RESUMEN
The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure is limited by pro-arrhythmic and positive chronotropic effects. Chronic use of these agents, while eliciting an improvement in the quality of life of patients with advanced heart failure, has been abandoned because of marked increase in mortality when compared to placebo. Nevertheless, patients with advanced heart failure can benefit from long-term positive inotropic support if the therapy can be delivered 'on demand' and in a manner that is both safe and effective. In this review, we will examine the use of a novel, non-stimulatory electrical signal that can acutely modulate left ventricular (LV) contractility in dogs with chronic heart failure in such a way as to elicit a positive inotropic support. Cardiac contractility modulation (CCM) with the Impulse Dynamic(trade mark) signal was examined in dogs with chronic heart failure produced by intracoronary microembolizations. Delivery of the CCM signal from a lead placed in the great coronary vein for periods up to 10 minutes resulted in significant improvements in cardiac output, LV peak+dP/dt, LV fractional area of shortening and LV ejection fraction measured angiographically. Discontinuation of the signal resulted in a return of all functional parameters to baseline values. In cardiomyocytes isolated from dogs with chronic heart failure, application of the CCM signal resulted in improved shortening, rate of change of shortening and rate of change of relengthening suggesting that CCM application is associated with intrinsic improvement of cardiomyocyte function. The improvement in isolated cardiomyocyte function after application of the CCM signal was accompanied by an increase in the peak and integral of the Ca(2+) transient suggesting modulation of calcium cycling by CCM application. In a limited number of normal dogs, intermittent chronic delivery of the CCM signal for up to 7 days showed chronic maintenance of LV functional improvement. In conclusion, pre-clinical results to date with the Impulse Dynamics CCM signal indicate that this non-pharmacologic therapeutic modality can provide short-term positive inotropic support to the failing heart and as such, may be a useful adjunct in the treatment of advanced heart failure. Additional, long-term studies in dogs with heart failure are needed to establish the safety and efficacy of this therapeutic modality for the chronic treatment of this disease syndrome.
Asunto(s)
Terapia por Estimulación Eléctrica/métodos , Insuficiencia Cardíaca/terapia , Contracción Miocárdica/fisiología , Animales , Perros , Terapia por Estimulación Eléctrica/instrumentación , Insuficiencia Cardíaca/fisiopatología , Función Ventricular Izquierda/fisiologíaRESUMEN
BACKGROUND AND AIM: Surgical resection of myocardium that acutely reduces left ventricular (LV) volume in patients with advanced heart failure (HF), the so-called "Batista Operation," remains controversial. We examined the effects of acute LV reduction with the Acorn Cardiac Support Device (CSD) in dogs with HF (LV ejection fraction < 30%). METHODS: HF was produced in 15 dogs by intracoronary microembolization. In nine dogs, intravenous dobutamine was administered to reduce LV end-diastolic dimension (LVEDD) by 10%-25%. While on dobutamine infusion, the CSD, a preformed knitted polyester device, was surgically placed around the ventricles, anchored to the arteriovenous (AV) groove, and tailored anteriorly to fit snugly over the ventricles. Dogs were then weaned off dobutamine. RESULTS: On average, the procedure reduced LVEDD by 7 +/- 1 mm (range 5-12 mm). Of the nine dogs, two died before completion of the study and seven survived for the entire period. Six dogs did not undergo device placement and served as controls. All were followed for 3 months prior to sacrifice. In controls, LV end-diastolic volume increased after 3 months (66 +/- 5 mL vs 77 +/- 6 mL; p = 0.007), while in CSD-treated dogs (n = 7), it decreased (80 +/- 5 mL vs 60 +/- 3 mL; p = 0.002). In controls, LV ejection fraction (EF) decreased after 3 months (27 +/- 1% vs 23 +/- 1%; p = 0.001) but was unchanged in CSD-treated dogs (25 +/- 1% vs 26 +/- 1%; p = 0.66). Compared to controls, CSD-treated dogs showed improved LV diastolic dysfunction and chamber sphericity, decreased wall stress, and no functional mitral regurgitation (MR). CONCLUSION: In dogs with advanced HF, acute LV reduction with the Acorn CSD prevents progressive global LV dilatation and ameliorates functional MR.
Asunto(s)
Insuficiencia Cardíaca/cirugía , Ventrículos Cardíacos/cirugía , Corazón Auxiliar , Disfunción Ventricular Izquierda/prevención & control , Remodelación Ventricular , Enfermedad Aguda , Animales , Enfermedad Crónica , Angiografía Coronaria , Dilatación Patológica/prevención & control , Progresión de la Enfermedad , Perros , Ecocardiografía Doppler , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Índice de Severidad de la Enfermedad , Volumen Sistólico , Resultado del Tratamiento , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Chronic heart failure (HF) is associated with morphologic abnormalities of cardiac mitochondria including hyperplasia, reduced organelle size and compromised structural integrity. In this study, we examined whether functional abnormalities of mitochondrial respiration are also present in myocardium of patients with advanced HF. Mitochondrial respiration was examined using a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles obtained from myocardium of failed explanted human hearts due to ischemic (ICM, n=9) or idiopathic dilated (IDC, n=9) cardiomyopathy. Myocardial specimens from five normal donor hearts served as controls (CON). Basal respiratory rate, respiratory rate after addition of the substrates glutamate and malate (V(SUB)), state 3 respiration (after addition of ADP, V(ADP)) and respiration after the addition of atractyloside (V(AT)) were measured in scar-free muscle bundles obtained from the subendocardial (ENDO) and subepicardial (EPI) thirds of the left ventricular (LV) free wall, interventricular septum and right ventricular (RV) free wall. There were no differences in basal and substrate-supported respiration between CON and HF regardless of etiology. V(ADP)was significantly depressed both in ICM and IDC compared to CON in all the regions studied. The respiratory control ratio, V(ADP)/V(AT), was also significantly decreased in HF compared to CON. In both ICM and IDC, V(ADP)was significantly lower in ENDO compared to EPI. The results indicate that mitochondrial respiration is abnormal in the failing human heart. The findings support the concept of low myocardial energy production in HF via oxidative phosphorylation, an abnormality with a potentially impact on global cardiac performance.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Mitocondrias/metabolismo , Mitocondrias/fisiología , Consumo de Oxígeno , Adulto , Atractilósido/farmacología , Endocardio/metabolismo , Inhibidores Enzimáticos/farmacología , Femenino , Ácido Glutámico/metabolismo , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos , Humanos , Malatos/metabolismo , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , FosforilaciónRESUMEN
OBJECTIVES: The purpose of this study was to determine if therapy with beta-blockade is associated with reduced cardiomyocyte apoptosis. BACKGROUND: Chronic treatment with beta-adrenergic blocking agents has been shown to improve left ventricular (LV) ejection fraction and attenuate progressive LV remodeling in heart failure (HF). Cardiomyocyte apoptosis has also been shown to occur in the failing heart. METHODS: Moderate HF was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to three months therapy with metoprolol (MET, 25 mg twice daily, n = 7) or to no therapy at all (n = 7). At the end of three months, dogs were sacrificed, and nuclear DNA fragmentation (nDNAf), a marker of apoptosis, was assessed in LV tissue using the TUNEL assay. The number of cardiomyocytes with positive nDNAf labeling per 1,000 was quantified in LV regions bordering old infarcts and in regions remote from infarcts. Endonuclease activity and expression of the antiapoptotic protein Bcl-2 and the proapoptotic proteins Bax and caspase-3 were also evaluated in LV tissue. RESULTS: The number of nDNAf events per 1,000 cardiomyocytes was lower in dogs treated with MET compared with untreated dogs with HF in the border regions (0.35 +/- 0.07 vs. 5.32 +/- 0.77, p < 0.001) as well as the remote regions (0.07 +/- 0.05 vs. 0.39 +/- 0.12, p < 0.05). Endonuclease activity was also significantly lower in MET-treated compared with untreated dogs (25 +/- 3 vs. 37 +/- 2 ng [3H]DNA rendered soluble/min/mg protein). Western blotting for Bcl-2, Bax and caspase-3 showed increased expression of Bcl-2, decreased expression of caspase-3 and no change in Bax in MET-treated compared with untreated dogs. CONCLUSIONS: Chronic therapy with MET attenuates cardiomyocyte apoptosis in dogs with moderate HF. Attenuation of ongoing cardiomyocyte loss through apoptosis may be one mechanism through which beta-blockers elicit their benefits in HF.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Apoptosis/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/patología , Metoprolol/farmacología , Miocardio/citología , Proteínas Proto-Oncogénicas c-bcl-2 , Animales , Calsecuestrina/biosíntesis , Caspasa 3 , Caspasas/biosíntesis , ADN/efectos de los fármacos , Perros , Genes bcl-2 , Proteínas Proto-Oncogénicas/biosíntesis , Proteína X Asociada a bcl-2RESUMEN
BACKGROUND: We examined the effects of passive containment of the cardiac ventricles with a surgically placed epicardial prosthetic wrap on indexes of left ventricular (LV) remodeling in dogs with heart failure. METHODS: Heart failure (LV ejection fraction 30% to 40%) was produced in 12 dogs by intracoronary microembolization. Six dogs underwent mid-sternotomy and pericardiotomy with placement of a preformed-knitted polyester device (Acorn Cardiac Support Device [CSD], Acorn Cardiovascular, Inc, St. Paul, MN) snugly around the ventricles and anchored to the atrioventricular groove. Six dogs did not undergo surgery and served as controls. Dogs were followed for 3 months prior to sacrifice. RESULTS: In controls, LV end-diastolic volume increased after 3 months (67 +/- 12 versus 83 +/- 8 ml; p = 0.04), while in CSD-treated dogs, it decreased (68 +/- 10 versus 61 +/- 10 ml; p = 0.002). CSD-containment of LV size was associated with increased LV systolic fractional area of shortening, while in controls, fractional area of shortening decreased. CSD-treated dogs also showed amelioration of myocyte hypertrophy and attenuation of interstitial fibrosis compared to controls. CONCLUSIONS: In dogs with heart failure, passive epicardial containment of the ventricles with the Acorn CSD ameliorates LV remodeling and improves LV systolic function.
Asunto(s)
Implantación de Prótesis Vascular , Trombosis Coronaria/cirugía , Pericardio/cirugía , Poliésteres , Disfunción Ventricular Izquierda/cirugía , Remodelación Ventricular/fisiología , Animales , Volumen Cardíaco/fisiología , Trombosis Coronaria/patología , Perros , Contracción Miocárdica/fisiología , Pericardio/patología , Técnicas de Sutura , Disfunción Ventricular Izquierda/patologíaRESUMEN
BACKGROUND: Inhibition of dopamine beta-hydroxylase (DBH) results in a decrease in norepinephrine synthesis. The present study was a randomized, blinded, placebo-controlled investigation of the long-term effects of therapy with the DBH inhibitor nepicastat (NCT) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with chronic heart failure (HF). METHODS AND RESULTS: Moderate HF (LV ejection fraction [LVEF] 30% to 40%) was produced in 30 dogs by intracoronary microembolization. Dogs were randomized to low-dose NCT (0.5 mg/kg twice daily, n=7) (L-NCT), high-dose NCT (2 mg/kg twice daily, n=7) (H-NCT), L-NCT plus enalapril (10 mg twice daily, n=8) (L-NCT+ENA), or placebo (PL, n=8). Transmyocardial (coronary sinus-arterial) plasma norepinephrine (tNEPI), LVEF, end-systolic volume, and end-diastolic volume were measured before and 3 months after initiating therapy. tNEPI levels were higher in PL compared with NL (86+/-20 versus 13+/-14 pg/mL, P:<0.01). L-NCT alone and L-NCT+ENA reduced tNEPI toward normal (28+/-4 and 39+/-17 pg/mL respectively), whereas HD-NCT reduced tNEPI to below normal levels (3+/-10 pg/mL). In PL dogs, LVEF decreased but was unchanged with L-NCT and increased with L-NCT+ENA. L-NCT and L-NCT+ENA prevented progressive LV remodeling, as evidenced by lack of ongoing increase in end-diastolic volume and end-systolic volume, whereas H-NCT did not CONCLUSIONS: In dogs with HF, therapy with L-NCT prevented progressive LV dysfunction and remodeling. The addition of ENA to L-NCT afforded a greater increase in LV systolic function. NCT at doses that normalize tNEPI may be useful in the treatment of chronic HF.
Asunto(s)
Dopamina beta-Hidroxilasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Imidazoles/farmacología , Tionas/farmacología , Disfunción Ventricular Izquierda/tratamiento farmacológico , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Enalapril/administración & dosificación , Enalapril/farmacología , Inhibidores Enzimáticos/administración & dosificación , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/enzimología , Imidazoles/administración & dosificación , Norepinefrina/sangre , Volumen Sistólico/efectos de los fármacos , Tionas/administración & dosificación , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/complicaciones , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
OBJECTIVES: In this study, we examined the effects of long-term therapy with bosentan on the progression of LV dysfunction and remodeling in dogs with moderate HF. BACKGROUND: Acute intravenous administration of bosentan, a mixed endothelin-1 type A and type B receptor antagonist, was shown to improve left ventricular (LV) function in patients and dogs with heart failure (HF). METHODS: Left ventricular dysfunction was induced by multiple, sequential intracoronary microembolizations in 14 dogs. Embolizations were discontinued when LV ejection fraction (EF) was between 30% and 40%. Dogs were randomized to three months of therapy with bosentan (30 mg/kg twice daily, n = 7) or no therapy at all (control, n = 7). RESULTS: In untreated dogs, EF decreased from 35 +/- 1% before initiating therapy to 29 +/- 1% at the end of three months of therapy (p = 0.001), and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 71 +/- 3 vs. 84 +/- 8 ml, p = 0.08; ESV: 46 +/- 2 vs. 60 +/- 6 ml, p = 0.03). By contrast, in dogs treated with bosentan, EF tended to increase from 34 +/- 2% before initiating therapy to 39 +/- 1% at the end of three months of therapy (p = 0.06), and EDV and ESV decreased (EDV: 75 +/- 3 vs. 71 +/- 4 ml, p = 0.05; ESV: 48 +/- 2 vs. 43 +/- 3 ml, p = 0.01). Furthermore, compared with untreated dogs, dogs treated with bosentan showed significantly less LV cardiomyocyte hypertrophy and LV volume fraction of interstitial fibrosis. CONCLUSIONS: In dogs with moderate HF, long-term therapy with bosentan prevents the progression of LV dysfunction and attenuates LV chamber remodeling. The findings support the use of mixed endothelin-1 receptor antagonists as adjuncts to the long-term treatment of HF.
Asunto(s)
Antihipertensivos/farmacología , Insuficiencia Cardíaca/fisiopatología , Sulfonamidas/farmacología , Disfunción Ventricular Izquierda/fisiopatología , Remodelación Ventricular/efectos de los fármacos , Animales , Bosentán , Progresión de la Enfermedad , Perros , Insuficiencia Cardíaca/patología , Infusiones Intravenosas , Miocardio/patología , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Disfunción Ventricular Izquierda/patología , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiología , Remodelación Ventricular/fisiologíaRESUMEN
An important feature of heart failure is the progressive deterioration of left ventricular function that occurs in the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known. We and others have advanced the hypothesis that this hemodynamic deterioration results from progressive intrinsic contractile dysfunction of viable cardiomyocytes and/or from ongoing loss of cardiomyocytes. This review will focus on the concept of ongoing cardiac myocyte loss as a contributing factor to the progression of left ventricular dysfunction that characterizes the heart failure state. Specifically, the discussion will center on apoptosis or "programmed cell death" as a potential mediator of cardiomyocyte loss. In recent years, several studies have shown that constituent myocytes of failed explanted human hearts and hearts of animals with experimentally induced heart failure undergo apoptosis. Studies have also shown that cardiomyocyte apoptosis occurs following acute myocardial infarction, in the hypertrophied heart as well as in the aging heart; conditions frequently associated with the development of failure. While available data support the existence of myocyte apoptosis in the failing heart, lacking are studies which address the importance of myocyte apoptosis in the progression of LV dysfunction. As part of this discussion, we will address this issue and construct a case in support of a concept that the failing myocardium is subject to regional hypoxia, an abnormality that can potentially trigger cardiomyocyte apoptosis. If loss of cardiac myocytes through apoptosis can be shown to be an important contributor to the progression of heart failure, and if exact physiologic and molecular factors that trigger apoptosis in the heart can be identified, the stage will be set for the development of novel therapeutic modalities aimed at preventing, or at the very least retarding, the process of progressive ventricular dysfunction and the ultimate transition toward end-stage, intractable heart failure.
Asunto(s)
Apoptosis/fisiología , Insuficiencia Cardíaca/fisiopatología , Isquemia Miocárdica/fisiopatología , Miocitos Cardíacos/citología , Disfunción Ventricular Izquierda/fisiopatología , Animales , Muerte Celular/fisiología , Células Cultivadas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perros , Humanos , Inmunohistoquímica , Miocardio/patología , Miocitos Cardíacos/fisiología , Valores de Referencia , Sensibilidad y EspecificidadRESUMEN
The objective of the present study was to determine the effects of early long-term monotherapy with the angiotensin II AT1-receptor antagonist valsartan on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure (HF). Studies were performed in 30 dogs with moderate HF produced by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction was 30-40%. Two weeks after the last embolization, dogs were randomized to 3 mo of oral therapy with low-dose valsartan (400 mg twice daily, n = 10), to high-dose valsartan (800 mg twice daily, n = 10), or to no treatment at all (control, n = 10). Treatment with valsartan significantly reduced mean aortic pressure and LV end-diastolic pressure compared with control. In untreated dogs, LV ejection fraction decreased (37 +/- 1 vs. 29 +/- 1%, P = 0.001) and end-systolic volume (ESV) and end-diastolic volume (EDV) increased (81 +/- 5 vs. 92 +/- 5 ml, P < 0.001; 51 +/- 3 vs. 65 +/- 3 ml, P = 0.001, respectively) after 3 mo of follow-up compared with those levels before follow-up. In dogs treated for 3 mo with low-dose valsartan, ejection fraction was preserved (37 +/- 1 vs. 38 +/- 2%, pretreatment vs. posttreatment) as was ESV but not EDV. In dogs treated for 3 mo with high-dose valsartan, ejection fraction decreased (35 +/- 1 vs. 31 +/- 2%, P = 0.02) and ESV and EDV increased in a manner comparable to those levels in controls. Valsartan had no significant effects on cardiomyocyte hypertrophy or on the extent of interstitial fibrosis. We conclude that, for dogs with moderate HF, early long-term therapy with the AT1-receptor blocker valsartan decreases preload and afterload but has only limited benefits in attenuating the progression of LV dysfunction and chamber remodeling.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Gasto Cardíaco Bajo/fisiopatología , Disfunción Ventricular Izquierda/fisiopatología , Animales , Gasto Cardíaco Bajo/tratamiento farmacológico , Gasto Cardíaco Bajo/patología , Progresión de la Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Tetrazoles/uso terapéutico , Valina/análogos & derivados , Valina/uso terapéutico , Valsartán , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/patología , Remodelación Ventricular/efectos de los fármacosRESUMEN
A characteristic feature of heart failure is the progressive deterioration of left ventricular function that occurs in the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this haemodynamic deterioration are not known but may be related to progressive intrinsic contractile dysfunction of cardiomyocytes and/or to ongoing degeneration and loss of viable cardiomyocytes. In this review we examine the concept of ongoing cardiac myocyte loss as a potential factor responsible for the progression of left ventricular dysfunction in heart failure. The discussion focuses on apoptosis or 'programmed cell death' as a potential mediator of cardiomyocyte loss. While available data support the existence of myocyte apoptosis in the failing heart, studies addressing possible physiological and molecular triggers of this process of cell death in the failing heart are lacking. As a part of the discussion, we construct a case in support of the concept that the failing myocardium is subject to regional hypoxia, an abnormality that can potentially trigger cardiomyocyte apoptosis. If loss of cardiomyocytes through apoptosis can be shown to be an important contributor to the progression of heart failure, and if the trigger of cardiomyocyte apoptosis in the failing heart can be identified, the foundation would be strengthened for the development of novel, target-specific therapeutic modalities aimed at preventing, or at the very least retarding, the process of progressive ventricular dysfunction and the transition toward intractable heart failure.
Asunto(s)
Apoptosis , Insuficiencia Cardíaca/fisiopatología , Miocardio/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Insuficiencia Cardíaca/patología , Miocardio/patología , Sensibilidad y Especificidad , Disfunción Ventricular Izquierda/patologíaRESUMEN
Chronic heart failure (HF) is associated with morphologic abnormalities of cardiac mitochondria that include hyperplasia, reduced organelle size and compromised structural integrity. In the present study, we examined mitochondrial respiration in myocardium of 10 normal dogs and 10 dogs with chronic HF (LV ejection fraction 24+/-2%) produced by intracoronary micro-embolizations. Mitochondrial respiratory rates were determined using a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles. Basal respiratory rate (VO), respiratory rate after addition of substrates, glutamate and malate (VSUB) and state 3 respiratory rate (VADP, after addition of ADP), were measured in tissue samples from the subendocardial and subepicardial LV free wall, interventricular septum and right-ventricular free wall. No differences were observed in basal respiratory rates between normal and HF tissue, while VSUB was significantly lower in HF compared to normal. VADP was 50-60% lower in HF compared to normal tissue (P<0.001). The results indicate abnormal mitochondrial respiratory activity in myocardium of dogs with chronic HF. These findings support the concept of low myocardial energy production in HF that can contribute to the global cardiac dysfunction.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Corazón/fisiopatología , Mitocondrias Cardíacas/fisiología , Animales , Gasto Cardíaco , Modelos Animales de Enfermedad , Perros , Metabolismo Energético , Consumo de Oxígeno , Volumen SistólicoRESUMEN
Cardiomyocyte apoptosis or programmed cell death has been shown to occur in end-stage explanted failed human hearts and in dogs with chronic heart failure (HF). We tested the hypothesis that early long-term monotherapy with an angiotensin-converting enzyme (ACE) inhibitor attenuates cardiomyocyte apoptosis in dogs with moderate HF. Left ventricular (LV) dysfunction (ejection fraction 30-40%) was produced in dogs by multiple sequential intracoronary microembolizations. Dogs were randomized to 3 mo of therapy with enalapril (Ena, 10 mg twice daily, n = 7) or to no therapy at all (control, n = 7). After 3 mo of therapy, dogs were euthanized and the hearts removed. Presence of nuclear DNA fragmentation (nDNAf), a marker of apoptosis, was assessed in frozen LV sections using the immunohistochemical deoxynucleotidal transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method. Sections were also stained with ventricular anti-myosin antibody to identify cells of cardiocyte origin. From each dog, 80 fields (x40) were selected at random, 40 from LV regions bordering old infarcts and 40 from LV regions remote from any infarcts, for quantifying the number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes. The average number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes was significantly lower in Ena-treated dogs compared with controls (0.81 +/- 0.13 vs. 2.65 +/- 0.81, P < 0.029). This difference was due to a significantly lower incidence of cardiomyocyte nDNAf events in LV regions bordering scarred tissue (infarcts) in Ena-treated dogs compared with controls. We conclude that early long-term Ena therapy attenuates cardiomyocyte apoptosis in dogs with moderate HF. Attenuation of cardiomyocyte apoptosis may be one mechanism by which ACE inhibitors preserve global LV function in HF.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Apoptosis/efectos de los fármacos , Enalapril/farmacología , Insuficiencia Cardíaca/fisiopatología , Corazón/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Miocardio/patología , Animales , Fragmentación del ADN , Perros , Corazón/fisiopatología , Humanos , Ventriculografía con Radionúclidos/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
A characteristic feature of heart failure is the progressive worsening of ventricular function over months or years despite the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known but may be related to progressive intrinsic contractile dysfunction of residual viable cardiac myocytes, or to ongoing degeneration and loss of myocytes, or both. This report will address the concept of ongoing cardiac myocyte loss that may occur during the course of evolving heart failure viewed from the perspective of apoptosis or "programmed cell death" as the potential mediator of cardiac muscle cell loss. In recent years, several studies have shown that constituent myocytes of failed explanted human hearts and hearts of animals with experimentally induced heart failure undergo apoptosis. Recent studies have shown that cardiac myocyte apoptosis also occurs after acute myocardial infarction, as well as in the hypertrophied heart and the aging heart, conditions frequently associated with the development of heart failure. Considerable work has also been conducted and novel concepts advanced to explain potential molecular triggers of cardiac myocyte apoptosis in heart failure. Although available data support the existence of myocyte apoptosis in the failing heart, questions essential to our understanding of the importance of myocyte apoptosis in this disease process remain unanswered. Lacking are studies aimed at identifying physiological factors inherent to heart failure that trigger myocyte apoptosis. Also lacking are studies that address the importance of myocyte apoptosis in the progression of left ventricular dysfunction. If loss of cardiac myocytes through apoptosis can be shown to be an important contributor to the progression of heart failure, and if factors that trigger apoptosis in the heart can be identified, such knowledge can potentially lead to the development of novel therapeutic modalities aimed at preventing, or at the very least retarding, the process of progressive ventricular dysfunction and the ultimate transition toward end-stage, intractable heart failure.
Asunto(s)
Apoptosis , Insuficiencia Cardíaca/fisiopatología , Animales , Humanos , Hipertrofia Ventricular Izquierda/fisiopatología , Infarto del Miocardio/fisiopatología , Necrosis , Daño por Reperfusión/fisiopatologíaRESUMEN
Progressive deterioration of left ventricular function is a characteristic feature of the heart failure state and is often speculated to result from ongoing loss of viable myocytes. We previously showed that in dogs with chronic heart failure, cardiocyte death through apoptosis occurs in the border region of fibrous scars (old infarcts). In the present study we examined the structural integrity of cardiocytes in regions bordering fibrous scars using transmission electron microscopy. Morphometric studies were performed using left ventricular tissue obtained from ten dogs with chronic heart failure produced by intracoronary microembolizations. Mitochondrial number increased significantly with proximity to the scar, while mitochondrial size decreased leading to a gradual decrease in mitochondrial volume fraction. Severe injury to mitochondria was present in only 5% of organelles in myocytes far from the scar but increased markedly to 28-41% in myocytes adjacent to or incorporated within the scar. Similarly, severe myofibrillar abnormalities were present in only 3% of myocytes that were far from the scar but increased significantly to 12-73% in myocytes adjacent to or incorporated within the scar. These results indicate that in dogs with chronic heart failure, constituent myocytes of left ventricular regions bordering fibrous scars manifest heterogeneity in the extent of degeneration. The extent of degeneration is greatest in myocytes closest to the scar and least in myocytes far from the scar. We postulate that this wavefront of myocyte degeneration is a dynamic process that may lead to progressive expansion of the scar through loss of viable myocytes and ultimately may contribute, in part, to the progressive left ventricular dysfunction that characterizes the heart failure state.
Asunto(s)
Cicatriz/patología , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/patología , Miocardio/ultraestructura , Animales , Tamaño de la Célula , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perros , Embolia/complicaciones , Fibrosis/patología , Insuficiencia Cardíaca/etiología , Microscopía Electrónica , Microesferas , Mitocondrias Cardíacas/ultraestructura , Sarcómeros/ultraestructuraRESUMEN
Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Animales , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Antagonistas de los Receptores de Bradiquinina , Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/fisiopatología , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Imidazoles/farmacología , Cininas/fisiología , Masculino , Modelos Cardiovasculares , Infarto del Miocardio/complicaciones , Miocardio/patología , Piridinas/farmacología , Ramipril/farmacología , Ratas , Ratas Endogámicas Lew , Receptor de Angiotensina Tipo 1 , Tetrazoles/farmacologíaRESUMEN
The proportion of slow-twitch, fatigue-resistant type 1 skeletal muscle (SM) fibers is often reduced in heart failure (HF), while the proportion of fatigue-sensitive type-II fibers increases. This maladaptation may be partially responsible for the exercise intolerance that characterize HF. In this study, we examined the effects of early monotherapy with the angiotensin-converting enzyme inhibor, enalapril, and the beta-blocker, metoprolol, on SM fiber type composition in 18 dogs with moderate HF produced by intracoronary microembolizations. HF dogs were randomized to 3 mo therapy with enalapril (10 mg twice daily), metoprolol (25 mg twice daily), or no treatment. Triceps muscle biopsies were obtained at baseline, before randomization, and at the end of 30 mo of therapy. Type I and type II SM fibers were differentiated by myofibrillar adenosinetriphosphatase (pH 9.4). In untreated dogs, the proportion of type I fibers was 27 +/- 1% before randomization and decreased to 23 +/- 1% (P < 0.05) at the end of 3 mo of follow up. In dogs treated with enalapril or metoprolol, the proportion of type I fibers was 30 +/- 4 and 28 +/- 2% before randomization and 33 +/- 4 and 33 +/- 1%, respectively, after 3 mo of therapy. In conclusion, in dogs with moderate HF, early therapy with enalapril or metoprolol prevents the progressive decline in the proportion of type I SM fibers.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Gasto Cardíaco Bajo/patología , Fibras Musculares Esqueléticas/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Animales , Gasto Cardíaco Bajo/fisiopatología , Perros , Enalapril/farmacología , Femenino , Miembro Anterior , Masculino , Metoprolol/farmacología , Fibras Musculares Esqueléticas/ultraestructura , Músculo Esquelético/patología , Resistencia Física , Esfuerzo FísicoRESUMEN
It is often speculated that progressive deterioration of left ventricular function in heart failure is due to ongoing loss of viable cardiocytes. In this study, we examined the possibility that cardiocyte loss in heart failure may be due, in part, to apoptosis, an active process of gene-directed cellular self-destruction. Studies were performed in left ventricular tissue obtained from 10 dogs with chronic heart failure produced by multiple intracoronary microembolizations (left ventricular ejection fraction 27 +/- 1%) and from 5 normal dogs. Evidence for cardiocyte apoptosis was based on transmission electron microscopy criteria and on in situ immunohistochemical labeling of nuclear DNA fragmentation. There was no evidence of apoptotic cardiocytes in normal dogs. Features of cardiocyte apoptosis were observed in dogs with heart failure primarily in regions bordering old infarcts. Electron microscopic features of cardiocyte apoptosis included (1) intact sarcolemma and inner organelles in the presence of compaction and segregation of nuclear chromatin into sharply delineated masses that about the nuclear envelope, (2) intact sarcolemma in the presence of cytoplasm shrinkage, blebbing, and nuclear fragmentation, and (3) intact sarcolemma in the presence of complete disorganization of inner organelles and disappearance of nucleolemma. A count of all of the apoptotic bodies positively labeled for nuclear DNA fragments showed that 11% were of cardiocyte origin confirmed by positive labeling with striated muscle antimyosin antibody. We conclude that morphological and biochemical features of cardiocyte apoptosis exist in the left ventricular myocardium of dogs with chronic heart failure.
Asunto(s)
Apoptosis , Insuficiencia Cardíaca/patología , Miocardio/patología , Animales , Apoptosis/genética , Enfermedad Crónica , Daño del ADN , Perros , Ventrículos Cardíacos/patología , Microscopía Electrónica , Miocardio/ultraestructura , Sarcolema/ultraestructuraRESUMEN
After transient episodes of ischemia, benefits of thrombolytic or angioplastic therapy may be limited by reperfusion injury. Angiotensin-converting enzyme inhibitors protect the heart against ischemia/reperfusion injury, an effect mediated by kinins. We examined whether the protective effect of the angiotensin-converting enzyme inhibitor ramiprilat on myocardial ischemia/reperfusion is due to kinin stimulation of prostaglandin and/or nitric oxide release. The left anterior descending coronary artery of Lewis inbred rats was occluded for 30 minutes, followed by 120 minutes of reperfusion. Immediately before reperfusion rats were treated with vehicle, ramiprilat, or the angiotensin II type 1 receptor antagonist losartan. We tested whether pretreatment with the kinin receptor antagonist Hoe 140, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, or the cyclooxygenase inhibitor indomethacin blocked the effect of ramiprilat on infarct size and reperfusion arrhythmias. In controls, infarct size as a percentage of the area at risk was 79 +/- 3%; ramiprilat reduced this to 49 +/- 4% (P < .001), but losartan had little effect (74 +/- 6%, P = NS). Pretreatment with Hoe 140, NG-nitro-L-arginine methyl ester, or indomethacin abolished the beneficial effect of ramiprilat. Compared with the 30-minute ischemia/120-minute reperfusion group, nonreperfused hearts with 30 minutes of ischemia had significantly smaller infarct size as a percentage of the area at risk, whereas in the 150-minute ischemia group it was significantly larger. This suggests that reperfusion caused a significant part of the myocardial injury, but it also suggests that compared with prolonged ischemia, reperfusion salvaged some of the myocardium. Ventricular arrhythmias mirrored the changes in infarct size. Thus, angiotensin-converting enzyme inhibitors protect the myocardium against ischemia/reperfusion injury and arrhythmias; these beneficial effects are mediated primarily by a kinin-prostaglandin-nitric oxide pathway, not inhibition of angiotensin II formation.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Arritmias Cardíacas/prevención & control , Isquemia Miocárdica/patología , Daño por Reperfusión/prevención & control , Animales , Antiinflamatorios no Esteroideos/farmacología , Arginina/análogos & derivados , Arginina/farmacología , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Antagonistas de los Receptores de Bradiquinina , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores Enzimáticos/farmacología , Hemodinámica/efectos de los fármacos , Indometacina/farmacología , Masculino , Infarto del Miocardio/patología , NG-Nitroarginina Metil Éster , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ramipril/análogos & derivados , Ramipril/farmacología , Ratas , Ratas Endogámicas LewRESUMEN
Progressive deterioration of left ventricular (LV) function is a characteristic feature of the heart failure (HF) state. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known but may be related to progressive intrinsic dysfunction, degeneration and loss of viable cardiocytes. In the present study, we tested the hypothesis that accumulation of collagen in the cardiac interstitium (reactive interstitial fibrosis, RIF), known to occur in HF, results in reduced capillary density (CD = capillary/fiber ratio) and increased oxygen diffusion distance (ODD) which can lead to hypoxia and dysfunction of the collagen encircled myocyte. Studies were performed in LV tissue obtained from 10 dogs with chronic HF (LV ejection fraction 26 +/- 1%) produced by multiple sequential intracoronary microembolizations. In each dog, CD and ODD were evaluated in LV regions that manifested severe RIF (volume fraction 16 +/- 2%) and in LV regions of little or no RIF (volume fraction 4 +/- 1%). In regions of severe RIF, CD was significantly decreased compared to regions of no RIF (0.92 +/- 0.02 vs. 1.05 +/- 0.03) (P < 0.003). Similarly, ODD was significantly increased in regions of severe RIF compared to regions of no RIF (15.3 +/- 0.4 vs. 12.2 +/- 0.3 microns) (P < 0.001). These data suggest that in dogs with chronic HF, constituent myocytes of LV regions which manifest severe RIF may be subjected to chronic hypoxia; a condition that can adversely impact the function and viability of the collagen encircled cardiocyte.