Carvedilol prevents and reverses hypertrophy-induced cardiac dysfunction.
OBJECTIVE
Histological studies have provided evidence that carvedilol can prevent cardiac hypertrophy in spontaneously hypertensive-stroke prone rats (SP) fed a high-fat and -salt diet. However, the effects of carvedilol on cardiac function have not been studied in these animals. In addition, the ability of carvedilol to reverse established cardiac hypertrophy and dysfunction under these conditions remains to be determined. Here we have evaluated the ability of carvedilol to prevent and reverse cardiac hypertrophy and progressive dysfunction using echocardiography.


METHODS
Two echocardiology studies were conducted to determine the effects of carvedilol treatment on cardiac hypertrophy and dysfunction. In the first prevention study, four groups of rats were evaluated. SP were fed a high-fat (24.5% in food) and high-salt (1% in water) diet (SFD) without (SP-SFD control group) or with carvedilol (SP-SFD carvedilol group; carvedilol concentration 2,400 parts per million) for 18 weeks. Carvedilol was administered in the food at an optimum concentration (i.e. known to provide clinically relevant blood concentrations and reduce cardiac hypertrophy determined from previous studies). In addition, SP and WKY rats were fed a normal diet (SP normal diet group and WKY normal diet group). These groups are known to not develop the same significant cardiac hypertrophy and dysfunction within this limited time of study, and provided two more normal control groups for comparison. In the second reversal study, one group of SP was fed SFD for 12 weeks (SP-SFD pretreatment period) to induce cardiac hypertrophy. Carvedilol (2,400 parts per million) was then added to the diet for an additional 6 weeks (SP-SFD carvedilol treatment period).


RESULTS
In the first prevention study, carvedilol prolonged longevity (p < 0.05) and prevented left-ventricular hypertrophy and dysfunction (p < 0.05; SP-SFD control vs. SP-SFD carvedilol group). M-mode-measured and -calculated parameters demonstrated that carvedilol treatment in the SP-SFD carvedilol group prevented increases in left-ventricular wall thickness (p < 0.05) and decreases in diastolic chamber diameter and volume, stroke volume, ejection fraction and cardiac output (all p < 0.05) that occurred in the SP-SFD control group. Further, cardiac measurements in the SP-SFD carvedilol group were normalized to levels similar to those in the SP and WKY normal diet groups. All SFD-fed groups exhibited similar, significantly elevated blood pressure during the study. In the second reversal study, carvedilol treatment for 6 weeks reversed the cardiac hypertrophy and dysfunction that developed in SP-fed SFD for 12 weeks prior to carvedilol intervention. Under these conditions, carvedilol improved/normalized left-ventricular wall thickness, diastolic ventricular-chamber diameter and volume, stroke volume, ejection fraction and cardiac output (all p < 0.05).


CONCLUSIONS
These data indicate that carvedilol provides protection from and facilitates reversal of progressive cardiac remodeling and dysfunction in this SP-SFD model of cardiac hypertrophy/heart failure. Since these effects occurred in the absence of effects on blood pressure, other known actions of carvedilol, especially its antioxidant activity, for example, may explain this significant cardiac protection. In addition, research using this SP-SFD model of cardiac hypertrophy/end-organ injury appears to translate well to human cardiovascular disease.
Barone
Frank C
FC
High Throughput Biology, Discovery Research, King of Prussia, PA, USA. frank.c.barone@verizon.net
Willette
Robert N
RN
Nelson
Allen H
AH
Ohlstein
Eliot H
EH
Brooks
David P
DP
Coatney
Robert W
RW
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000517:prevention & control*; D000077261:Carvedilol; D004032:Diet; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D016896:Treatment Outcome; D014463:Ultrasonography; D014665:Vasodilator Agents / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D000975:Antioxidants; D002227:Carbazoles; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol