Cevher Ozcan

Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation

Background In patients with atrial fibrillation that is refractory to drug therapy, radio-frequency ablation of the atrioventricular node and implantation of a permanent pacemaker are an alternative therapeutic approach. The effect of this procedure on long-term survival is unknown. Methods We studied all patients who underwent ablation of the atrioventricular node and implantation of a permanent pacemaker at the Mayo Clinic between 1990 and 1998. Observed survival was compared with the survival rates in two control populations: age- and sex-matched members of the Minnesota population between 1970 and 1990 and consecutive patients with atrial fibrillation who received drug therapy in 1993. Results A total of 350 patients (mean [±SD] age, 68±11 years) were studied. During a mean of 36±26 months of follow-up, 78 patients died. The observed survival rate was significantly lower than the expected survival rate based on the general Minnesota population (P<0.001). Previous myocardial infarction (P< 0.001), a hi...

Cellular remodeling in heart failure disrupts KATP channel‐dependent stress tolerance

ATP‐sensitive potassium (KATP) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on KATP channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor α induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, KATP channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, KATP channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by KATP channel openers. Thus, disease‐induced KATP channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.

Significant effects of atrioventricular node ablation and pacemaker implantation on left ventricular function and long-term survival in patients with atrial fibrillation and left ventricular dysfunction

Control of ventricular rate by atrioventricular node ablation and pacemaker implantation in patients with drug-refractory atrial fibrillation (AF) is associated with improved left ventricular (LV) function. The objective of this study was to determine the effect of atrioventricular node ablation on long-term survival in patients with AF and LV dysfunction. Survival was determined by the Kaplan-Meier method for 56 study patients with LV ejection fraction (EF) < or =40% who underwent atrioventricular node ablation and pacemaker implantation and 56 age- and gender-matched control patients with AF and LVEF >40%, and age- and gender-matched control subjects from Minnesota. Groups were compared using the log-rank test. In study patients (age 69 +/- 10 years; 45 men), LVEF was 26% +/- 8% and 34% +/- 13% (p <0.001) before and after ablation, respectively. During follow-up (40 +/- 23 months), 23 patients died. Observed survival was worse than that of normal subjects (p <0.001) and control patients (p = 0.005). After ablation, LVEF nearly normalized (> or =45%) in 16 study patients (29%), in whom observed survival was comparable to that of normal subjects (p = 0.37). Coronary artery disease, hyperlipidemia, chronic renal failure, previous myocardial infarction, and coronary artery operation were independent predictors for mortality. Near normalization of LVEF occurred in 29% of study patients, suggesting that AF-induced EF reduction is reversible in many patients. Normal survival in patients with reversible LV dysfunction highlights potential survival benefits of rate control. Poor survival in patients with persistent LV dysfunction confirms the importance of optimal medical therapy.

Increased calcium vulnerability of senescent cardiac mitochondria : protective role for a mitochondrial potassium channel opener

In senescence, endogenous mechanisms of cardioprotection are apparently attenuated resulting in increased vulnerability to ischemia-reperfusion. In particular, mitochondria, which are essential in maintaining cardiac energetic and ionic homeostasis, are susceptible to Ca2+ overload, a component of metabolic injury. However, effective means of protecting senescent mitochondria are lacking. Here, mitochondrial function and structure were assessed using ion-selective mini-electrodes, high-performance liquid chromatography and electron microscopy. Aging decreased ADP-induced oxygen consumption and prolonged the time associated with ADP to ATP conversion, which manifested as a reduced rate of oxidative phosphorylation. Aging also reduced mitochondrial Ca2+ handling, and increased Ca2+-induced mitochondrial damage. Diazoxide, a potassium channel opener, reduced Ca2+ loading and protected the functional and structural integrity of senescent mitochondria from Ca2+-induced injury. In this way, the present study identifies the potential usefulness for pharmacotherapy in protecting vulnerable senescent mitochondria from conditions of Ca2+ overload, such as ischemia-reperfusion.

Genetics of atrial fibrillation: implications for future research directions and personalized medicine.

Atrial fibrillation (AF) was first described in humans approximately 100 years ago,1 and familial forms of AF were reported over 70 years ago.2,3 Within the last ten years, three critical developments have advanced our understanding of the genetic basis of AF. First, multiple epidemiological studies have demonstrated that AF is heritable. Second, rare mutations predisposing to AF have been identified in potassium and sodium channels, gap junction proteins and signaling molecules. Finally, population-based, genome-wide association studies (GWAS) have implicated novel biological pathways responsible for AF. The molecular biology of established mutations underlying AF has been well summarized.4,5 Here, we focus on the approaches employed to identify AF susceptibility loci and describe the findings from recent GWAS of AF. We also address future directions in the field of AF genetics that may improve our understanding of AF pathophysiology, risk prediction, prevention and patient management.

Stable transfection of UCP1 confers resistance to hypoxia/reoxygenation in a heart-derived cell line

Mitochondrial uncoupling proteins, which secure physiological uncoupling of oxidative phosphorylation, have been proposed to serve as an oxidative-stress compensatory mechanism. Here, heart-derived H9c2 cells acquired improved resistance to injury upon transfection of the prototypic uncoupling protein UCP1. Following hypoxia/reoxygenation, stable overexpression of UCP1 provided enhanced cardioblast survival with preserved mitochondrial structure and function, while limiting reactive oxygen species formation. Thus, transfection of mitochondrial UCP1 provides a strategy for generation of a stress-resistant cardiac cell phenotype.

Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning

Overexpression of mitochondrial uncoupling proteins (UCPs) attenuates ischemia-reperfusion (I/R) injury in cultured cardiomyocytes. However, it is not known whether UCPs play an essential role in cardioprotection in the intact heart. This study evaluated the cardioprotective efficacy of UCPs against I/R injury and characterized the mechanism of UCP-mediated protection in addition to the role of UCPs in ischemic preconditioning (IPC). Cardiac UCP3 knockout (UCP3(-/-)) and wild-type (WT) mice hearts were subjected to ex vivo and in vivo models of I/R injury and IPC. Isolated UCP3(-/-) mouse hearts were retrogradely perfused and found to have poorer recovery of left ventricular function compared with WT hearts under I/R conditions. In vivo occlusion of the left coronary artery resulted in twofold larger infarcts in UCP3(-/-) mice compared with WT mice. Moreover, the incidence of in vivo I/R arrhythmias was higher in UCP3(-/-) mice. Myocardial energetics were significantly impaired with I/R, as reflected by a decreased ATP content and an increase in the AMP-to-ATP ratio. UCP3(-/-) hearts generated more reactive oxygen species (ROS) than WT hearts during I/R. Pretreatment of UCP3(-/-) hearts with the pharmacological uncoupling agent carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone improved postischemic functional recovery. Also the protective efficacy of IPC was abolished in UCP3(-/-) mice. We conclude that UCP3 plays a critical role in cardioprotection against I/R injury and the IPC phenomenon. There is increased myocardial vulnerability to I/R injury in hearts lacking UCP3. The mechanisms of UCP3-mediated cardioprotection include regulation of myocardial energetics and ROS generation by UCP3 during I/R.

Restoration of Ca2+-inhibited oxidative phosphorylation in cardiac mitochondria by mitochondrial Ca2+ unloading.

Mitochondria, the major source of cellular ATP, display high vulnerability to metabolic stress, in particular to excessive Ca2+ loading. Here, we show that Ca2+-inhibited mitochondrial ATP generation could be restored through stimulated Ca2+ discharge from mitochondrial matrix. This was demonstrated using a Ca2+ ionophore or through Na+/Ca2+ exchange-mediated decrease of mitochondrial Ca2+ load. Furthermore, diazoxide, a mitochondrial potassium channel opener, which maintained mitochondrial Ca2+ homeostasis, also restored Ca2+-inhibited ATP synthesis and preserved the structural integrity of Ca2+-challenged mitochondria. Thus, under conditions of excessive mitochondrial Ca2+ overload targeting mitochondrial Ca2+ transport pathways restores oxidative phosphorylation required for vital cellular processes. This study, therefore, identifies an effective strategy capable to rescue Ca2+-disrupted mitochondrial energetics.

Effective pharmacotherapy against oxidative injury: alternative utility of an ATP-sensitive potassium channel opener.

Cardiomyocyte viability following ischemia-reperfusion critically depends on mitochondrial function. In this regard, potassium channel openers (KCOs) targeting mitochondria have emerged as powerful cardioprotective agents when applied at the onset of ischemia. However, it is controversial whether openers are still protective when applied at the onset of reoxygenation. Here, H9c2 cardiomyocytes and mitochondria isolated from the rat heart ventricle were subjected to ischemia-reoxygenation or oxidative stress in the absence or presence of 100 μM diazoxide, a potassium channel opener. Ischemia-reoxygenation or oxidative stress significantly reduced cell viability, induced structural damage in association with increased mitochondrial protein release, and impaired oxidative phosphorylation. However, treatment with diazoxide before anoxia or at the onset of reoxygenation, as well as during oxidative stress, prevented cell death and mitochondrial dysfunction and preserved cellular and mitochondrial structural integrity. These protective effects were blocked by 5-hydroxydecanoate. Thus, treatment with potassium channel openers even at the time of reoxygenation may provide a significant protection of the myocardium. The protective mechanism is at least in part endogenous to the mitochondria because protection was also observed in isolated mitochondria.

LKB1 Knockout Mouse Develops Spontaneous Atrial Fibrillation and Provides Mechanistic Insights Into Human Disease Process

Background Atrial fibrillation (AF) is a complex disease process, and the molecular mechanisms underlying initiation and progression of the disease are unclear. Consequently, AF has been difficult to model. In this study, we have presented a novel transgenic mouse model of AF that mimics human disease and characterized the mechanisms of atrial electroanatomical remodeling in the genesis of AF. Methods and Results Cardiac‐specific liver kinase B1 (LKB1) knockout (KO) mice were generated, and 47% aged 4 weeks and 95% aged 12 weeks developed spontaneous AF from sinus rhythm by demonstrating paroxysmal and persistent stages of the disease. Electrocardiographic characteristics of sinus rhythm were similar in KO and wild‐type mice. Atrioventricular block and atrial flutter were common in KO mice. Heart rate was slower with persistent AF. In parallel with AF, KO mice developed progressive biatrial enlargement with inflammation, heterogeneous fibrosis, and loss of cardiomyocyte population with apoptosis and necrosis. Atrial tissue was infiltrated with inflammatory cells. C‐reactive protein, interleukin 6, and tumor necrosis factor α were significantly elevated in serum. KO atria demonstrated elevated reactive oxygen species and decreased AMP‐activated protein kinase activity. Cardiomyocyte and myofibrillar ultrastructure were disrupted. Intercellular matrix and gap junction were interrupted. Connexins 40 and 43 were reduced. Persistent AF caused left ventricular dysfunction and heart failure. Survival and exercise capacity were worse in KO mice. Conclusions LKB1 KO mice develop spontaneous AF from sinus rhythm and progress into persistent AF by replicating the human AF disease process. Progressive inflammatory atrial cardiomyopathy is the genesis of AF, through mechanistic electrical and structural remodeling.