Chronic treatment with Carvedilol improves ventricular function and reducesmyocyte apoptosis in an animal model of heart failure
BMC Physiology volume 3, Article number: 6 (2003)
β-blocker treatmenthas emerged as an effective treatment modality for heart failure.Interestingly, β-blockers can activate both pro-apoptotic and anti-apoptoticpathways. Nevertheless, the mechanism for improved cardiac functionseen with β-blocker treatment remains largely unknown. Carvedilolis a non-selective β-blocker with α-receptor blockade and antioxidantproperties. We therefore studied the impact of the effects of carvedilolin an animal model of end-stage heart failure.
To test whetherchronic treatment with β-blockade decreases apoptosis, we treated myopathicturkeys with two dosages of carvedilol, 1 mg/kg (DCM1)and 20 mg/kg (DCM20), for four weeks and compared themto non-treated DCM animals (DCM0) and to control turkeys(CON). Echocardiographic measurements showed that non-treated DCManimals had a significantly lower fractional shortening (FS) whencompared to CON (68.73 ± 1.37 vs. 18.76 ± 0.59%, p < 0.001). Bothdoses of carvedilol significantly improved FS (33.83 ± 10.11 and27.73 ± 6.18% vs. 18.76 ± 0.59 % for untreated DCM, p < 0.001).DCM left ventricles were characterized by a higher percentage ofapoptotic nuclei when compared to CON (5.64 ± 0.49 vs. 1.72 ± 0.12%,respectively p < 0.001). Both doses of carvedilol significantlyreduced the number of apoptotic nuclei (2.32 ± 0.23% and 2.36 ±0.26% 1 mg and 20 mg/kg respectively).
Carvedilol improvesventricular function. Furthermore, treatment with carvedilol decreasedthe incidence of apoptosis in cardiac myocytes from failing heartsat both doses. These data suggest that the inhibition of apoptosiswith carvedilol may lead to improvement in ventricular functionand may underlie a beneficial effect of β-blockade independent ofheart rate lowering effects.
Loss of myocytes is thought to contribute to the progressivedecline in left ventricular function and the development of congestiveheart failure. Recent studies have proposed that myocyte loss incardiomyopathy can occur by apoptosis without an inflammatory response [reviewedin [1–3]]. In heart failure,growth stimulation initially occurs as a compensatory effort tomeet chronically altered hemodynamic demands and is mediated by systemicand/or local up-regulation of mediators of adrenergic pathways andby various cytokines [4, 5]. However, cytokinescan be directly toxic to cardiac myocytes and result in increasedapoptotic cell death [3, 6]. Local up-regulationof angiotensin II induces immediate-early genes, which may leadto increased protein synthesis and myocardial hypertrophy or, alternatively,may up-regulate expression of apoptotic proteins (such as p53) incardiac myocytes. The initial increase in circulating norepinephrineis thought to maintain cardiac function through inotropic mechanisms.However, a direct cardiac myocyte toxicity from norepinephrine iswell recognized [6, 7]. Furthermore, pressure-overloadand stretch associated release of angiotensin II has been shownto induce myocyte apoptosis [8–10].In an elegant paper by Telger et al., it has clearly been demonstratedthat cardiac hypertrophy is initially preceded by a wave of apoptosisof cardiac myocytes followed by cell growth and a decrease in programmedcell death . Apoptosis may,therefore, be the consequence of prolonged growth stimulation (adrenergicand renin-angiotensin axes) of adult cardiac myocytes, which areterminally differentiated. Similarly, certain cytokines (such astumor necrosis factor) can induce growth as well as apoptosis . As proposed by Telger et al. it isbecoming clear that cell growth and programmed cell death are infact two linked processes .
Over the last five years, β-blocker therapy has become one ofthe main treatment modalities for heart failure. Of particular interestis the use of carvedilol [12–16].Carvedilol is a novel multiple-action neurohormonal antagonist.Its primary activities are nonselective β-adrenoceptor blockade,vasodilatation (mediated through α1-adrenoceptor blockade), andantioxidant activity . In many clinical studies,carvedilol has been shown to improve left ventricular function andsymptoms in patients with ischemic heart disease or idiopathic dilatedcardiomyopathy [13–16] andto dramatically reduce mortality .However, it remains unclear how carvedilol improves ventricular functionin heart failure.
In an animal model of cardiomyopathy that has many similaritiesto human heart failure, we tested the hypothesis that a reductionin apoptosis may be responsible for the beneficial effects of carvedilol.As such, attenuation of apoptosis in the myocardium may representa novel and important mechanism that contributes beneficial effects onthe myocardium.
Baseline Characteristics of Dilated Cardiomyopathic Animals
We have previously shown that removal of furazolidone from thefeed after three weeks results in progressive cardiac dilatationand heart failure . At the time ofrandomization of the DCM group into three groups i.e., DCM0 (notreatment), DCM1 (lower dose carvedilol) or DCM20 (higherdose carvedilol), fractional shortening was not different betweenthe groups (p > 0.1). Evidence for severe heart failure was markedby significantly reduced left ventricle fractional shortening (controls63.67 ± 1.04% n = 34 vs. DCM 11.95 ± 0.59% n = 18, p < 0.001).
Effect of Carvedilol on Ventricular Function
We investigated the effect of carvedilol by administering twodifferent dosages (1 mg and 20 mg/kg body weight per day) to controland DCM turkeys for four weeks. We studied two dosages (pharmacologicaland non-pharmacological) as a difference in dose-dependency forcardiac function improvement has previously been demonstrated byus with another non-selective beta-blocker .Furthermore, we wanted to determine if carvedilol might exert beneficialeffects independent of heart rate effects. The lower dose (1 mg/kg)did not reduce heart rate. However, the higher dose reduced HR byapproximately 15% for 8 hours.
In vivo contractile performance of the heart was assessed bythe determination of fractional shortening of the left ventricle.As shown in Table 1 and Figure 1, fractional shortening was increasedby 32 and 45% in DCM1 and DCM20 animals, respectively,compared to non-treated DCM animals (DCM0). Comparedwith baseline values at the time of randomization, the improvementin fractional shortening was of 57% in DCM1 and 65% inDCM20. Associated with improved cardiac function wasa reduction in the incidence of apoptotic nuclei (see below).
The body weight was significantly decreased in DCM animals comparedto control animals (p < 0.001 compared to control) (Table 2). This animal model is associated withcachexia. Carvedilol treatment resulted in a slight gain of bodyweight, 15% in the DCM1 group and 20% in the DCM20 groupcompared with the non-treated DCM group (DCM0). Carvediloalso increased the body weight of control animals (p < 0.001).These data indicate a favorable effect on cachexia. In non-treatedDCM animals the hearts weighed significantly less than control hearts(p = 0.01). DCM animals treated with carvedilol showed a significantincrease in HW compared to hearts from non-treated DCM animals (p< 0.001). Therefore the HW/BW ratio was lower for hearts fromcarvedilol treated DCM animals compared to hearts from non-treatedDCM animals. Interestingly, the HW/BW ratio was lower for carvediloltreated control animals compared to non-treated control animals.Left ventricle volume was significantly larger for non-treated DCMhearts. Carvedilol significantly decreased LV volume at both dosages.
Effect of Carvedilol on Cardiac Myocyte Apoptosis
Evaluation of tissue sections by the TUNEL technique revealed only small numbers of TUNEL-positive cells in the control hearts(Table 1 and Figure 2A). Hearts from DCManimals had a significant increase in the number of TUNEL-positive cells compared to controls (5.64 ± 0.49% vs. 1.72 ± 0.12% DCM and control respectively, p < 0.001), indicating the occurrence of apoptosis (Figure 2B).
In contrast to non-treated DCM hearts, myocardial tissue sectionsprepared from hearts from animals treated with carvedilol showeda significant reduction in the numbers of TUNEL-positive myocytenuclei. An example of such an observation is depicted in Figure 3A and 3B (DCM1 and DCM20 respectively).Both the lower and the higher doses of carvedilol were effectivein reducing apoptosis from 5.64 ± 0.49% in non-treated DCM animalsto almost control levels 2.32 ± 0.23% (DCM1) and 2.36± 0.26% (DCM20), p < 0.001, compared to DCM0 respectively(Figure 3C).
Effect of Carvedilol on a Heart Failure Model
The furazolidone-induced turkey model is a well characterizedexperimental model of dilated cardiomyopathy with features verysimilar to those found in human heart failure [19–22].Decreased contractile function (reduced fractional shortening ofthe left ventricle) and morphological changes (increased heart volumes,left ventricular dilatation, and myocyte hypertrophy) are characteristic featuresof this model [21, 22].
β-blocker treatment has emerged as an effective treatment modalityfor heart failure. Both in animal and human studies of heart failure, β-adrenergicblockade intervention appears to have beneficial effects on cardiacmyocyte function [1, 23, 24]. Of particularimportance, studies using carvedilol have shown remarkable improvementsin cardiac performance [12, 13, 15, 16] andreduction in mortality in humans .We have previously shown that propranolol, a nonselective β-blocker,is cardioprotective and prevents the development of heart failurein turkeys when given concurrently with furazolidone . Similarly, carteolol, a nonselective β-blocker,resulted in improvement in ejection fraction, reduction in ventricularvolumes, an increase in developed pressure as well as an increasein rate of survival in our turkey model . Improvementin cardiac function was associated with cellular remodeling of cardiacmyocytes. Cardiac myocytes from hearts treated with a non-selective β-blockeri.e., carteolol, had normal calcium cycling, normal myocardial energetics,normal β1 receptor density as well as regression of myocytehypertrophy and reduced connective tissue content . Furthermore, administration of carteolol hasbeen reported to prevent the development of virally induced cardiomyopathyin a murine model . In a canine modelwith left ventricular dysfunction produced by multiple sequentialintracoronary microembolizations, long term treatment with metoprolol,a β1-selective blocker, has been reported to preventthe progression of LV systolic dysfunction and LV chamber dilatation . Similarly, our present findings onthe effect of carvedilol indicated improvement of left ventricularfunction and smaller LV volumes. Carvedilol prevented progressionof LV systolic dysfunction and LV dilatation as previously reportedin other models using β-blockers [18, 26].
Animals with dilated cardiomyopathy which received carvedilolshowed significant improvement in LV systolic function after 4 weeks.Notably, the improvement of LV systolic function in animals treatedwith carvedilol was associated with a decrease of LV volumes comparedwith non-treated DCM animals. Importantly, both doses of carvedilolimproved LV contractile performance. Fractional shortening (%) wasincreased by an average of approximately 38% and impressively by80% in some individual animals. These data seem to agree with the resultsof human clinical studies, and are suggestive that carvedilol notonly slows deterioration of cardiac function, but also improvescardiac function.
The trend that the 20 mg/kg body weight dose might not have beenwell tolerated was demonstrated by some animals becoming moribundfor a short period after dosing which might be due to a reductionin heart rate and cardiac output with resultant reflect tachycardia.We have previously shown a negative force-interval relationship (i.e.,negative treppe) in failing hearts with this model . This is in line with data from humanstudies, which showed that when first administered, β-blockers actually slowheart rate and diminish ejection fraction .The higher dose of carvedilol significantly reduced heart rate andblood pressure for up to eight hours. Animals that tolerated thehigher dose did nevertheless benefit from the treatment. This issimilar to human clinical studies where greater benefit is derivedfrom higher dosages, if tolerated .
Apoptosis in Animal Models of Heart Failure
Heart failure is characterized by progressive deterioration ofglobal left ventricular function over time. The mechanisms responsiblefor the worsening of cardiac function are not clear. Loss of cardiacmyocytes has been suspected to be a feature of the cardiomyopathicprocess that contributes to progressive decline in left ventricularfunction and the development of congestive heart failure . Evidence supporting the concept ofmyocyte apoptosis occurrence and contribution in the progressionof heart failure has been obtained from a variety of observations,including in vitro studies, experimental animal modelsof cardiac dysfunction, and studies on cardiac tissue obtainedfrom patients with end-stage heart failure [5, 7–9, 29].
We sought to evaluate the incidence and the extent of apoptosisin our animal model of heart failure. Using the TUNEL techniqueas a means of detection, we were able to document the occurrenceof apoptosis in ventricles from failing hearts, which was characterizedby a higher percentage of apoptotic nuclei when compared to controls (5.64%vs. 1.72%). These apoptotic indexes are within the range of valuesin heart failure reported in the literature (0.2% to 35%) [3, 30–33]. The high degreeof variability reported in the literature in the magnitude of apoptosis maybe due to the diversity and specificity of methods used to quantifyapoptotic nuclei.
When reporting apoptotic nuclei using the TUNEL assay, two observationsshould be considered; 1) although apoptosis occurred in our modelof heart failure, we might have missed, in random histologicalsections, evidence of apoptosis thereby under estimating the severityof programmed cell death due to the fact that apoptotic cells undergorapid phagocytosis with the entire process lasting less than twohours in some cell systems , and 2) apoptosisin the present study was evaluated at a single time point when theheart was still undergoing LV remodeling. Hence, the documentationof apoptosis at this stage may not reflect the true magnitude ofits occurrence during the initiation and transition to heart failure.In a rat model of pressure-overload hypertrophy produced by aorticbanding, apoptosis appeared to peak at four days and gradually subsidedafter one month of aortic banding .Therefore, a longitudinal study of apoptosis in failing hearts frominitiation to transition to failure is worth pursuing. In this way,the incidence of apoptosis can be documented as the heart movesprogressively from normal to compensated hypertrophy and finallyto overt decompensated heart failure. These animals were in compensated heartfailure and, often in the non-treated group, went into decompensatedheart failure when stressed during echocardiographic examination.
With improved cardiac function, there should be a reduction inactivation of the adrenergic-renin-angiotensin axes as well as adecrease in activated cytokines such as tumor-necrosis factor-α.In our model of heart failure, cardiac function correlated withthe incidence of apoptosis. As described in Table 1 and Figure 3,there were a higher number of apoptotic cells in hearts with a reductionin fractional shortening. In contrast, control hearts with normalventricular function showed low rates of apoptosis. The extent andoccurrence of apoptosis may partially explain the lack of an overallincrease in heart weight in hearts from non-treated DCM animals,despite a pronounced increase in heart size. These observations,and the results from several animal models, demonstrate that apoptoticcells are present in failing hearts, suggesting that apoptosis mightbe a mechanism involved, at least in part, in the progression ofheart failure and the reduction of myocyte mass.
Carvedilol Inhibition of Apoptosis and Improvement of VentricularFunction
The extent of apoptosis in cardiomyopathic animals was significantlyreduced by treatment with carvedilol. Both the lower and higherdoses of carvedilol were effective in decreasing the rate of apoptosis(approximately a 58% reduction). This observation represents animportant finding in demonstrating the effectiveness of a cardiovasculardrug to protect against continual cardiac myocyte apoptosis in failinghearts in vivo. Furthermore, the inhibition of apoptosisby carvedilol was accompanied by signs of improvement in left ventricularfunction and heart size (i.e. reduced LV volume) in the myopathicanimals. Whether the improved function, small heart size and decreasedwall stress were responsible for a reduction in apoptosis is notknown. However, the derived cardiac benefit was independent of heartrate effects because benefit was obtained at both dosages.
Our data support the conclusions of Rossig et al. in endothelialcells. They reported levels of apoptotic cells for control andNYHA III-IV hearts that were similar to our observations . We similarly believe that the suppressionof apoptosis by carvedilol is likely due to its antioxidative propertiesrather than the β-blocking effects . Webase this on our observation that a similar reduction in the incidenceof apoptosis was seen at both a non-pharmacological (no effect onheart rate or blood pressure) as well as a pharmacological doseof carvedilol. In a canine model of chronic heart failure producedby multiple sequential intracoronary embolizations, metprolol, a β1 selectiveblocker, reduced the incidence of apoptosis supporting our experimentalobservations with carvedilol .The incidence of apoptosis was 5.32 ± 0.77 in heart failure animalsthat were not treated which is similar to our findings of 5.64 ±0.49 in hearts from untreated animals with heart failure. Recently,Li et al. have demonstrated that spontaneously hypertensive rats(SHR) with symptoms of heart failure had significantly higher levels ofapoptotic myocytes than control myocytes .When treated with an angiotensin-converting enzyme inhibitor, thenumber of apoptotic cells in the SHR with symptoms of heart failurewas dramatically reduced to control levels; controls were SHR withoutsymptoms of heart failure . Kajstura et al.have also reported that angiotensin II increased the percentageof apoptotic cells in isolated adult rat ventricular myocytes, andthis effect was mediated by AT-1 receptors .Although ventricular function was not assessed in these studies,the observations raise the possibility that, like our findings withcarvedilol, the beneficial effect of ACE-inhibitors or AT-1 receptorblockers in heart failure may in part be attributed to an inhibitionof myocyte apoptosis with a resultant improvement in in vivo cardiacfunction, a concept that needs further study.
The data presented suggest that attenuation of apoptosis mayunderlie the beneficial effect of β-blockade on ventricular function,and that the inhibition of apoptosis can possibly lead to improvementin ventricular function. This represents a novel mechanism to slowthe progressive deterioration of myocardial function that can occurin patients with cardiac failure. Because reactive oxygen radicalsplay a role in inducing cell apoptosis  andthe potent antioxidant property of carvedilol , we speculate that the beneficial effectsattributed to carvedilol (i.e. inhibition of apoptosis and improvementof LV function) are mediated, in part, by its prevention of oxygen-derived freeradical damage [35, 40]. Our data supportsthis idea.
With the clear demonstration that cardiac myocyte apoptosis ispresent in our heart failure model strategies for prevention ofapoptosis can be tested. The clinical consensus has been that higherdoses of β-blockade should incur more benefits on ventricular remodeling.However, our studies demonstrated similar benefits at a therapeuticand sub-therapeutic dose. In light of the beneficial effect of carvedilolon the progression of heart failure, and its unique multi-actionsthat are not shared by any other β-blocking drug or by any otheragent currently used in the treatment of heart failure, our findingsrepresent an important new mechanism of improved cardiac function.
The development of animal models of heart failure in which apoptosisis an important feature will allow the modulation of cell deathpathways through targeted interventions. Understanding the roleof specific signaling pathways in cardiac myocyte apoptosis anddeveloping strategies to manipulate these intracellular pathwaysmay provide in the near future novel therapeutic approaches forthe management of heart failure.
In conclusion, our model of heart failure, which shows a highlevel of congruence with the human condition, has been shown tohave a high level of apoptosis that corresponds with cardiac failure.Carvedilol, a non-selective β-blocker with α-blocking propertiesas well as antioxidant properties, significantly reduced the incidenceof programmed cell death while improving cardiac function. Thiseffect was independent of heart rate lowering effects, i.e. β-blockade.The beneficial effects of carvedilol can therefore be obtained withsubtherapeutic doses. This is a novel observation and importantin treating patients who may not tolerate higher doses (heart rateand blood pressure lowering) of carvedilol. The apoptotic processis linked to the development and progression of heart failure aswell as the improvement in cardiac function seen with β-blockade.
One day-old broad-breasted white turkey poults, obtained froma commercial breeder, were wing-banded for easy identification.At seven days of age, they were weighed and randomly divided intotwo groups using a random number generator. The control group (n= 34) was maintained on a normal ration, free from any additives,and the experimental group (n = 91) was fed 700 parts per millionfurazolidone (Fz) for three weeks. Furazolidone was stopped afterday twenty-eight and the animals were randomized into three groups:one group did not receive carvedilol treatment, DCM0 (n= 52), whereas the other two groups, DCM1 (n = 19) andDCM20 (n = 20), were treated with carvedilol in the samedosages as respective aged-matched control animals (see following).Similarly, age matched control animals were randomized into threegroups: one group received no pharmacological agent (Con0.n = 13), whereas the other two groups received different dosagesof carvedilol, 1 mg/kg (Con1 n = 11) or 20 mg/kg bodyweight (Con20 n = 10). The lower dose of carvedilol didnot lower heart rate or blood pressure. However, the higher doseof carvedilol resulted in a significant reduction in heart rate(15%) and blood pressure (9%) for up to eight hours. We performeddose range studies using nine concentrations of carvedilol (datanot shown). At the time of euthanasia, body weights, heart weights(after removal of the atria), and LV volumes were obtained on allexperimental animals.
Echocardiographic views were obtained using a 7.5 MHz transduceron unsedated and quietly resting animals. Several cardiac cycleswere recorded on a videotape and the two dimensional images subsequentlyplayed back for analysis. Diastolic left ventricular internal dimension (LVIDd)and systolic left ventricular internal dimension (LVIDs) were alsomeasured and used to determine the fractional shortening. Fractionalshortening (%) of the left ventricle was calculated as (LVIDd -LVIDs/ LVIDd) × 100.
Randomly selected hearts from control and cardiomyopathic turkeypoults were rapidly removed, flushed with PBS and infused with atissue embedding medium (Tissue-Tek, OCT Compound, Miles Inc., Elkhart,IN) and frozen in liquid nitrogen. Serial 7 μm cross-sections from heartblocks were cut and fixed to coated slides. Frozen heart sectionswere fixed in 10% neutral formalin (4% formaldehyde) for 10 minutesat room temperature and post-fixed in Methanol/Acetone (1:1) for10 minutes at -20°C. Detection of apoptotic cardiac myocytes was achievedby direct immunofluorescence detection of digoxigenin-labeled genomicDNA using the ApopTag Plus in Situ apoptosis detection kit – Fluorescein(Intergen, Purchase, NY). This method used the TUNEL techniqueto stain DNA fragments in nuclei of apoptotic cells. Tissue sectionswere then counter-stained with Hoechst 33258 stain (1 μg/ml) (Sigma),and viewed with an epifluorescence microscope (Zeiss Axiophot) equippedwith filter sets for fluorescein and Hoechst staining. To quantify apoptosis,four to five randomly selected microscopic fields per section wereexamined. The percentage of apoptotic cells was determined by countingthe total number of nuclei and TUNEL positive nuclei (apoptoticmyocytes). Samples were numbered to conceal the identity of differentgroups during counting. Sections of interest were photographed usinga microscope-integrated 35-mm camera.
Data given in the text are means ± SD. The difference betweenthe means was evaluated using student's t test. P <0.05 was considered significant.
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This work is supported by a research contract from SmithKlineBeecham Pharmaceuticals to Gwathmey, Inc. and in part by grantsfrom NIH: HL-49574 & HL-52249 (JKG), NIH HL49574 Minority Supplement(CCO) and T32 HL07374-23 (MXL).
CCO drafted and edited the manuscript. AAD carried out creationof the animal model. ECHOs and the echocardiographic measurementswere analyzed by NL and JKG. DL, KS and GJ carried out the TUNELassays. CCO, CPM, RJH and JKG participated in the design of thestudy. CCO and JKG performed the statistical analysis, and datainterpretation. MXL performed figure generation and animal dosing.RJH and JKG conceived of the study, and participated in its designand coordination. All authors read and approved the final manuscript.
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Okafor, C.C., Perreault-Micale, C., Hajjar, R.J. et al. Chronic treatment with Carvedilol improves ventricular function and reducesmyocyte apoptosis in an animal model of heart failure. BMC Physiol 3, 6 (2003). https://doi.org/10.1186/1472-6793-3-6