Epidemiology of sudden cardiac death in rural South India - insights from the andhra pradesh rural health initiative

Background

Sudden cardiac death (SCD) is a common initial presentation of coronary artery disease (CAD). Despite the growing epidemic of CAD in India, the epidemiology of SCD is largely unknown.

Objective

The objective of the study was to define the prevalence and determinants of sudden cardiac deaths in rural South India.

Methods

Prospective mortality surveillance was conducted in 45 villages (180,162 subjects) in rural South India between January 2006 and October 2007. Trained multipurpose health workers sought to do verbal autopsies within 4 weeks of any death. Detailed questionnaires including comorbidities and circumstances surrounding death were recorded. SCD was adjudicated using the modified Hinkle-Thaler classification.

Results

A total of 1916 deaths occurred in the study population over the 22 month time period and verbal autopsy was obtained in 1827 (95%) subjects. Overall mean age of the deceased was 62 ± 20 years and 1007 (55%) were men. Cardiovascular and cerebrovascular diseases together accounted for 559 deaths (31%), followed by infectious disease (163 deaths, 9%), cancer (126 deaths, 7%) and suicide (93 deaths, 5%).Of the 1827 deaths, after excluding accidental deaths (89 deaths), 309 deaths (17%) met criteria for SCD. Cardiovascular disease was the underlying causes in the majority of the SCD events (231/309 (75%)). On multivariate analyses, previous MI/CAD (p < 0.001, OR 14.25), hypertension (p < 0.001, OR 1.84), and age groups between 40-60 yrs (p=0.029) were significantly associated with SCD.

Conclusion

Sudden cardiac death accounted for up to half of the cardiovascular deaths in rural Southern India. Traditional cardiovascular risk factors were strongly associated with SCD.     

Characterization of the cardiac sodium channel SCN5A mutation, N1325S, in single murine ventricular myocytes

The N(1325)S mutation in the cardiac sodium channel gene SCN5A causes the type-3 long-QT syndrome but the arrhythmogenic trigger associated with N(1325)S has not been characterized. In this study, we investigated the triggers for cardiac events in the expanded N(1325)S family. Among 11 symptomatic patients with document triggers, six died suddenly during sleep or while sitting (bradycardia-induced trigger), three died suddenly, and two developed syncope due to stress and excitement (non-bradycardia-induced). Patch-clamping studies revealed that the late sodium current (I(Na,L)) generated by mutation N(1325)S in ventricular myocytes from TG-NS/LQT3 mice was reduced with increased pacing, which explains bradycardia-induced mortalities in the family. The non-bradycardic triggers are related to the finding that APD became prolonged and unstable at increasing rates, often with alternating repolarization phases which was corrected with verapamil. This implies that Ca2+ influx and intracellular Ca2+ ([Ca2+]i) ions are involved and that [Ca2+]i inhomogeneity may be the underlying mechanisms behind non-bradycardia LQT3 arrhythmogenesis associated with mutation N(1325)S.     

Regulatory system for the G1‐arrest during neuronal development in Drosophila

Neuronal network consists of many types of neuron and glial cells. This diversity is guaranteed by the constant cell proliferation of neuronal stem cells following stop cell cycle re‐entry, which leads to differentiation during development. Neuronal differentiation occurs mainly at the specific cell cycle phase, the G1 phase. Therefore, cell cycle exit at the G1 phase is quite an important issue in understanding the process of neuronal cell development. Recent studies have revealed that aberrant S phase re‐entry from the G1 phase often links cellular survival. In this review we discuss the different types of G1 arrest on the process of neuronal development in Drosophila. We also describe the issue that aberrant S phase entry often causes apoptosis, and the same mechanism might contribute to sensory organ defects, such as deafness.     

FERM domain-containing unconventional myosin VIIA interacts with integrin β5 subunit and regulates αvβ5-mediated cell adhesion and migration

Unconventional myosin VIIA (Myo7a) has been known to associate with hereditary deafness. Here we present a novel function of Myo7a by identifying that Myo7a directly interacts with integrin β5 subunit and regulates cell adhesion and motility in an integrin-dependent manner. We found that Myo7a bound to the cytoplasmic tail of integrin β5. Further, we pinpointed an integrin-binding domain at F3 of the first FERM domain and F1 of the second FERM domain. Functionally, Myo7a-induced cell adhesion and migration were mediated by integrin αvβ5. These findings indicated that Myo7a interacts with integrin β5 and selectively promotes integrin αvβ5-mediated cell migration.     

Losing the beat: deficits in temporal coordination

Tapping or clapping to an auditory beat, an easy task for most individuals, reveals precise temporal synchronization with auditory patterns such as music, even in the presence of temporal fluctuations. Most models of beat-tracking rely on the theoretical concept of pulse: a perceived regular beat generated by an internal oscillation that forms the foundation of entrainment abilities. Although tapping to the beat is a natural sensorimotor activity for most individuals, not everyone can track an auditory beat. Recently, the case of Mathieu was documented (Phillips-Silver et al. 2011 Neuropsychologia 49, 961–969. (doi:10.1016/j.neuropsychologia.2011.02.002)). Mathieu presented himself as having difficulty following a beat and exhibited synchronization failures. We examined beat-tracking in normal control participants, Mathieu, and a second beat-deaf individual, who tapped with an auditory metronome in which unpredictable perturbations were introduced to disrupt entrainment. Both beat-deaf cases exhibited failures in error correction in response to the perturbation task while exhibiting normal spontaneous motor tempi (in the absence of an auditory stimulus), supporting a deficit specific to perception–action coupling. A damped harmonic oscillator model was applied to the temporal adaptation responses; the model''s parameters of relaxation time and endogenous frequency accounted for differences between the beat-deaf cases as well as the control group individuals.     

Methylation of the DFNA5 increases risk of lymph node metastasis in human breast cancer

The pathogenesis of breast cancer involves multiple genetic and epigenetic events. In this study, we report an epigenetic alteration of DFNA5 in human breast cancer. DFNA5 gene was silenced in breast cancer cell lines that were methylated in the DFNA5 promoter, and restored by treatment with the demethylating agent, 5-aza-dC, and gene knock-down of DFNA5 increased cellular invasiveness in vitro. The mRNA expression of DFNA5 in breast cancer tissues was down-regulated as compared to normal tissues. Moreover, the DFNA5 promoter was found to be methylated in primary tumor tissues with high frequency (53%, 18/34). Quantitative methylation-specific PCR of DFNA5 clearly discriminated primary breast cancer tissues from normal breast tissues (15.3%, 2/13). Moreover, methylation status of DFNA5 was correlated with lymph node metastasis in breast cancer patients. Our data implicate DFNA5 promoter methylation as a novel molecular biomarker in human breast cancer.     

Ventricular arrhythmogenesis: Insights from murine models

Ventricular arrhythmias are the key underlying cause of sudden cardiac death, a common cause of mortality and a significant public health burden. Insights into the electrophysiological basis of such phenomena have been obtained using a wide range of recording techniques and a diversity of experimental models. As in other fields of biology, the murine system presents both a wealth of opportunities and important challenges when employed to model the human case. This article begins by reviewing the extent to which the murine heart is representative of that of the human. It then presents a novel physiological classification of mechanisms of arrhythmogenesis, critically assessing the extent to which the study of murine hearts has offered worthwhile insights.     

Drugs that interact with cardiac electro-mechanics: old and new targets for treatment

The concept of mechano-electrical feedback was derived from the observation that a short stretch applied to the beating heart can invoke an electrical response in the form of an afterdepolarization or a premature ventricular beat. More recent work has identified stretch-activated channels whose specific inhibition might help to treat atrial fibrillation in the near future. But the interaction between electrical and mechanical function of the heart is a continuum from short-term (within milliseconds) to long-term (within weeks or months) effects. The long-term effects of pressure overload have been well-described on the molecular and cellular level, and substances that interact with these processes are used in clinical routine in the care of patients with cardiac hypertrophy and heart failure. These treatments help to prevent lethal arrhythmias (sudden death) and potentially atrial fibrillation. The intermediate interaction between mechanical and electrical function of the heart is less well-understood. Several recently identified regulatory mechanisms may provide novel antiarrhythmic targets associated with the "intermediate" response of the myocardium to stretch.     

Survival of bundleless hair cells and subsequent bundle replacement in the bullfrog's saccule

Our senses of hearing and balance depend upon hair cells, the sensory receptors of the inner ear. Millions of people suffer from hearing and balance deficits caused by damage to hair cells as a result of exposure to noise, aminoglycoside antibiotics, and antitumor drugs. In some species such damage can be reversed through the production of new cells. This proliferative response is limited in mammals but it has been hypothesized that damaged hair cells might survive and undergo intracellular repair. We examined the fate of bullfrog saccular hair cells after exposure to a low dose of the aminoglycoside antibiotic gentamicin to determine whether hair cells could survive such treatment and subsequently be repaired. In organ cultures of the bullfrog saccule a combination of time‐lapse video microscopy, two‐photon microscopy, electron microscopy, and immunocytochemistry showed that hair cells can lose their hair bundle and survive as bundleless cells for at least 1 week. Time‐lapse and electron microscopy revealed stages in the separation of the bundle from the cell body. Scanning electron microscopy (SEM) of cultures fixed 2, 4, and 7 days after antibiotic treatment showed that numerous new hair bundles were produced between 4 and 7 days of culture. Further examination revealed hair cells with small repaired hair bundles alongside damaged remnants of larger surviving bundles. The results indicate that sensory hair cells can undergo intracellular self‐repair in the absence of mitosis, offering new possibilities for functional hair cell recovery and an explanation for non‐proliferative recovery. © 2002 Wiley Periodicals, Inc. J Neurobiol 50: 81–92, 2002; DOI 10.1002/neu.10002