Dinender Kumar

Adriamycin-induced heart failure: mechanisms and modulation

Adriamycin (doxorubicin) is one of the most effective chemotherapeutic agents against a variety of cancers, but its usefulness is seriously curtailed by the risk of developing heart failure. Available laboratory evidence suggests that an increase in oxidative stress, brought about by increased free radical production and decreased myocardial endogenous antioxidants, plays an important role in the pathogenesis of heart failure. Adriamycin-induced apoptosis and hyperlipidemia may also be involved in the process. Probucol, a lipid-lowering drug and an antioxidant, completely prevents the occurrence of heart failure by reducing oxidative stress as well as by the modulation of apoptis and high lipid concentrations. Thus, combined therapy with adriamycin and probucol has a high potential for optimizing the treatment of cancer patients.

The role of oxidative stress in the genesis of heart disease

Although researchers in radiation and cancer biology have known about the existence of free radicals and their potential role in pathobiology for several decades, cardiac biologists only began to take notice of these noxious species in the 1970s. Exponential growth of free radical research occurred after the discovery of superoxide dismutase in 1969. This antioxidant enzyme is responsible for the dismutation of superoxide radical--a free radical chain initiator. A fine balance between free radicals and a variety of endogenous antioxidants is believed to exist. Any disturbance in this equilibrium in favour of free radicals causes an increase in oxidative stress and initiates subcellular changes leading to cardiomyopathy and heart failure. Our knowledge about the role of free radicals in the pathogenesis of cardiac dysfunction is fast approaching the point where newer therapies employing antioxidants are in sight.

Apoptosis in adriamycin cardiomyopathy and its modulation by probucol

The dose-dependent cardiomyopathy and heart failure due to adriamycin have been shown to be due to increased oxidative stress and loss of myocytes. We examined the incidence of myocardial apoptosis as well as changes in the expression of apoptotic regulatory gene products in an established animal model of adriamycin cardiomyopathy. Rats were treated with adriamycin (cumulative dose, 15 mg/kg), and the hearts were examined for apoptosis as well as expression of Bax, caspase 3, and Bcl-2 at 0, 4, 10, 16, and 21 days after the treatment. A significant increase in the incidence of apoptosis was seen at 4 days, followed by a decline at 10 and 16 days of posttreatment. At 21 days, the number of apoptotic cells increased again and included cells of the conducting system. Expression of Bax corresponded to these biphasic changes, whereas the converse was true for the expression of Bcl-2. The latter peaked at 10 days followed by a decline at 16 and 21 days. The Bax/Bcl-2 ratio also correlated with the incidence of apoptosis. Expression of caspase 3 correlated with increased apoptosis, but only at early time points. Probucol (cumulative dose, 120 mg/kg), a known antioxidant as well as promoter of endogenous antioxidants, significantly reduced the incidence of apoptosis as well as expression of Bax. Adriamycin-induced hemodynamic changes were also prevented by probucol. These data suggest that adriamycin-induced apoptosis is mediated by oxidative stress and may play a role in the development of heart failure.

Apoptosis in Isolated Adult Cardiomyocytes Exposed to Adriamycina

Abstract: Adriamycin (doxorubicin) is a highly potent antineoplastic agent, but its use is limited by the risk of developing cardiomyopathy and congestive heart failure. Available evidence suggests that adriamycin‐induced congestive heart failure is mediated by oxidative stress. We examined the possibility of adriamycin‐induced apoptosis in isolated adult rat cardiomyocytes and its inhibition by trolox, a water‐soluble antioxidant. Cardiomyocytes isolated from rat hearts were exposed to 20 μM adriamycin for 1 h and examined at different post‐treatment durations (0–23 h). Adriamycin caused a significant decrease in rod‐shaped cells and an increase in round cells. Both Hoechst 33258 staining and TUNEL assay revealed a significantly increased number of apoptotic myocytes and nucleosomal fragmentation upon exposure to adriamycin. In agarose gel electrophoresis, DNA laddering was found to be more intense in adriamycin‐exposed myocytes. A bright smear at the leading edge of the gels suggested indiscriminate fragmentation of DNA and myocyte necrosis by adriamycin. Both types of DNA degradations due to adriamycin were significantly reduced by trolox. We suggest that adriamycin‐induced cell death involves both apoptosis and necrosis and these may be mediated by oxidative stress.

Distribution of cells bearing B-cell alloantigen(s) in North Indian rheumatic fever/rheumatic heart disease patients.

Numerous investigators have developed monoclonal antibodies against B-cell alloantigen(s) of rheumatic fever. However, the developed monoclonals do not have the same significance in all the populations. We have developed a battery of monoclonals against B-cell alloantigens of North Indian rheumatic fever patients. In the present study, we have used these monoclonals to examine the frequency of rheumatic antigens in 30 patients with recurrence of rheumatic activity (RRA), 30 of rheumatic heart disease (RHD) patients and 50 controls using alkaline phosphatase anti-alkaline phosphatase (APAAP) technique. These patients were examined at the time of registry and after three months follow up. RRA patients showed higher percentage of lymphocyte positive as compare to RHD and controls. Interestingly, On follow-up RRA patients showed significant decline in positive lymphocyte as compare to first visit whereas no such change was observed in RHD patients. There were 90–93% of RRA and RHD patients positive with these monoclonals. A significant age variation of rheumatic cells was also noticed in all groups of rheumatic patients. We conclude that monoclonals raised from the same ethnic population are highly specific and cost effective to use them to develop an easy field test system such as APAAP, to identify the individual at risk, to develop rheumatic fever. It is also suggested that the alloantigen marker may persist through out life and gets activated after recurrence of the disease.

ON THE ROLE OF COENZYME Q10 IN CARDIOVASCULAR DISEASES

Judging from the response, Dr Bliznakov appears to have completely missed the point of our article published in the section on ‘Cardiovascular Conundra Series’ [1]. Our paper discusses only concepts as well as provides a glimpse of the evolution of our knowledge-base on the significance of oxidative stress in heart disease, since the time of the first discovery of oxygen. The paper was never meant to offer a detailed discussion of any individual, favourite antioxidant. We all know that a current list of potential antioxidants can run into several pages and it keeps growing everyday. Thus, any attempt to mention all antioxidants in any significant way will be a futile exercise. In Dr Bliznakov’s commentary, it is alleged that we have not provided enough clinical data on the use of antioxidants in different heart disease conditions. For the past 20 years, our laboratory has focussed …

Oxidative stress in heart failure : Current understanding and prospective

Our knowledge of the pathophysiology of heart failure has advanced far beyond the classic concept of the hemodynamic overload model and associated neurohumoral changes. Current interest lies in understanding the fundamentals of cellular defects to identify new molecular targets for therapies. Some of the new target sites being explored are inflammatory cytokines, nitric oxide, oxidative stress and apoptosis during the remodelling processes such as cardiac hypertrophy and dilation. The present review provides an overview of the chemistry/biochemistry of free radicals as well as a discussion of some defense mechanisms that have evolved and adapted to combat these toxic oxygen species. The probable role of oxidative stress in the pathogenesis of heart failure both from animal data and heart failure patients is also presented.