Combined Effects of Low-dose Oral Spironolactone and Captopril Therapy in a Rat Model of Spontaneous Hypertension and Heart Failure

Kambara, Atsushi; Holycross, Bethany J.; Wung, Peter K.; Schanbacher, Brandon L; Ghosh, Subham; McCune, Sylvia A.; Bauer, John; Kwiatkowski, Paweł

doi:10.1097/00005344-200306000-00002

Cited by 33 publications

(24 citation statements)

References 37 publications

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“…Second, improved survival occurred independent of any significant effect of exercise on the hypertensive status of the SHHF rats. Not surprisingly, pharmacological reduction of blood pressure in the SHHF model has been shown to prevent and/or improve a number of common morphological, biochemical, and humoral correlates of CHF and generally improves morbidity and mortality (7,24,64). Our results demonstrate that even in the face of a sustained basal hypertension, low-intensity exercise training is capable of delaying the onset of LV dilation and end-stage HF.…”

Section: Discussionmentioning

confidence: 55%

Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats

Emter

McCune²,

Sparagna³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats. Am J Physiol Heart Circ Physiol 289: H2030 -H2038, 2005. First published July 1, 2005; doi:10.1152/ajpheart.00526.2005.-Data regarding the effectiveness of chronic exercise training in improving survival in patients with congestive heart failure (CHF) are inconclusive. Therefore, we conducted a study to determine the effect of exercise training on survival in a well-defined animal model of heart failure (HF), using the lean male spontaneously hypertensive HF (SHHF) rat. In this model, animals typically present with decompensated, dilated HF between ϳ18 and 23 mo of age. SHHF rats were assigned to sedentary or exercise-trained groups at 9 and 16 mo of age. Exercise training consisted of 6 mo of low-intensity treadmill running. Exercise training delayed the onset of overt HF and improved survival (P Ͻ 0.01), independent of any effects on the hypertensive status of the rats. Training delayed the myosin heavy chain (MyHC) isoform shift from ␣-to ␤-MyHC that was seen in sedentary animals that developed HF. Exercise was associated with a concurrent increase in cardiomyocyte length (Ϸ6%), width, and area and prevented the increase in the length-to-width ratio seen in sedentary animals in HF. The increases in proteinuria, plasma atrial natriuretic peptide, and serum leptin levels observed in rats with HF were suppressed by low-intensity exercise training. No significant alterations in sarco (endo)plasmic reticulum Ca 2ϩ ATPase, phospholamban, or Na ϩ / Ca 2ϩ exchanger protein expression were found in response to training. Our results indicate that 6 mo of low-intensity exercise training delays the onset of decompensated HF and improves survival in the male SHHF rat. Similarly, exercise intervention prevented or suppressed alterations in several key variables that normally occur with the development of overt CHF. These data support the idea that exercise may be a useful and inexpensive intervention in the treatment of HF. myosin heavy chain; proteinuria; cardiomyocyte morphology; atrial natriuretic peptide; leptin HEART DISEASE is a leading cause of death among men and women in Western industrialized societies. Cardiovascular disease (CVD) currently affects over 70 million Americans, 65 million of which are estimated to have high blood pressure and nearly 5 million are diagnosed with congestive heart failure (CHF) (2). With the diagnosis of CHF, life expectancy decreases dramatically and chances of survival decrease with 70 -80% of patients dying within 8 yr (2). Although chronic exercise training has clearly been shown to be beneficial in attenuating risk factors for CVD, including high blood pressure and cholesterol levels, insulin resistance, and obesity (9,14,53,58), the utility of exercise as a clinical intervention for patients with developing CHF is less clear. Currently, there is a lack of clarity regarding the efficacy of chronic exercise training as a treatment and in reducing mortali...

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Section: Discussionmentioning

confidence: 55%

Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats

Emter

McCune²,

Sparagna³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…Myocyte size is increased as early as 2 mo of age in SHHF rats, and progressive myocyte and cardiac hypertrophy have been reported through 12 mo of age in the SHHF rats (28). During heart failure, the SHHF rats have intracardiac thrombi, myocyte hypertrophy, and increased cardiac interstitial fibrosis (17).…”

Section: Discussionmentioning

confidence: 99%

Abnormal diastolic currents in ventricular myocytes from spontaneous hypertensive heart failure rats

Sridhar¹,

Dech²,

Lacombe³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Abnormal diastolic currents in ventricular myocytes from spontaneous hypertensive heart failure rats. Am J Physiol Heart Circ Physiol 291: H2192-H2198, 2006. First published June 9, 2006 doi:10.1152/ajpheart.01146.2005.-Hypertension is a common cause of heart failure, and ventricular arrhythmias are a major cause of death in heart failure. The spontaneous hypertension heart failure (SHHF) rat model was used to study altered ventricular electrophysiology in hypertension and heart failure. We hypothesized that a reduction in the inward rectifier K ϩ current (IK1) and expression of pacemaker current (If) would favor abnormal automaticity in the SHHF ventricle. SHHF ventricular myocytes were isolated at 2 and 8 mo of age and during end-stage heart failure (Ն17 mo); myocytes from age-matched rats served as controls. Inward IK1 was significantly reduced at both 8 and Ն17 mo in SHHF rats compared with controls. There was a reduction in inward IK1 due to aging in the controls only at Ն17 mo. We found a significant increase in If at all ages in the SHHF rats, compared with young controls. In controls, there was an age-dependent increase in If. Action potential recordings in the SHHF rats demonstrated abnormal automaticity, which was abolished by the addition of an If blocker (10 M zatebradine). Increased If during hypertension alone or combined increases in If with reduced IK1 during the progression to hypertensive heart failure contribute to a substrate for arrhythmogenesis. aging; pacemaker current; inward rectifier potassium current; abnormal automaticity HYPERTENSION CAN LEAD TO COMPENSATORY hypertrophy in cardiac muscle. Chronically, these compensatory mechanisms can become maladaptive, and cardiomyopathy and heart failure can result (22). Experimental animal studies in hypertrophy and heart failure have shown abnormalities in ion channel function, altered expression and function of proteins involved in excitation-contraction coupling, and an increased propensity for cardiac arrhythmias (16,30,32). Clinically, ventricular arrhythmias occur in 80% of heart failure patients (11). However, the mechanisms of arrhythmogenic electrophysiological remodeling during hypertension and hypertensive heart failure are not fully elucidated.Spontaneous hypertensive heart failure (SHHF) rats develop hypertension at an early age. In contrast to spontaneously hypertensive rats (SHRs), the SHHF rats consistently develop reproducible, hypertensive heart failure in an age-dependent manner (26). Echocardiographic studies in the SHHF rat demonstrate left ventricular dysfunction (left ventricular ejection fraction Ͻ40%) at 17-18 mo of age (31). There is also evidence of progressive cardiac hypertrophy in the SHHF rats, evidenced as an increase in heart weights (36).Hypertension and heart failure can increase the pacemaker current (I f ) in the ventricular myocardium (4 -7). This can pathologically alter the diastolic phase of the action potential and enhance abnormal automaticity. In addition, aging has been shown to increase I f density i...

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“…Supportive evidence is coming from experimental models and other clinical conditions. 26 Therapies directed at inhibiting AII formation and at binding to the AT 1 receptor have been shown to reduce end-organ damage in the kidneys in diabetics and hypertensives. [27][28][29][30][31] In CHARM-Preserved, however, only a minority of patients were taking an ACE inhibitor, so these differences in eGFR between trials probably are multifactorial and not primarily attributable to the background use of an ACE inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure

Hillege

Nitsch²,

Pfeffer³

et al. 2006

Circulation

815

470

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Background— Decreased renal function has been found to be an independent risk factor for cardiovascular outcomes in patients with chronic heart failure (CHF) with markedly reduced left ventricular ejection fraction (LVEF). The aim of this analysis was to evaluate the prognostic importance of renal function in a broader spectrum of patients with CHF. Methods and Results— The Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity (CHARM) program consisted of three component trials that enrolled patients with symptomatic CHF, based on use of ACE inhibitors and reduced (≤40%) or preserved LVEF (>40%). Entry baseline creatinine was required to be below 3.0 mg/dL (265 μmol/L). Routine baseline serum creatinine assessments were done in 2680 North American patients. An analysis of the estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease equation and LVEF on risk of cardiovascular death or hospitalization for heart failure, as well as on all-cause mortality, was conducted on these 2680 patients. The proportion of patients with eGFR <60 mL/min per 1.73 m 2 was 36.0%; 42.6% for CHARM-Alternative, 33.0% for CHARM-Added, and 34.7% for CHARM-Preserved. During the median follow-up of 34.4 months (total 6493 person-years), the primary outcome of cardiovascular death or hospital admission for worsening CHF occurred in 950 of 2680 subjects. Both reduced eGFR and lower LVEF were found to be significant independent predictors of worse outcome after adjustment for major confounding baseline clinical characteristics. The risk for cardiovascular death or hospitalization for worsening CHF as well as the risk for all-cause mortality increased significantly below an eGFR of 60 mL/min per 1.73 m 2 (adjusted hazard ratio, 1.54 for 45 to 60 mL/min per 1.73 m 2 and 1.86 for <45 mL/min per 1.73 m 2 for the primary outcome, both P <0.001, and hazard ratio of 1.50, P =0.006, and 1.91, P =0.001, respectively, for all-cause mortality). The prognostic value of eGFR was not significantly different among the three component trials. There was no significant interaction between renal function, the effect of candesartan, and clinical outcome. Conclusions— Impaired renal function is independently associated with heightened risk for death, cardiovascular death, and hospitalization for heart failure in patients with CHF with both preserved as well as reduced LVEF. There was no evidence that the beneficial effect of candesartan was modified by baseline eGFR.

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Combined Effects of Low-dose Oral Spironolactone and Captopril Therapy in a Rat Model of Spontaneous Hypertension and Heart Failure

Cited by 33 publications

References 37 publications

Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats

Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats

Abnormal diastolic currents in ventricular myocytes from spontaneous hypertensive heart failure rats

Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure

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