Mortality benefit with AF ablation: Impact of normal sinus rhythm seen in CABANA and EAST AFnet.

Atrial fibrillation (AF) is significantly associated with morbidity and mortality and erodes the quality and quantity of life. It is standard of care to treat patients with AF and an increased risk of stroke with oral anticoagulation therapy, but the more daunting question many clinicians face is whether to pursue a "rate-only" or "rhythm" control strategy. Historical studies over the years have sought to answer this question but have found no significant difference in major clinical outcomes between the two strategies. There are opportunities based on new data to improve the natural history of the disease. The EAST AFnet trial for the first time revealed a significant morbidity and mortality advantage to rhythm control therapy when performed early in the disease process of AF and in the setting of comprehensive medical management that was maintained. The CABANA trial clearly demonstrated that catheter ablation was a more effective long-term treatment of AF in general and significantly lowers risk of AF progression compared to medical therapy. Like multiple prior trials of rhythm management strategies, when rhythm control was effective in these trials, independent of therapy assignment, there was a significantly lower risk of adverse outcomes and death. These contemporary data provide optimism that the pervasive mortality risk in patients with AF observed over the past 50 years may be improved by the timing, use, and efficacy of use of therapeutic interventions.

Atrial Fibrillation Ablation in a Patient With SV ASD and PAPVR Preceding Transcatheter Septal Closure.

Atrial fibrillation (AF) is common in adults with unrepaired atrial septal defects (ASDs). Sinus venosus (SV) ASDs associated with partial anomalous pulmonary venous return (PAPVR) are traditionally managed surgically. We report the first AF catheter ablation in a patient with SV ASD and PAPVR preceding transcatheter ASD repair with a covered stent. (Level of Difficulty: Advanced.).

CaMKII as a Therapeutic Target in Cardiovascular Disease.

CaMKII (the multifunctional Ca2+ and calmodulin-dependent protein kinase II) is a highly validated signal for promoting a variety of common diseases, particularly in the cardiovascular system. Despite substantial amounts of convincing preclinical data, CaMKII inhibitors have yet to emerge in clinical practice. Therapeutic inhibition is challenged by the diversity of CaMKII isoforms and splice variants and by physiological CaMKII activity that contributes to learning and memory. Thus, uncoupling the harmful and beneficial aspects of CaMKII will be paramount to developing effective therapies. In the last decade, several targeting strategies have emerged, including small molecules, peptides, and nucleotides, which hold promise in discriminating pathological from physiological CaMKII activity. Here we review the cellular and molecular biology of CaMKII, discuss its role in physiological and pathological signaling, and consider new findings and approaches for developing CaMKII therapeutics.

MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII.

Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species.

Tbx6 is a determinant of cardiac and neural cell fate decisions in multipotent P19CL6 cells.

Multipotent P19CL6 cells differentiate into cardiac myocytes or neural lineages when stimulated with dimethyl sulfoxide (DMSO) or retinoic acid (RA), respectively. Expression of the transcription factor Tbx6 was found to increase during cardiac myocyte differentiation and to decrease during neural differentiation. Overexpression of Tbx6 was not sufficient to drive P19CL6 cells to a cardiac myocyte fate or to accelerate DMSO-induced differentiation. In contrast, knockdown of Tbx6 dramatically inhibited DMSO-induced differentiation of P19CL6 cells to cardiac myocytes, as evidenced by the loss of striated muscle-specific markers and spontaneous beating. Tbx6 knockdown was also accompanied by almost complete loss of Nkx2.5, a transcription factor involved in the specification of the cardiac myocyte lineage, indicating that Nkx2.5 is downstream of Tbx6. In distinction to its positive role in cardiac myocyte differentiation, Tbx6 knockdown augmented RA-induced differentiation of P19CL6 cells to both neurons and glia, and accelerated the rate of neurite formation. Conversely, Tbx6 overexpression attenuated differentiation to neural lineages. Thus, in the P19CL6 model, Tbx6 is required for cardiac myocyte differentiation and represses neural differentiation. We propose a model in which Tbx6 is a part of a molecular switch that modulates divergent differentiation programs within a single progenitor cell.

Mechanisms of cell death in heart disease.

The major cardiac syndromes, myocardial infarction and heart failure, are responsible for a large portion of deaths worldwide. Genetic and pharmacological manipulations indicate that cell death is an important component in the pathogenesis of both diseases. Cells die primarily by apoptosis or necrosis, and autophagy has been associated with cell death. Apoptosis has long been recognized as a highly regulated process. Recent data indicate that a significant subset of necrotic deaths is also programmed. In the review, we discuss the molecular mechanisms that underlie these forms of cell death and their interconnections. The possibility is raised that small molecules aimed at inhibiting cell death may provide novel therapies for these common and lethal heart syndromes.

Bax regulates primary necrosis through mitochondrial dynamics.

The defining event in apoptosis is mitochondrial outer membrane permeabilization (MOMP), allowing apoptogen release. In contrast, the triggering event in primary necrosis is early opening of the inner membrane mitochondrial permeability transition pore (mPTP), precipitating mitochondrial dysfunction and cessation of ATP synthesis. Bcl-2 proteins Bax and Bak are the principal activators of MOMP and apoptosis. Unexpectedly, we find that deletion of Bax and Bak dramatically reduces necrotic injury during myocardial infarction in vivo. Triple knockout mice lacking Bax/Bak and cyclophilin D, a key regulator of necrosis, fail to show further reduction in infarct size over those deficient in Bax/Bak. Absence of Bax/Bak renders cells resistant to mPTP opening and necrosis, effects confirmed in isolated mitochondria. Reconstitution of these cells or mitochondria with wild-type Bax, or an oligomerization-deficient mutant that cannot support MOMP and apoptosis, restores mPTP opening and necrosis, implicating distinct mechanisms for Bax-regulated necrosis and apoptosis. Both forms of Bax restore mitochondrial fusion in Bax/Bak-null cells, which otherwise exhibit fragmented mitochondria. Cells lacking mitofusin 2 (Mfn2), which exhibit similar fusion defects, are protected to the same extent as Bax/Bak-null cells. Conversely, restoration of fused mitochondria through inhibition of fission potentiates mPTP opening in the absence of Bax/Bak or Mfn2, indicating that the fused state itself is critical. These data demonstrate that Bax-driven fusion lowers the threshold for mPTP opening and necrosis. Thus, Bax and Bak play wider roles in cell death than previously appreciated and may be optimal therapeutic targets for diseases that involve both forms of cell death.

Programmed necrosis, not apoptosis, in the heart.

It is well known that apoptosis is an actively mediated cell suicide process. In contrast, necrosis, a morphologically distinct form of cell death, has traditionally been regarded as passive and unregulated. Over the past decade, however, experiments in Caenorhabditis elegans and mammalian cells have revealed that a significant proportion of necrotic death is, in fact, actively mediated by the doomed cell. Although a comprehensive understanding of necrosis is still lacking, some key molecular events have come into focus. Cardiac myocyte apoptosis and necrosis are prominent features of the major cardiac syndromes. Accordingly, the recognition of necrosis as a regulated process mandates a reexamination of cell death in the heart. This review discusses pathways that mediate programmed necrosis, how they intersect with apoptotic pathways, roles of necrosis in heart disease, and new therapeutic opportunities that the regulated nature of necrosis presents.