Sandeep Sagar

Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart

Aging is associated with progressive decline in energetic reserves compromising cardiac performance and tolerance to injury. Although deviations in mitochondrial functions have been documented in senescent heart, the molecular bases for the decline in energy metabolism are only partially understood. Here, high-throughput transcription profiles of genes coding for mitochondrial proteins in ventricles from adult (6-months) and aged (24-months) rats were compared using microarrays. Out of 614 genes encoding for mitochondrial proteins, 94 were differentially expressed with 95% downregulated in the aged. The majority of changes affected genes coding for proteins involved in oxidative phosphorylation (39), substrate metabolism (14) and tricarboxylic acid cycle (6). Compared to adult, gene expression changes in aged hearts translated into a reduced mitochondrial functional capacity, with decreased NADH-dehydrogenase and F(0)F(1) ATPase complex activities and capacity for oxygen-utilization and ATP synthesis. Expression of genes coding for transcription co-activator factors involved in the regulation of mitochondrial metabolism and biogenesis were downregulated in aged ventricles without reduction in mitochondrial density. Thus, aging induces a selective decline in activities of oxidative phosphorylation complexes I and V within a broader transcriptional downregulation of mitochondrial genes, providing a substrate for reduced energetic efficiency associated with senescence.

Effect of Long-Term Right Ventricular Pacing in Young Adults With Structurally Normal Heart

Background— Right ventricular pacing increases the risk of heart failure in adults with structural heart disease. The impact of prolonged right ventricular pacing in adults without structural heart disease is not fully characterized and may depend on interactions of pacing with abnormal substrate predisposing to ventricular dysfunction. Methods and Results— We assessed the effect of right ventricular pacing in patients who underwent pacemaker implantation for isolated congenital atrioventricular block between 1964 and 2005. To assess for immunologic contribution to cardiac dysfunction, outcomes were compared between patients with (Ab+) and without (Ab−) antinuclear antibody during adulthood and an age- and sex-matched Olmsted County, Minnesota, population. Of 103 patients (mean±SD age, 32±19 years), 18 were Ab+. Long-term survival free of new heart failure after pacemaker implantation in isolated congenital atrioventricular block patients was worse than in the matched population (P<0.001). This difference was attributable to the development of heart failure in 12 Ab+ patients (67%; P<0.001), without differences between Ab− patients (2%) and the matched population (2%; P=0.7). Compared with baseline, at last follow-up, left ventricular ejection fraction did not decline in Ab− (53±9% to 57±12%) but decreased in Ab+(52±10% to 38±12%; P=0.03) patients. Survival was similar in Ab− patients and the Minnesota population (98%; P=0.7) but worse in Ab+ patients (79%; P<0.01). Conclusions— The natural history of patients with isolated congenital atrioventricular block who require pacing depends upon their antibody status. Antinuclear antibody status was a predictor for the development of heart failure and death. Long-term right ventricular pacing alone does not appear to be associated with development of heart failure, deterioration in ventricular function, or reduced survival in Ab− isolated congenital atrioventricular block patients.

Genomic and Proteomic Analysis of Myocarditis and Dilated Cardiomyopathy

Myocarditis is defined as an inflammation of the myocardium that results in injury to the cardiac myocytes. Myocarditis is also thought to be a common cause of dilated cardiomyopathy (DCM) from evidence of viral persistence in the myocardium in patients with idiopathic DCM. Genome and proteome screening techniques that do not require mechanistic knowledge of disease pathogenesis have recently begun to reveal disease-specific profiles. These studies are now yielding novel mechanisms, biomarkers, and potential therapeutic targets. This article reviews several examples of noncandidate genomic and proteomic screening, as well as the potential strengths and pitfalls of these strategies for the evaluation of myocarditis and nonischemic DCM.

Combined surgical and ablative cure for localized sternal compression–induced cardiomyopathy and ventricular tachyarrhythmia

FIGURE 1. A, Preprocedure electrocardiogram showing monomorphic nonsu block morphology. B, Postprocedure electrocardiogram showing sinus rhythm From the Departments of Internal Medicine, Cardiology, Pediatric Surgery, and the Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minn. Disclosures: Authors have nothing to disclose with regard to commercial support. Received for publication Feb 17, 2012; accepted for publication March 16, 2012; available ahead of print April 16, 2012. Address for reprints: Samuel J. Asirvatham, MD, Divisions of Cardiovascular Diseases and Internal Medicine and Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (E-mail: asirvatham.samuel@mayo.edu). J Thorac Cardiovasc Surg 2012;144:e85-7 0022-5223/

Cardiac Resynchronization by Restoration of Native Ventricular Activation Reversal of Iatrogenic Mitral Regurgitation and Heart Failure

0.00 Published byElsevier Inc. on behalf of The American Association for Thoracic Surgery http://dx.doi.org/10.1016/j.jtcvs.2012.03.033

Images in cardiovascular medicine. Cardiac resynchronization by restoration of native ventricular activation: reversal of iatrogenic mitral regurgitation and heart failure.

A 56-year-old woman was transferred to our institution for evaluation of New York Heart Association class IV congestive heart failure that was refractory despite treatment with furosemide, carvedilol, digitalis, spironolactone, and valsartan. She was bedridden before her transfer and was referred for consideration of cardiac transplantation. Prior treatment at another institution included bypass of the left anterior descending coronary artery, a left internal mammary graft for unstable angina, and implantation of a dual-chamber cardioverter/defibrillator for ventricular tachycardia. The device was programmed for DDDR pacing, with rate limits of 80 to 130 bpm and an atrioventricular (AV) delay of 160 ms. In this setting, the patient had been paced in the right ventricle 100% of the time for 6 months before she presented at our institution. Deterioration of her condition began after cardioverter/defibrillator placement and persisted despite increasing pharmacotherapy. At the time of hospital admission, she was in florid congestive heart failure and had hypotension, elevated jugular venous pressure, bilateral lung crepitations, a murmur of mitral regurgitation, and pitting edema of the lower extremities. The initial ECG (at hospital admission) showed AV sequential pacing at 80 bpm with wide, paced QRS complexes that showed a left bundle-branch block configuration (Figure, A). The initial echocardiogram showed a dilated left ventricle, severe mitral regurgitation (MR) (regurgitant volume, 69 mL), and a left ventricular ejection fraction of 25% (Figure, B and Movie I). A chest radiograph confirmed pulmonary congestion and cardiomegaly, and the ventricular pacing lead was in the conventional right ventricular apex position near the septum (Figure, C). Figure ECGs, echocardiographic images, and chest radiographs of a patient with AV sequential pacing (DDDR pacing with 160-millisecond AV delay). The pacemaker was reprogrammed to DDIR pacing with prolonged (300 ms) AV delay to restore native ventricular conduction. ... The cardioverter/defibrillator was reprogrammed for DDIR pacing, with an AV delay of 300 ms to promote ventricular activation via the native conduction system. The QRS complexes became narrow (Figure, D), and the severity of MR markedly decreased from severe to trivial (shown by echocardiography on the day of reprogramming) (Figure, E and Movie II). The patients symptoms improved immediately, and she was able to ambulate. At the day-15 follow-up examination, the cardiothoracic ratio, measured by chest radiography, had decreased from 0.7 to 0.6 (Figure, C and F). Four months later, she had maintained her improved condition and had New York Heart Association class II symptoms that were associated with atrial pacing and ventricular activation via the native conduction system (Figure, G). An echocardiographic examination showed a further decrease in left ventricle size, improvement in ejection fraction to 40%, and absence of MR (Figure, H and Movie III). No marked change in the left atrial volume was noted at presentation (75 mL) or at last follow-up (78 mL). The calculated pulmonary artery pressures were 35 mm Hg on admission and 37 mm Hg after the pacemaker was reprogrammed for DDIR pacing. The cardiothoracic ratio, measured by chest radiography, had decreased to 0.5 (Figure, I). This case illustrates iatrogenic severe mitral regurgitation and congestive heart failure that was due to abnormal activation of ventricles that were paced from the right ventricular apex position. The disappearance of MR after reprogramming suggested that right ventricle apical pacing caused dyssynchronous contraction of the papillary muscles (Figure, E and H). Reprogramming the cardioverter/defibrillator to DDIR pacing with prolonged AV delay resynchronized ventricular function by restoring native ventricular activation (Figure, D and G). This provided a normal QRS duration with no intraventricular conduction defect and was associated with dramatic improvement of symptoms. The patient no longer needed an upgrade procedure (for cardiac resynchronization therapy) or a cardiac transplant. In patients with iatrogenic left bundle-branch block (due to ventricular pacing, absence of AV block, and narrow QRS ventricular activation), restoration of native conduction by AV interval reprogramming should be attempted before therapies such as surgical upgrade to biventricular pacing are considered.A 56-year-old woman was transferred to our institution for evaluation of New York Heart Association class IV congestive heart failure that was refractory despite treatment with furosemide, carvedilol, digitalis, spironolactone, and valsartan. She was bedridden before her transfer and was referred for consideration of cardiac transplantation. Prior treatment at another institution included bypass of the left anterior descending coronary artery, a left internal mammary graft for unstable angina, and implantation of a dual-chamber cardioverter/defibrillator for ventricular tachycardia. The device was programmed for DDDR pacing, with rate limits of 80 to 130 bpm and an atrioventricular (AV) delay of 160 ms. In this setting, the patient had been paced in the right ventricle 100% of the time for 6 months before she presented at our institution. Deterioration of her condition began after cardioverter/defibrillator placement and persisted despite increasing pharmacotherapy. At the time of hospital admission, she was in florid congestive heart failure and had hypotension, elevated jugular venous pressure, bilateral lung crepitations, a murmur of mitral regurgitation, and pitting edema of the lower extremities. The initial ECG (at hospital admission) showed AV sequential pacing at 80 bpm …

Cardiac Resynchronization by Restoration of Native Ventricular Activation

A 56-year-old woman was transferred to our institution for evaluation of New York Heart Association class IV congestive heart failure that was refractory despite treatment with furosemide, carvedilol, digitalis, spironolactone, and valsartan. She was bedridden before her transfer and was referred for consideration of cardiac transplantation. Prior treatment at another institution included bypass of the left anterior descending coronary artery, a left internal mammary graft for unstable angina, and implantation of a dual-chamber cardioverter/defibrillator for ventricular tachycardia. The device was programmed for DDDR pacing, with rate limits of 80 to 130 bpm and an atrioventricular (AV) delay of 160 ms. In this setting, the patient had been paced in the right ventricle 100% of the time for 6 months before she presented at our institution. Deterioration of her condition began after cardioverter/defibrillator placement and persisted despite increasing pharmacotherapy. At the time of hospital admission, she was in florid congestive heart failure and had hypotension, elevated jugular venous pressure, bilateral lung crepitations, a murmur of mitral regurgitation, and pitting edema of the lower extremities. The initial ECG (at hospital admission) showed AV sequential pacing at 80 bpm with wide, paced QRS complexes that showed a left bundle-branch block configuration (Figure, A). The initial echocardiogram showed a dilated left ventricle, severe mitral regurgitation (MR) (regurgitant volume, 69 mL), and a left ventricular ejection fraction of 25% (Figure, B and Movie I). A chest radiograph confirmed pulmonary congestion and cardiomegaly, and the ventricular pacing lead was in the conventional right ventricular apex position near the septum (Figure, C). Figure ECGs, echocardiographic images, and chest radiographs of a patient with AV sequential pacing (DDDR pacing with 160-millisecond AV delay). The pacemaker was reprogrammed to DDIR pacing with prolonged (300 ms) AV delay to restore native ventricular conduction. ... The cardioverter/defibrillator was reprogrammed for DDIR pacing, with an AV delay of 300 ms to promote ventricular activation via the native conduction system. The QRS complexes became narrow (Figure, D), and the severity of MR markedly decreased from severe to trivial (shown by echocardiography on the day of reprogramming) (Figure, E and Movie II). The patients symptoms improved immediately, and she was able to ambulate. At the day-15 follow-up examination, the cardiothoracic ratio, measured by chest radiography, had decreased from 0.7 to 0.6 (Figure, C and F). Four months later, she had maintained her improved condition and had New York Heart Association class II symptoms that were associated with atrial pacing and ventricular activation via the native conduction system (Figure, G). An echocardiographic examination showed a further decrease in left ventricle size, improvement in ejection fraction to 40%, and absence of MR (Figure, H and Movie III). No marked change in the left atrial volume was noted at presentation (75 mL) or at last follow-up (78 mL). The calculated pulmonary artery pressures were 35 mm Hg on admission and 37 mm Hg after the pacemaker was reprogrammed for DDIR pacing. The cardiothoracic ratio, measured by chest radiography, had decreased to 0.5 (Figure, I). This case illustrates iatrogenic severe mitral regurgitation and congestive heart failure that was due to abnormal activation of ventricles that were paced from the right ventricular apex position. The disappearance of MR after reprogramming suggested that right ventricle apical pacing caused dyssynchronous contraction of the papillary muscles (Figure, E and H). Reprogramming the cardioverter/defibrillator to DDIR pacing with prolonged AV delay resynchronized ventricular function by restoring native ventricular activation (Figure, D and G). This provided a normal QRS duration with no intraventricular conduction defect and was associated with dramatic improvement of symptoms. The patient no longer needed an upgrade procedure (for cardiac resynchronization therapy) or a cardiac transplant. In patients with iatrogenic left bundle-branch block (due to ventricular pacing, absence of AV block, and narrow QRS ventricular activation), restoration of native conduction by AV interval reprogramming should be attempted before therapies such as surgical upgrade to biventricular pacing are considered.A 56-year-old woman was transferred to our institution for evaluation of New York Heart Association class IV congestive heart failure that was refractory despite treatment with furosemide, carvedilol, digitalis, spironolactone, and valsartan. She was bedridden before her transfer and was referred for consideration of cardiac transplantation. Prior treatment at another institution included bypass of the left anterior descending coronary artery, a left internal mammary graft for unstable angina, and implantation of a dual-chamber cardioverter/defibrillator for ventricular tachycardia. The device was programmed for DDDR pacing, with rate limits of 80 to 130 bpm and an atrioventricular (AV) delay of 160 ms. In this setting, the patient had been paced in the right ventricle 100% of the time for 6 months before she presented at our institution. Deterioration of her condition began after cardioverter/defibrillator placement and persisted despite increasing pharmacotherapy. At the time of hospital admission, she was in florid congestive heart failure and had hypotension, elevated jugular venous pressure, bilateral lung crepitations, a murmur of mitral regurgitation, and pitting edema of the lower extremities. The initial ECG (at hospital admission) showed AV sequential pacing at 80 bpm …

Aging and cardioprotection

A 56-year-old woman was transferred to our institution for evaluation of New York Heart Association class IV congestive heart failure that was refractory despite treatment with furosemide, carvedilol, digitalis, spironolactone, and valsartan. She was bedridden before her transfer and was referred for consideration of cardiac transplantation. Prior treatment at another institution included bypass of the left anterior descending coronary artery, a left internal mammary graft for unstable angina, and implantation of a dual-chamber cardioverter/defibrillator for ventricular tachycardia. The device was programmed for DDDR pacing, with rate limits of 80 to 130 bpm and an atrioventricular (AV) delay of 160 ms. In this setting, the patient had been paced in the right ventricle 100% of the time for 6 months before she presented at our institution. Deterioration of her condition began after cardioverter/defibrillator placement and persisted despite increasing pharmacotherapy. At the time of hospital admission, she was in florid congestive heart failure and had hypotension, elevated jugular venous pressure, bilateral lung crepitations, a murmur of mitral regurgitation, and pitting edema of the lower extremities. The initial ECG (at hospital admission) showed AV sequential pacing at 80 bpm with wide, paced QRS complexes that showed a left bundle-branch block configuration (Figure, A). The initial echocardiogram showed a dilated left ventricle, severe mitral regurgitation (MR) (regurgitant volume, 69 mL), and a left ventricular ejection fraction of 25% (Figure, B and Movie I). A chest radiograph confirmed pulmonary congestion and cardiomegaly, and the ventricular pacing lead was in the conventional right ventricular apex position near the septum (Figure, C). Figure ECGs, echocardiographic images, and chest radiographs of a patient with AV sequential pacing (DDDR pacing with 160-millisecond AV delay). The pacemaker was reprogrammed to DDIR pacing with prolonged (300 ms) AV delay to restore native ventricular conduction. ... The cardioverter/defibrillator was reprogrammed for DDIR pacing, with an AV delay of 300 ms to promote ventricular activation via the native conduction system. The QRS complexes became narrow (Figure, D), and the severity of MR markedly decreased from severe to trivial (shown by echocardiography on the day of reprogramming) (Figure, E and Movie II). The patients symptoms improved immediately, and she was able to ambulate. At the day-15 follow-up examination, the cardiothoracic ratio, measured by chest radiography, had decreased from 0.7 to 0.6 (Figure, C and F). Four months later, she had maintained her improved condition and had New York Heart Association class II symptoms that were associated with atrial pacing and ventricular activation via the native conduction system (Figure, G). An echocardiographic examination showed a further decrease in left ventricle size, improvement in ejection fraction to 40%, and absence of MR (Figure, H and Movie III). No marked change in the left atrial volume was noted at presentation (75 mL) or at last follow-up (78 mL). The calculated pulmonary artery pressures were 35 mm Hg on admission and 37 mm Hg after the pacemaker was reprogrammed for DDIR pacing. The cardiothoracic ratio, measured by chest radiography, had decreased to 0.5 (Figure, I). This case illustrates iatrogenic severe mitral regurgitation and congestive heart failure that was due to abnormal activation of ventricles that were paced from the right ventricular apex position. The disappearance of MR after reprogramming suggested that right ventricle apical pacing caused dyssynchronous contraction of the papillary muscles (Figure, E and H). Reprogramming the cardioverter/defibrillator to DDIR pacing with prolonged AV delay resynchronized ventricular function by restoring native ventricular activation (Figure, D and G). This provided a normal QRS duration with no intraventricular conduction defect and was associated with dramatic improvement of symptoms. The patient no longer needed an upgrade procedure (for cardiac resynchronization therapy) or a cardiac transplant. In patients with iatrogenic left bundle-branch block (due to ventricular pacing, absence of AV block, and narrow QRS ventricular activation), restoration of native conduction by AV interval reprogramming should be attempted before therapies such as surgical upgrade to biventricular pacing are considered.A 56-year-old woman was transferred to our institution for evaluation of New York Heart Association class IV congestive heart failure that was refractory despite treatment with furosemide, carvedilol, digitalis, spironolactone, and valsartan. She was bedridden before her transfer and was referred for consideration of cardiac transplantation. Prior treatment at another institution included bypass of the left anterior descending coronary artery, a left internal mammary graft for unstable angina, and implantation of a dual-chamber cardioverter/defibrillator for ventricular tachycardia. The device was programmed for DDDR pacing, with rate limits of 80 to 130 bpm and an atrioventricular (AV) delay of 160 ms. In this setting, the patient had been paced in the right ventricle 100% of the time for 6 months before she presented at our institution. Deterioration of her condition began after cardioverter/defibrillator placement and persisted despite increasing pharmacotherapy. At the time of hospital admission, she was in florid congestive heart failure and had hypotension, elevated jugular venous pressure, bilateral lung crepitations, a murmur of mitral regurgitation, and pitting edema of the lower extremities. The initial ECG (at hospital admission) showed AV sequential pacing at 80 bpm …