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Abstract-Gender-related differences responsible for the better prognosis of females with heart failure have not been clearly established. To address this issue, we investigated potential gender-related differences in myocyte remodeling in spontaneously hypertensive heart failure rats. Echocardiograms and myocyte growth were compared between males and females at compensated (2, 4, and 6 months) and decompensated (18 months in males and 24 months in females) stages of cardiac hypertrophy. Although left ventricular diastolic dimensions did not differ significantly between failing male and female rats, fractional shortening declined significantly only in failing males. Myocyte cross-sectional area did not change after 4 months of age in both genders, which is likely to be responsible for the absence of a change in left ventricular wall thickness during the progression to heart failure. Myocyte volume and cross-sectional area were significantly larger in males than females at 2, 4, and 6 months of age, although there were no significant differences at the failing stage. Reduced adaptive hypertrophic reserve was observed in males, which is likely to contribute to the higher morbidity and mortality of males with chronic heart failure. (Hypertension. 1999;33:676-680.)Key Words: heart failure Ⅲ remodeling, ventricular Ⅲ myocytes H eart failure is one of the major causes of death in the United States, with 4 to 5 million individuals living in the United States estimated to have chronic heart failure. Irrespective of the underlying cause, in end-stage heart failure, chamber dilation and an increased ratio of chamber diameter to wall thickness are common characteristics. Hypertension is still one of the major underlying diseases leading to heart failure. A thickened wall with normal ventricular chamber diameter is found at the compensated stage of hypertension, followed by chamber dilation and an increase in the ratio of chamber diameter to wall thickness in the decompensated stage. It has also been reported that males are more prone to heart failure caused by hypertension than females. 1,2 According to the Statistical Abstract of the United States, 3 139% more males than females died of heart disease between the ages of 45 to 64 years; however, after the age of 65, the number of females who died of heart disease exceeded that of males by 22%. 3 Since the prognosis of heart failure is much worse in males than females, it is important to identify potential gender-related differences responsible for the better prognosis in females. The purpose of the present study was to explore potential gender-related differences in myocyte remodeling in spontaneously hypertensive heart failure (SHHF) rats. In this genetic model of hypertension and heart failure, the progression to failure is accelerated in males. It has already been demonstrated that myocyte remodeling in female SHHF rats is similar to that observed in humans with hypertension progressing to failure. 4 It is not known, however, whether this adverse myocyte remodeling is ac...

Abstract-Progression to failure in hypertension is associated with ventricular dilation, excessive myocyte lengthening, and an increase in myocyte length/width ratio. The temporal development of these changes in relation to impaired pump performance is unknown. We examined isolated myocytes from 1-to 12-month-old spontaneously hypertensive heart failure (SHHF) rats who develop heart failure at approximately 24 months of age. Left ventricular myocyte cross-sectional area reached a maximum of Ϸ350 to 400 m 2 at 3 months of age and did not change significantly thereafter. Nonetheless, LV systolic wall stress, a known stimulus for myocyte transverse growth, increased progressively between 3 and 12 months of age. Unlike the situation in normally aging rats with stable body mass, myocyte length in SHHF rats continued to increase with aging (PϽ0.05 from 9 to 12 months of age). In summary, (1) left ventricular myocyte transverse growth reaches an upper limit by 3 months of age although systolic wall stress continues to rise; and (2) cell length is significantly increased by 12 months of age. This study suggests that maladaptive remodeling of cardiac myocyte shape begins long before pump failure in hypertension. Additionally, it appears that the left ventricle may be robbed of an important adaptive mechanism to normalize wall stress (eg, myocyte transverse growth) early in the progression to failure. (Hypertension. 1998;32:753-757.)

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Reversal of myocyte hypertrophy was produced in hypertensive/heart failure rats with an AT(1). The ACEI was effective but to a lesser extent. Results indicate that it is possible to significantly reverse myocyte remodeling pharmacologically even if therapy is initiated near the onset of failure. Further work is needed to determine whether similar results can be obtained in humans.

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The effects of Cl channel blockers on large-conductance (LC-type) Cl channels of cultured vascular smooth muscle cells (VSMC) were studied in order to characterize the channel pharmacologically. Intracellular disulphonic stilbene derivatives, such as 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS) and 4-acetamido-4-isothiocyanostilbene-2,2'-disulphonic acid (SITS) inhibited Cl channel activity in a dose-dependent manner. An obvious inhibitory effect of DIDS in this condition was obtained at concentrations higher than 5 microM, and the complete inhibition was obtained at around 100 microM, which was almost 10 times less than the effective dose of SITS. The inhibitory effect of DIDS was reversible at a drug concentration of lower than 50 microM. Single-channel conductance decreased as the concentration of DIDS increased. This decrease in the conductance was a consequence of unresolved openings of the channel due to fast blocking and unblocking rates of the drug. The Cl channel was also obviously inhibited by extracellular DIDS at a concentration of 1 mM. In addition, in cell-attached patches, 500 microM DIDS applied extracellularly inhibited Cl channel activated by the application of polymyxin B. We also investigated the effect of Zn on Cl channels in VSMC. Intracellular Zn dose dependently and reversibly blocked the channel at the positive intracellular potential range, whereas at the negative intracellular potential range it did not block the channel activity. Results in this study suggest the diversity of Cl channels among various tissues.

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