Because decreases in the ratio of myocardial insoluble to soluble collagen parallel LV dilatation in rats, reductions in myocardial collagen cross-linking may be an important mechanism contributing to LV dilatation in heart disease.

Collagen cross-linking may determine the diverse relation that exists between increases in myocardial collagen concentrations and either myocardial stiffness or chamber remodelling in hypertension. These findings support the notion that fibrosis contributes to myocardial stiffness as well as LV dilatation in LVH, albeit an effect that is modulated by collagen quality.

Abstract-It is uncertain whether chronic ␤-adrenoreceptor (␤-AR)-activation in hypertension could initiate the progression from compensated left ventricular (LV) hypertrophy to pump dysfunction. It is also uncertain if this effect is through adverse LV remodeling (chamber dilatation with wall thinning and pump dysfunction) or intrinsic myocardial contractile dysfunction. We evaluated the effect of 5 months of isoprenaline (0.02 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) on hemodynamics, LV wall thickness, cavity size, and interstitial characteristics in spontaneously hypertensive rats (SHR) with compensated LV hypertrophy. In the absence of myocyte necrosis, changes in volume preload, pressure afterload, and heart rate or decreases in baseline systolic myocardial elastance (load independent measure of intrinsic myocardial contractility), ISO produced a right shift in LV diastolic pressure-volume (P-V) relations (chamber dilatation), a decrease in LV wall thickness despite a further increase in LV weight in SHR, LV pump dysfunction (right shift in LV systolic P-V relations), and deleterious interstitial remodeling (increments in total and noncrosslinked myocardial collagen concentrations). The isoprenaline-induced LV geometric, chamber performance, and interstitial changes were similar to alterations noted during decompensation in older SHR. In summary, in the absence of tissue necrosis and baseline intrinsic myocardial contractile dysfunction, chronic ␤-AR activation induces interstitial and chamber remodeling and, hence, pump dysfunction. These data suggest that chronic sympathetic activation initiates the progression from compensated concentric LV hypertrophy in hypertension to cardiac dysfunction primarily through deleterious cardiac remodeling rather than intrinsic myocardial contractile dysfunction.

Abstract-Whether left ventricular (LV) hypertrophy is important in the development of LV failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling in hypertension has not been established. We examined the effect of an antihypertensive agent without the ability to regress LV hypertrophy on the development of LV changes in spontaneously hypertensive rats (SHR). Hydralazine given to SHR from 5.2 to 26 months of age returned systolic blood pressure to Wistar Kyoto (WKY) control values but failed to prevent the increase in LV mass noted in SHR (at 26 months of age: WKY, 0.99Ϯ0.02 g; untreated SHR, 1.40Ϯ0.02 g; treated SHR, 1.36Ϯ0.02 g; PϽ0.001 in SHR versus WKY). In comparison to both 16-month-old SHR and age-matched WKY, 26-month-old untreated SHR developed signs consistent with heart failure, LV dilatation (an increased LV internal radius), an eccentric LV geometry, advanced myocyte necrosis, an increase in myocardial collagen solubility (an index of decreases in myocardial collagen cross-linking), and marked increases in myocardial total, type III, and non-cross-linked myocardial collagen concentrations. Despite the inability of hydralazine to regress LV hypertrophy, treated SHR did not develop signs of heart failure, myocyte necrosis, decreases in myocardial collagen cross-linking, or increases in myocardial total, type III, and non-cross-linked collagen at 26 months of age. Moreover, treatment attenuated the development of LV dilatation and an eccentric LV geometry. In conclusion, antihypertensive therapy that does not attenuate LV hypertrophy but achieves normal blood pressure in SHR, is able to hinder the development of heart failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling. Key Words: hypertrophy, cardiac Ⅲ heart failure Ⅲ collagen P atients with a history of hypertension have at least a 6-fold greater risk of developing heart failure than do individuals without such a history 1 . Heart failure in hypertension can occur as a consequence of either diastolic dysfunction or systolic abnormalities associated with detrimental chamber (left ventricle [LV] dilatation and the development of an eccentric cardiac geometry) 2,3 and interstitial (reparative fibrosis with qualitative changes in collagen) 4 -6 remodeling. Although hypertensive patients with LV hypertrophy have a clear increased risk for cardiovascular events 7-10 and the development of diastolic heart failure, 11 clinical studies have provided only limited data regarding the importance of hypertensive LV hypertrophy as a risk factor for the development of heart failure associated with advanced cardiac damage and detrimental LV remodeling. [7][8][9][10] The aim of the present study, therefore, was to determine whether the use of an antihypertensive agent with no significant effect on modifying LV hypertrophy is able to influence the development of detrimental LV remodeling, LV damage, and heart failure in hypertensive heart disease. Hydralazine, a directactin...

The effect of hydrochlorothiazide (1 mg/kg per day) on left ventricular (LV) mass and systolic and diastolic function was investigated in two-kidney, one clip (2K1C) renovascular hypertensive rats. Hydrochlorothiazide was administered from 8 weeks, and LV mass and function were measured at 16 weeks after surgery to induce hypertension. Cardiac performance was determined from cardiac output, stroke volume (per 100 g of body weight), and stroke work (per gram of LV weight) versus LV end-diastolic pressure (LVEDP) and versus LV strain relations in anesthetized open-chest, ventilated rats. LV compliance was determined from the LVEDP versus strain relation. Strain was calculated from LV end-diastolic short-axis diameter values. Hydrochlorothiazide reduced systolic blood pressure in 2K1C rats to levels similar to those in sham-operated controls (sham) at 12 weeks after surgery. A reduced afterload failed to influence LV mass, as left LV hypertrophy developed to the same extent in treated 2K1C rats. 2K1C hypertension produced abnormal cardiac performance with altered cardiac output, stroke volume, and stroke work versus LVEDP relations (stroke work versus LVEDP, intercept of 2K1C versus sham,p<0.001). This was attributed to a decreased ventricular compliance (strain versus LVEDP, slope of 2K1C versus sham, p< 0.001). In contrast, hydrochlorothiazide improved ventricular compliance (strain versus LVEDP, slope of 2K1C versus 2K1C hydrochlorothiazide, p<0.01) and thus returned the stroke work versus LVEDP relation to sham values (intercept of 2K1C versus 2K1C hydrochlorothiazide, p< 0.001). We conclude that hydrochlorothiazide reduces blood pressure but not the development of ventricular hypertrophy in 2K1C rats. Although a reduced blood pressure did not produce regression of ventricular hypertrophy, it was associated with an improved ventricular compliance and thus performance. This study underscores the value of equating changes in ventricular hypertrophy with changes in cardiac function when the value of antihypertensive agents is being assessed. Received July 14, 1992; accepted in revised form December 15, 1992. Please note: After the manuscript was accepted, the authors sent a letter and revised manuscript because they discovered they had made a statistical error. The changes were sent to both reviewers. The manuscript with the revised changes was accepted January 27, 1993. ventricular performance. Studies on ventricular function in human hypertension are ethically limited by an inability to assess cardiac function over a range of controlled ventricular filling volumes and pressures. Abnormal ventricular systolic and diastolic functional changes in hypertensive heart disease may be detected only at controlled filling pressures.5 Therefore, improvement of ventricular function with hydrochlorothiazide may be detected only over a range of filling volumes and pressures. The effect of hydrochlorothiazide on cardiac performance at controlled filling volumes and pressures in hypertensive heart disease has not been investiga...