain further insight into the mechanics of diastology by comparison of LV untwisting measured by speckle tracking echocardiography (STE) in young healthy adults with normal and “pseudorestrictive” LV filling, and dilated cardiomyopathy (DCM) patients with “true restrictive” LV filling. Methods: The study comprised 20 healthy volunteers with a Doppler LV‐inflow pattern compatible with restrictive LV filling but a diastolic early phase filling velocity/early diastolic velocity of the mitral annulus (E/Em) ratio <8 (“pseudorestrictive”), 20 for age and gender‐matched healthy volunteers with normal LV filling and an E/Em ratio <8, and 10 DCM patients with “true restrictive” LV filling and an E/Em ratio >15. LV untwisting parameters were determined by STE. Results: Compared to healthy subjects, DCM patients had decreased peak diastolic untwisting velocity (−62 ± 33 degrees/s vs −113 ± 25 degrees/s, P < 0.01) and untwisting rate (−15 ± 9 degrees/s vs −51 ± 24 degrees/s, P < 0.01). Compared to healthy subjects with normal LV filling, healthy subjects with “pseudorestrictive” LV filling had increased peak diastolic untwisting velocity (−123 ± 25 degrees/s vs −104 ± 30 degrees/s, P < 0.05) and untwisting rate (−59 ± 23 degrees/s vs −44 ± 22 degrees/s, P < 0.05). Conclusion: Faster LV untwisting plays a pivotal role in the rapid early diastolic filling occasionally seen in young healthy individuals. In contrast, in DCM patients untwisting is severely delayed and this impairment to utilize suction may reduce LV filling. (Echocardiography 2010;27:269‐274)     

Survival after myocardial infarction in rats: captopril versus losartan

Objectives. This study sought to compare the effects of angiotension-converting enzyme inhibition versus angiotensin II receptor blockade on survival in rats with myocardial infarction.Background. The effects of speciifc nonpeptide angiotensin receptor blocking agents on survival after myocardial infarction are unknown.Methods. Rats with a moderate to large myocardial infarction were treated with captpril (2 g/liter drinking water, n= 87) or losartan (2 g/liter drinking water, n= 96). Therapy was initiated immediately after coronary artery ligation and continued for 1 years.Results. Uncensored median survival in captopril-treated rats that survived at least 48 h was 201.5 days versus 236.0 days for losartan-treated rats (p = 0.066). Median survival censored for rats with lung infections was 201.5 days in captopril-treated rats versus 243.0 days for losartan-treated rats (p = 0.028). Conscious hemodynamic measurements and remodeling data obtained at 1 year in the surviving rats (n = 5 for captopril; n = 9 for losartan) revealed no differences in heart weight, left ventricular pressure, dP/dt, cardiac index, time constant of relaxation or any variable of left ventricular remodeling. The only differences (mean ± SD) were an increase in heart rate (293 ± 19 vs. 260 ± 15 beats/min, p < 0.05) and a decrease in peak developed pressure (153 ± 21 vs. 180 ± 16 mm Hg, p < 0.05) in the losartan-treated rats.Conclusions. We conclude that in this experimental model of heatr failure, there was no difference between survival after angiotensin II receptor blockade with losartan and with angiotensin-converting enzyme inhibition with captopril.     

Left Ventricular Diastolic Filling With an Implantable Ventricular Assist Device: Beat to Beat Variability With Overall Improvement

Objectives. We studied the effects of left ventricular (LV) unloading by an implantable ventricular assist device on LV diastolic filling.Background. Although many investigators have reported reliable systemic and peripheral circulatory support with implantable LV assist devices, little is known about their effect on cardiac performance.Methods. Peak velocities of early diastolic filling, late diastolic filling, late to early filling ratio, deceleration time of early filling, diastolic filling period and atrial filling fraction were measured by intraoperative transesophageal Doppler echocardiography before and after insertion of an LV assist device in eight patients. A numerical model was developed to simulate this situation.Results. Before device insertion, all patients showed either a restrictive or a monophasic transmitral flow pattern. After device insertion, transmitral flow showed rapid beat to beat variation in each patient, from abnormal relaxation to restrictive patterns. However, when the average values obtained from 10 consecutive beats were considered, overall filling was significantly normalized from baseline, with early filling velocity falling from 87 ± 31 to 64 ± 26 cm/s (p < 0.01) and late filling velocity rising from 8 ± 11 to 32 ± 23 cm/s (p < 0.05), resulting in an increase in the late to early filling ratio from 0.13 ± 0.18 to 0.59 ± 0.38 (p < 0.01) and a rise in the atrial filling fraction from 8 ± 10% to 26 ± 17% (p < 0.01). The deceleration time (from 112 ± 40 to 160 ± 44 ms, p < 0.05) and the filling period corrected by the RR interval (from 39 ± 8% to 54 ± 10%, p < 0.005) were also significantly prolonged. In the computer model, asynchronous LV assistance produced significant beat to beat variation in filling indexes, but overall a normalization of deceleration time as well as other variables.Conclusions. With LV assistance, transmitral flow showed rapidly varying patterns beat by beat in each patient, but overall diastolic filling tended to normalize with an increase of atrial contribution to the filling. Because of the variable nature of the transmitral flow pattern with the assist device, the timing of the device cycle must be considered when inferring diastolic function from transmitral flow pattern.     

Increased Atrial Contribution to Left Ventricular Filling Compensates for Impaired Early Filling During Exercise in Heart Failure With Preserved Ejection Fraction

BackgroundThe role of left atrial (LA) function on exercise remains poorly understood in heart failure with preserved ejection fraction (HfpEF) despite its key role in optimizing left ventricular (LV) diastolic function. We used resting and exercise radionuclide ventriculography to investigate the role of LA function in the pathophysiology of HfpEF.Methods and ResultsA total of 25 patients with HfpEF and 15 age- and gender-matched controls were recruited. All subjects underwent resting echocardiogram, metabolic exercise testing to peak effort, and radionuclide ventriculography (at rest and exercise [to 35% of heart rate reserve]). At rest LA and LV function were similar in patients and controls. During exercise, HfpEF patients had lower left ventricular ejection fraction (69 ± 9% vs. 73 ± 10%, P < .05) and lower peak early filling rate (387 ± 109 end-diastolic count/sec vs. 561 ± 156 end-diastolic count/sec, P < .001). During exercise, the atrial contribution to LV filling was significantly higher in patients than controls (46 ± 11% vs. 30 ± 9%, P < .001). Atrial contribution to LV filling correlated negatively with peak early filling rate during exercise (r = -0.6, P < .001). Peak early filling rate correlated positively with peak oxygen consumption (r = 0.485, P = .004) and negatively with minute/carbon dioxide production (r = -0.423, P = .013).ConclusionPatients with HfpEF have increased atrial contribution to LV filling as a compensatory response to impaired early LV filling during cycle exercise.     

Mechanism of left a trial enlargement related to ventricular diastolic impairment in hypertension

Background and hypothesis: Systemic hypertension is the leading cause of left ventricular (LV) hypertrophy. The present study aimed to investigate the mechanism of left atrial (LA) enlargement in patients with hypertensive heart disease during cardiac catheterization. Methods: Data were obtained from eight control subjects and seven patients with hypertensive heart disease. Left atrial and LV pressures from catheter-tip micromanometer, and LA and LV volumes from biplane cineangiograms were analyzed during the same cardiac cycle. Results: Left atrial maximal volume were 93 ± 26 ml in patients with hypertensive heart disease and 63 ± 12 ml in control subjects (p<0.05). In patients with hypertensive heart disease, time constant of LV relaxation was significantly greater than that in controls (54 ± 18 vs. 31 ± 16 ms, respectively p<0.01). Left atrial maximal volume correlated with time constant of LV relaxation (r = 0.86, p<0.01). The ratio of LV filling volume before LA contraction to LV stroke volume in patients with hypertensive heart disease was significantly lower than that in control subjects (65 ± 13 vs. 76 ± 7%, respectively p<0.05). On the other hand, the ratio of LV filling volume during LA contraction to stroke volume in patients with hypertensive heart disease was significantly higher than that in controls (35 ± 13 vs. 24± 7%, respectively p<0.05). Left atrial volume before LA contraction in patients with hypertensive heart disease was significantly larger than that in controls (74 ± 22 vs. 47 ± 10 ml, respectively, p<0.01). During LA contraction, LA work was significantly increased in patients with hypertensive heart disease compared with that in controls (274 ± 101 vs. 94 ± 42 mmHg. ml, respectively p<0.001). Left atrial work showed significant correlation with LA volume before LA contraction (r = 0.75, p <0.01). Conclusion: Left ventricular diastolic filling was impaired in patients with hypertensive heart disease. Enlargement of left atrium might be attributed to the impairment of blood flow from left atrium to left ventricle due to the increased LV stiffness.     

Nebivolol prevents myocardial fibrosis and diastolic dysfunction in salt-loaded spontaneously hypertensive rats

BackgroundWe have demonstrated previously that a high-salt diet (HS) produces myocardial fibrosis, left ventricular (LV) dysfunction, and renal insufficiency in adult spontaneously hypertensive rats (SHR), and that blockade of the renin-angiotensin system prevented those adverse effects of HS.Methods and ResultsEight-week-old male SHR were divided into four groups: controls received regular rat chow (0.6 NaCl); the other three were given HS. The second group was given placebo; the third, nebivolol (2 × 10 mg/kg/day) orally; and, the fourth, the same dose of nebivolol by osmotic minipump. Rats received respective treatments for 8 weeks. The data demonstrated that the HS induced increased cardiac mass (2.85 ± 0.05 vs. 5.36 ± 0.22 mg/g; P < .05 in control and HS groups, respectively); LV fibrosis as indicated by higher hydroxyproline concentration; further increase in arterial pressure (161 ± 7 vs. 184 ± 8 mm Hg; P < .05); myocardial ischemia; and LV diastolic dysfunction. Nebivolol ameliorated the adverse cardiac effects of HS, demonstrated by decreased LV mass and fibrosis and improved coronary hemodynamics and LV function.ConclusionsThe effects of nebivolol were independent of arterial pressure. The results of this study provide important laboratory data that support a rationale for nebivolol in the treatment of patients with hypertension having diastolic dysfunction with preserved ejection fraction.     

Ischemia-induced impairment of left ventricular relaxation: Relation to reduced diastolic filling rates of the left ventricle

An investigation was performed in order to better define the cause of reduced diastolic filling rates of the left ventricle (LV) observed in the setting of acute myocardial ischemia. Seven closed chest, anesthetized pigs were instrumented by placing a micromanometer-tip catheter in the LV and a balloon tip catheter in the midportion of the left anterior descending coronary (LAD) artery. The animal's red blood cells were labeled with technetium-99m and LV time-activity curves obtained by means of a computer-controlled, nonimaging cardiac probe (collimated, 3.5 cm DIA, sodium iodide crystal). Nuclear data obtained simultaneously with LV pressure data were used to evaluate diastolic pressure-count rate (i.e., volume) relations of the LV under control conditions and at 5 and 10 minutes after balloon occlusion of the animal's LAD. Diastolic filling rates, the time constant (“T”) of ventricular relaxation, the chamber passive stiffness constant (“K”), and maximum negative left ventricular $\text{DP}\text{DT}$ were computed for each experimental condition. Maximum negative $\text{DP}\text{DT}$ decreased compared with control (1690 + 699 mm Hg/sec; mean ± 1 SD) at both 5 minutes (1040 ± 493, p < 0.01) and 10 minutes (1360 ± 588, p < 0.05) after occlusion. Likewise “T” was prolonged versus control (45.3 ± 6.4) at both 5 minutes (56.8 ± 12.8, p < 0.01) and 10 minutes (54.0 ± 8.7, p < 0.05) after occlusion. In contrast both “K” and calculated left ventricular pressure at zero counts (i.e., volume) remained constant throughout the study. Left ventricular end-diastolic pressure also did not change significantly during the study. The mean, maximal, and mid to late LV diastolic filling rates all were prolonged significantly (p < 0.05) versus control at 5 minutes and 10 minutes after occlusion. The rate of early diastolic filling of the LV did not change significantly during the study, although it tended to decline along with the other rates. Thus, ischemia-induced changes in diastolic filling rates may be seen in the absence of changes in left ventricular chamber stiffness, and ischemia-induced impairment of left ventricular relaxation alone is sufficient to reduce the rate of diastolic filling of the LV.     

Cardiac Thyrotropin-releasing Hormone Inhibition Improves Ventricular Function and Reduces Hypertrophy and Fibrosis After Myocardial Infarction in Rats

BackgroundCardiac thyrotropin-releasing hormone (TRH) is a tripeptide with still unknown functions. We demonstrated that the left ventricle (LV) TRH system is hyperactivated in spontaneously hypertensive rats and its inhibition prevented cardiac hypertrophy and fibrosis. Therefore, we evaluated whether in vivo cardiac TRH inhibition could improve myocardial function and attenuate ventricular remodeling in a rat model of myocardial infarction (MI).Methods and ResultsIn Wistar rats, MI was induced by a permanent left anterior descending coronary artery ligation. A coronary injection of a specific small interfering RNA against TRH was applied simultaneously. The control group received a scrambled small interfering RNA. Cardiac remodeling variables were evaluated one week later. In MI rats, TRH inhibition decreased LV end-diastolic (1.049 ± 0.102 mL vs 1.339 ± 0.102 mL, P < .05), and end-systolic volumes (0.282 ± 0.043 mL vs 0.515 ± 0.037 mL, P < .001), and increased LV ejection fraction (71.89 ± 2.80% vs 65.69 ± 2.85%, P < .05). Although both MI groups presented similar infarct size, small interfering RNA against TRH treatment attenuated the cardiac hypertrophy index and myocardial interstitial collagen deposition in the peri-infarct myocardium. These effects were accompanied by attenuation in the rise of transforming growth factor-β, collagen I, and collagen III, as well as the fetal genes (atrial natriuretic peptide, B-type natriuretic peptide, and beta myosin heavy chain) expression in the peri-infarct region. In addition, the expression of Hif1α and vascular endothelial growth factor significantly increased compared with all groups.ConclusionsCardiac TRH inhibition improves LV systolic function and attenuates ventricular remodeling after MI. These novel findings support the idea that TRH inhibition may serve as a new therapeutic strategy against the progression of heart failure.     

Allicin Ameliorates Cardiac Hypertrophy and Fibrosis through Enhancing of Nrf2 Antioxidant Signaling Pathways

Aim

To evaluate the protective effects of allicin on Ang II-induced cardiac hypertrophy.

Methods

Sprague?CDawley male rats were randomized into 3 groups:1)sham group (saline)(n?=?12), 2) Ang II group(n?=?9), 3) allicin group (Ang II + allicin)(n?=?9). They received infusions of either saline or Ang II (250?ng/kg body weight per min) through mini-osmotic pumps implanted subcutaneously for 2?weeks and given a diet containing 180?mg/kg/day of allicin for 8 consecutive weeks. Hemodynamic, morphological, histological, and biochemical changes were evaluated at corresponding time points.

Results

Ang II infusion increased blood pressure, heart rate and heart weight to body weight ratio, and resulted in anatomical and functional changes, such as increased LV mass, posterior wall thickness and LV end-diastolic diameter, and decreased fractional shortening and EF compared with sham rats. Nrf2 and HO-1 in the hearts of rats in the Ang II group were moderately elevated at both mRNA and protein levels compared to sham group mice, but NQO1 and??-GCS were significantly lower. GPx activities, levels of GSH and T-AOC in the hearts of the rats in the Ang II group were also significantly lower, and the levels of TBARS, reactive oxygen species and protein carbonyl were significant increased. Allicin attenuated LV mass, posterior wall thickness and LV end-diastolic diameter (1.10?±?0.04 vs. 1.37?±?0.05, 2.26?±?0.08 vs. 2.96?±?0.12, 7.27?±?0.36 vs. 8.56?±?0.41, respectively; all P?<?0.05), and increased fractional shortening and EF (28.30?±?3.21 vs. 25.40?±?2.57, 60.27?±?5.63 vs. 51.30?±?4.78, respectively; both P?<?0.05) in the Ang II-induced hypertrophic rats compared to the untreated Ang II rats. Furthermore, allicin treatment attenuated the accumulation of interstitial collagen and collagen I/III (P?<?0.01 vs. the untreated Ang II group), decreased the levels of reactive oxygen species, protein carbonyl and TBARS and increased GPx activities. Moreover, allicin significantly increased mRNA expression and protein levels of Nrf2, NQO1, and ??-GCS ( P?<?0.01, P?<?0.05 vs. the untreated Ang II group).

Conclusion

Allicin could prevent the development of cardiac remodeling and the progression of cardiac hypertrophy to cardiac dysfunction caused by enhancing the Nrf2 antioxidant signaling pathways.     

Left ventricular diastolic performance at rest is essential for exercise capacity in patients with non-complicated myocardial infarction

IntroductionIn patients with recent myocardial infarction (MI) limited exercise capacity during physical activity is an important symptom and the base for future treatment. The myocardial injury after MI leads to both systolic and diastolic left ventricular (LV) dysfunction.ObjectiveThe aim of this study was to assess the relevance of systolic and diastolic LV function for cardiopulmonary exercise capacity in patients with prior MI.MethodsSixty-five consecutive patients after first MI without signs and symptoms of heart failure, aged 52 ± 6 years, were included in the study. The following echo parameters were evaluated: LV ejection fraction (LVEF), peak early and late diastolic velocities (E, A), deceleration time of E wave (dec t E), ratio of early trans-mitral to early annular diastolic velocities (E/e′), velocity propagation of early filling (Vp), and diameters and volumes of LV and left atrium (LA). CPET variables included: oxygen uptake at peak exercise (peak VO₂), oxygen pulse (VO₂ HR), VE/VCO₂ slope, circulatory power (CP) and recovery half time (T1/2).ResultsSignificant correlations were demonstrated between peak VO₂ and E/e’ (p < 0.001), peak VO₂ and dec t E (p < 0.001), VO₂ HR and E/e′ (p = 0.002) and between VE/VCO₂ and E/e′ (p < 0.001). Twenty patients with elevated LV filling pressure achieved significantly lower peak VO₂ (1624 vs. 1932 ml, p = 0.027) VO₂ HR (11.70 vs. 14.05, p = 0.011) and CP (287,073 vs. 361,719, p = 0.014). By using multivariate regression model we found that only E/e′ (p = 0.001) and dec t E (p = 0.008) significantly contributed to peak VO₂.ConclusionsDiastolic dysfunction, particularly LV filling pressure, determine exercise capacity, despite differences in LV ejection fraction in patients with prior MI.     

Effects of Nifedipine and Nitroglycerin on Left Ventricular Systolic Dysfunction and Impaired Diastolic Filling After Exercise-Induced Ischemia in Humans

Objectives. This study sought to determine whether calcium antagonist, compared with nitroglycerin, administration attenuates left ventricular dysfunction after exercise-induced ischemia in humans.Background. Exercise-induced ischemia impairs left ventricular systolic function and diastolic filling after exercise. The mechanism of this phenomenon is unknown but may relate to intracellular calcium overload.Methods. Echocardiography was performed in 131 patients before and 30 min, 2 h and 4 h after exercise stress test. Ischemia was defined as a reversible thallium stress defect. No medication, sublingual nitroglycerin or nifedipine was randomly given to each patient at peak exercise.Results. Isovolumetric relaxation time was significantly prolonged from rest (100 ± 19 ms [mean ± SD]) to 30 min (118 ± 20 ms, p < 0.0005), 2 h (117 ± 18 ms, p < 0.0005) and 4 h (110 ± 22 ms, p < 0.05) after exercise in 21 patients with exercise-induced ischemia who received no medication (ischemia-none group). Isovolumetric relaxation time similarly increased after exercise in 23 patients who received nitroglycerin and had exercise-induced ischemia (ischemia-NTG group) but was unchanged in 20 patients with exercise-induced ischemia who received nifedipine (ischemia-nifedipine group). Peak early filling velocity decreased in the ischemia-none and ischemia-NTG groups from rest to 30 min and 2 h after exercise, but peak early filling velocity was unchanged in the ischemia-nifedipine group. Ejection fraction decreased from rest to 30 min after exercise in the ischemia-none group (59 ± 12% vs. 51 ± 13%, p < 0.025) and ischemia-NTG group (59 ± 14% vs. 49 ± 14%, p < 0.005) but was unchanged in the ischemia-nifedipine group (50 ± 19% vs. 64 ± 18%, p = NS). A new regional left ventricular wall motion abnormality occurred more frequently 30 min after exercise in the ischemia-none group (11 [52%] of 21) and ischemia-NTG group (9 [39%] of 23) compared with the ischemia-nifedipine group (2 [10%] of 20, both p < 0.05). No change occurred in left ventricular systolic function and diastolic filling after exercise in the control groups.Conclusions. Exercise-induced ischemia impairs systolic function and diastolic filling after exercise. Sublingual nifedipine but not nitroglycerin attenuates this process and suggests that altered calcium homeostasis may play a role in left ventricular dysfunction that occurs after exercise-induced ischemia.     

Ventricular remodeling and transforming growth factor-beta 1 mRNA expression after nontransmural myocardial infarction in rats: effects of angiotensin converting enzyme inhibition and angiotensin II type 1 receptor blockade

With the application of early reperfusion therapy after acute MI, the incidence and importance of nontransmural infarction is increasing. In a rat model with nontransmural infarction, we evaluated 1) the changes of LV dimension, LV interstitial fibrosis and transforming growth factor-β1 (TGF-β1) mRNA expression and 2) the effects of angiotensin converting enzyme (ACE) inhibitor and angiotensin II type 1 (AT1) receptor antagonist treatment. Female Sprague-Dawley rats were subjected to 45 min of coronary occlusion followed by reperfusion, and five days after the operation the animals were randomized to untreated (n = 19), captopril-treated (n = 15) and losartan-treated (n = 14) groups. Twenty-six days after MI, echocardiographic examination revealed a remarkable dilatation of LV. Captopril or losartan treatment reduced the extent of LV cavity dilatation. Collagen volume fractions in noninfarcted septum as well as in peri-infarct area decreased with captopril or losartan treatment, compared to those of the untreated rats. In noninfarcted septum of untreated rats, TGF-β1 mRNA expression increased more than two fold (P < 0.05 vs. pre-MI) 5 and 10 days after MI. Captopril or losartan treatment suppressed the acute induction of TGF-β1 mRNA expressions. These results indicate that ACE inhibitor or AT1 receptor antagonist treatment after nontransmural infarction 1) attenuates LV remodeling as in transmural infarction and 2) decreases interstitial fibrosis at least partly by blocking the acute induction of TGF-β1 mRNA expression. Received: 10 December 1998, Returned for revision: 29 January 1999, Revision received: 15 March 1999, Accepted: 22 March 1999     

Infarct tissue characteristics of patients with versus without early revascularization for acute myocardial infarction: a contrast-enhancement cardiovascular magnetic resonance imaging study

Histopathological studies have suggested that early revascularization for acute myocardial infarction (MI) limits the size, transmural extent, and homogeneity of myocardial necrosis. However, the long-term effect of early revascularization on infarct tissue characteristics is largely unknown. Cardiovascular magnetic resonance (CMR) imaging with contrast enhancement (CE) allows non-invasive examination of infarct tissue characteristics and left ventricular (LV) dimensions and function in one examination. A total of 69 patients, referred for cardiac evaluation for various clinical reasons, were examined with CE-CMR >1?month (median 6, range 1?C213) post-acute MI. We compared patients with (n?=?33) versus without (n?=?36) successful early revascularization for acute MI. Cine-CMR measurements included the LV end-diastolic and end-systolic volumes (ESV), LV ejection fraction (LVEF, %), and wall motion score index (WMSI). CE images were analyzed for core, peri, and total infarct size (%), and for the number of transmural segments. In our population, patients with successful early revascularization had better LVEFs (46?±?16 vs. 34?±?14%; P?<?0.01), superior WMSIs (0.53, range 0.00?C2.29 vs. 1.42, range 0.00?C2.59; P?<?0.01), and smaller ESVs (121?±?70 vs. 166?±?82; P?=?0.02). However, there was no difference in core (9?±?6 vs. 11?±?6%), peri (9?±?4 vs. 10?±?4%), and total infarct size (18?±?9 vs. 21?±?9%; P?>?0.05 for all comparisons); only transmural extent (P?=?0.07) and infarct age (P?=?0.06) tended to be larger in patients without early revascularization. CMR wall motion abnormalities are significantly better after revascularization; these differences are particularly marked later after infarction. The difference in scar size is more subtle and does not reach significance in this study.     

Comparison of the effects of four ACE inhibitors on sympathetic reactivity to cold pressor test in essential hypertensive patients

Background. We compared the effects of four different structural angiotensin-converting enzyme (ACE) inhibitors on the hemodynamic profile and catecholamine response to the cold pressor test (CPT) in hypertensive patients. Methods. We studied 44 patients with mild to moderate essential hypertension. The patients were divided into four groups according to the ACE inhibitor [enalapril (E), fosinopril (F), captopril (C), or ramipril (R)]. They were given for 8 weeks. Sympathetic reactivity was evaluated by a CPT at baseline and at the end of therapy. Blood pressure (BP), heart rate (HR), and plasma norepinephrine (NE, pg ml⁻¹) were measured at the times 0, 2, 4, 6, 8, 10, and 15 min. The delta (subtracting the basal values from the min 2 values) and the area under the curve (AUC) of the response during the CPT were studied. Results. The rise in diastolic blood pressure (DBP) (AUC) during the cold stimulus was significantly attenuated by all inhibitors studied (P<0.01): E, 17±22 to 0±20; F, 23±41 to −4±40; C, 34±33 to 7±28; R, 32±28 to −1±25. Drug therapy also blunted the response of HR to cold stress (delta HR, bpm): E, 2±2 to 0±2, P<0.05; F, 2±2 to 0±2, P<0.05; C, 3±3 to −1±3, P<0.01; R, 2±4 to −2±3, P<0.05. The rise in plasma NE (AUC) during CPT was decreased by all ACE inhibitors: E, 198±405 to 24±148, P<0.05; F, 353±436 to 51±412, P<0.05; C, 315±318 to 124±516, P<0.05; R, 677±398 to 251±307, P<0.01. Conclusions. The results in our study suggest that the blunting effects of ACE inhibitors on adrenergic tone seem to be class-dependent.     

Effects of intravenous verapamil administration on left ventricular diastolic function in systemic hypertension

The effects of intravenous verapamil administration (0.1 mg/kg as a bolus followed by an infusion of 0.007 mg/kg/min) were studied using high-temporal-resolution radionuclide angiography in 27 patients with hypertension. Verapamil administration increased heart rate from 69 ± 11 to 75 ± 12 beats/min (p < 0.001) and decreased systolic, diastolic and mean blood pressures (BPs) from 155 ± 21/102 ± 12 mm Hg (mean 119 ± 14) to 142 ± 19/95 ± 12 mm Hg (mean 109 ± 13) (p < 0.001 for all). Ejection fraction decreased significantly (from 65 ± 10% to 60 ± 11%, p < 0.005); peak filling rate, however, increased significantly only in patients in whom it was subnormal in the basal study (from 2.2 ± 0.4 to 3.0 ± 0.6 end-diastolic counts/s, p < 0.001). These latter patients had significantly higher values of left ventricular (LV) mass index than patients with normal or increased peak filling rate (129 ± 22 vs 112 ± 22 g/m², respectively, p < 0.05). The isovolumic relaxation period changes were inversely related to the baseline values (r = 0.83, p < 0.001). In the subgroup of patients in whom isovolumic relaxation period lengthened, time to end systole decreased (from 360 ± 31 to 329 ± 30 ms, p < 0.025) and time to onset of rapid filling increased (from 420 ± 31 to 451 ± 34 ms, p < 0.025), whereas these 2 intervals had opposite patterns in patients in whom isovolumic relaxation period decreased or did not change. The delay in end systole during verapamil administration in patients in whom isovolumic relaxation period increased is likely a consequence of improved LV synchrony, as the coefficient of variation computed on functional images of LV time to end systole decreased, but it did not change in the other subgroup (from 26 ± 5% to 20 ± 3% [p < 0.005] and from 24 ± 3% to 24 ± 4% [difference not significant]).     

Long-acting calcium channel antagonist pranidipine prevents ventricular remodeling after myocardial infarction in rats

Summary The purpose of this study was to examine the effects of the long-acting calcium channel antagonist pranidipine on ventricular remodeling, systolic and diastolic cardiac function, circulating humoral factors, and cardiac mRNA expression in myocardial infarcted rats. Myocardial infarction (MI) was produced by ligation of the coronary artery in Wistar rats. Three mg/kg per day of pranidipine was randomly administered to the infarcted rats. Hemodynamic measurements, Doppler echocardiographic examinations, analyses of the plasma levels of humoral factors, and myocardial mRNA expression were performed at 4 weeks after myocardial infarction. Left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) increased to 24.2 ± 1.2mmHg and 5.4 ± 0.6mmHg. Pranidipine reduced LVEDP and CVP to 13.6 ± 1.4mmHg (P < 0.01) and 2.5 ± 0.4mmHg (P < 0.01). The weight of the left and right ventricles in MI was significantly higher than in the sham-operated rats (sham, 2.02 ± 0.04 and 0.47 ± 0.02g/kg; MI, 2.18 ± 0.05 and 0.79 ± 0.04g/kg;P < 0.01). Left ventricular end-diastolic dimension (LVDd) in MI increased to 10.3 ± 0.3mm (P < 0.01) (sham, 6.4 ± 0.3mm). Pranidipine prevented an increase in the weight of the left and right ventricles (2.02 ± 0.04 and 0.6 ± 0.03g/kg,P < 0.01) and LVDd (7.9 ± 0.2mm,P < 0.01 to MI). Plasma renin activity (PRA), and plasma epinephrine, norepinephrine, and dopamine concentrations in MI were higher than those of the sham-operated rats. Pranidipine decreased the PRA and plasma cathecolamine levels of the myocardial infarcted rats to the level of the sham-operated rats. Moreover, the rats in MI showed systolic dysfunction, shown by decreased fractional shortening (sham, 31 ± 2% vs MI, 15 ± 1%;P < 0.01) and diastolic dysfunction shown by the E-wave deceleration rate (sham, 12.8 ± 1.1 m/s²; MI, 32.6 ± 2.1m/s²;P < 0.01). Pranidipine significantly prevented systolic and diastolic dysfunction. The increases in β-myosin heavy chain (MHC), α-skeletal actin, and atrial natriuretic polypeptide mRNAs in the noninfarcted left ventricle and right ventricle at 4 weeks after the myocardial infarction were significantly suppressed by the treatment with pranidipine. On the other hand, depressed α-MHC was restored to normal levels by pranidipine in both regions. In conclusion, pranidipine prevents the left ventricular remodeling process accompanied by systolic and diastolic dysfunction, and inhibits abnormal cardiac gene expression after myocardial infarction.     

Markedly different effects on ventricular remodelling result in a decrease in inducibility of ventricular arrhythmias

Objectives. The purpose of this study was to determine wheteher the type and extent of ventricular remodelling after infarction influence inducebility of ventricular arrhthmias after infarction. Background. Although serious ventricular arrhythmias after infaction are related to ventricular dysfunction, the relation between inducibility of ventricular arrhythmias and ventricular remodeling remains incompletely understood.Methods. Rats that survived ligation of the left anterior descending coronary artery (n = 218) were randomized to receive placebo (saline solution) or captopril or propranolol therapy and were followed up for 5 weeks. Hemodynamic and neurohumoral blood measurements were obtained, and therapy was stopped. Two days later, susceptibility to ventricular arrhythmias was assessed by programmed electrical stimulation, and hearts were prepared for pathologic studies.Results. Placebo-treated rats with a large myocardial infarction had ventricular dysfunction, marked neurohumoral activation, ventricular enlargement (endocardial circumference 16 ± 3 [mean ± SD] to 20 ± 4 mm, p < 0.05) and increased cardiac fibrosis (volume density of collagen 23 ± 0.8% to 5.6 ± 2.4%, it p < 0.05). In many rats this resulted in easily inducible ventricular (inducibility quotient 4.9 ± 2.2). Captopril attenuated the development of ventricular dysfunction, neurohumoral activation, ventricular hypertrophy and dilation (endocardial circumference 18 ± 3 mm) and cardiac fibrosis (3.1 ± 0.8%, p < 0.05). These modifications were accompanied by inducibility of ventricular arrhythmias (inducibility quotient 1.1 ± 2.0, p < 0.05). Propranolol did not prevent ventricular dysfunction, had variable effects on neurohumoral activation and led to increased ventricular dilation (endocardial circumference 25 ± 4 mm, p < 0.05) and cardiac fibrosis (7.7 ± 1.2%, p < 0.05). Nevertheless, these morphologic changes led to decreased inducibility of ventricular arrhythmias (inducibility quotient 2.2 ±2.5%, p < 0.05).Conclusions. This study indicates that the inducibility of ventricular arrthymias can be reduced as a result of markedly different effects on ventricular remodeling, indicating that the relation between ventricular remodeling, arrhythmias and survival is more complex previously thought.     

Activity of Angiotensin‐Converting Enzyme After Treatment with L‐Arginine in Renovascular Hypertension

The renin‐angiotensin system plays a role in the pathophysiology of renovascular hypertension. In addition, some studies have demonstrated a beneficial effect of L‐arginine (L‐Arg), the precursor of nitric oxide (NO), in this model of hypertension. This study was designed to investigate the effects of L‐Arg on cardiovascular parameters and on the activity of the angiotensin‐converting enzyme (ACE), after 14 days of renovascular hypertension. The experiments were performed on conscious male Wistar rats. Two‐kidney, one‐clip renovascular hypertension (2K1C) was initiated in rats by clipping the left renal artery during 14 days, while control rats were sham‐operated. One group was submitted to a similar procedure and treated with L‐Arg (10 mg/ml; average intake of 300mg/day) from the 7th to the 14th day after surgery, whereas the respective control group received water instead. At the end of the treatment period, the mean arterial pressure (MAP) was measured in conscious animals. The rats were sacrificed and the ACE activity was assayed in heart and kidneys, using Hip‐His‐Leu as substrate. In a separate group, the heart was removed, the left ventricle (LV) was weighed and the LV/body weight ratios (LV/BW) were determined. We observed significant differences in MAP between the L‐Arg‐treated and untreated groups (129 ± 7 vs. 168 ± 6 mmHg; P < 0.01). The cardiac hypertrophy described for this model of hypertension was attenuated in the 2K1C‐L‐Arg‐treated group (14th day, wet LV/BW: 2K1C‐L‐Arg = 1.88 ± 0.1; 2K1C = 2.20 ± 0.1 mg/g; P < 0.05). L‐Arg administration caused an important decrease in cardiac ACE activity (2K1C‐L‐Arg: 118 ± 15; 2K1C: 266 ± 34 µmol/min/mg; P < 0.01). L‐Arg also decreased the ACE activity in the clipped kidney by 47% (P < 0.01), but not in the nonclipped kidney. These data suggest that increased NO formation and reduced angiotensin II formation are involved in the anthihypertensive effect of orally administered L‐arginine.