Madhav Lavu

Hydrogen sulfide-mediated cardioprotection: mechanisms and therapeutic potential.

H2S (hydrogen sulfide), viewed with dread for more than 300 years, is rapidly becoming a ubiquitously present and physiologically relevant signalling molecule. Knowledge of the production and metabolism of H2S has spurred interest in delineating its functions both in physiology and pathophysiology of disease. Although its role in blood pressure regulation and interaction with NO is controversial, H2S, through its anti-apoptotic, anti-inflammatory and antioxidant effects, has demonstrated significant cardioprotection. As a result, a number of sulfide-donor drugs, including garlic-derived polysulfides, are currently being designed and investigated for the treatment of cardiovascular conditions, specifically myocardial ischaemic disease. However, huge gaps remain in our knowledge about this gasotransmitter. Only by additional studies will we understand more about the role of this intriguing molecule in the treatment of cardiovascular disease.

Gene therapy for ischemic heart disease.

Current pharmacologic therapy for ischemic heart disease suffers multiple limitations such as compliance issues and side effects of medications. Revascularization procedures often end with need for repeat procedures. Patients remain symptomatic despite maximal medical therapy. Gene therapy offers an attractive alternative to current pharmacologic therapies and may be beneficial in refractory disease. Gene therapy with isoforms of growth factors such as VEGF, FGF and HGF induces angiogenesis, decreases apoptosis and leads to protection in the ischemic heart. Stem cell therapy augmented with gene therapy used for myogenesis has proven to be beneficial in numerous animal models of myocardial ischemia. Gene therapy coding for antioxidants, eNOS, HSP, mitogen-activated protein kinase and numerous other anti apoptotic proteins have demonstrated significant cardioprotection in animal models. Clinical trials have demonstrated safety in humans apart from symptomatic and objective improvements in cardiac function. Current research efforts are aimed at refining various gene transfection techniques and regulation of gene expression in vivo in the heart and circulation to improve clinical outcomes in patients that suffer from ischemic heart disease. In this review article we will attempt to summarize the current state of both preclinical and clinical studies of gene therapy to combat myocardial ischemic disease. This article is part of a Special Section entitled Special Section: Cardiovascular Gene Therapy.

Beta3-Adrenoreceptor Stimulation Ameliorates Myocardial Ischemia-Reperfusion Injury Via Endothelial Nitric Oxide Synthase and Neuronal Nitric Oxide Synthase Activation

OBJECTIVESnThis paper examined whether nebivolol protects the heart via nitric oxide (NO) synthase and NO-dependent signaling in an in vivo model of acute myocardial infarction.nnnBACKGROUNDnBeta(3)-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. We hypothesized that specific beta(3)-AR agonists would attenuate myocardial ischemia-reperfusion (MI/R) injury via eNOS activation and increased NO bioavailability.nnnMETHODSnMice were subjected to 45 min of myocardial ischemia in vivo followed by 24 h of reperfusion (R). Nebivolol (500 ng/kg), CL 316243 (1 μg/kg), BRL-37344 (1 μg/kg), or vehicle (VEH) was administered at the time of R. Myocardial area-at-risk (AAR) and infarct size (INF)/AAR was measured at 24 h of R. Cardiac tissue and plasma were collected to evaluate eNOS phosphorylation, neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase expression, and nitrite and nitrosothiol levels.nnnRESULTSnNebivolol (500 ng/kg) reduced INF/AAR by 37% (p < 0.001 vs. VEH) and serum troponin-I levels from 41 ± 4 ng/ml to 25 ± 4 ng/ml (p < 0.05 vs. VEH). CL 316243 and BRL-37344 reduced INF by 39% and 42%, respectively (p < 0.001 vs. VEH). Nebivolol and CL 316243 increased eNOS phosphorylation at Ser-1177 (p < 0.05 vs. VEH) and increased nitrite and total nitrosylated protein levels. Nebivolol and CL 316243 significantly increased myocardial nNOS expression. Nebivolol failed to reduce INF after MI/R in beta(3)-AR (-/-), eNOS(-/-), and in nNOS(-/-) mice.nnnCONCLUSIONSnOur results indicate that beta(3)-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta(3)-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability.

Acute Humanin Therapy Attenuates Myocardial Ischemia and Reperfusion Injury in Mice

Objective—Humanin (HN), an endogenous antiapoptotic peptide, has previously been shown to protect against Alzheimers disease and a variety of cellular insults. We evaluated the effects of a potent analog of HN (HNG) in an in vivo murine model of myocardial ischemia and reperfusion. Methods and Results—Male C57BL6/J mice (8 to 10 week old) were subjected to 45 minutes of left coronary artery occlusion followed by a 24-hour reperfusion. HNG or vehicle was administered IP 1 hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hours using Evans Blue dye and 2-3-5-triphenyl tetrazolium chloride staining. Left ventricular function was evaluated at 1 week after ischemia using high-resolution, 2D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0 to 24 hours) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. HNG reduced infarct size relative to the area-at-risk in a dose-dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced left ventricular ejection fraction and preserved postischemic left ventricular dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased phosphorylation of AMPK and phosphorylation of endothelial nitric oxide synthase in the heart and attenuated Bcl-2-associated X protein and B-cell lymphoma-2 levels following myocardial ischemia and reperfusion. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro. Conclusion—These data show that HNG provides cardioprotection in a mouse model of myocardial ischemia and reperfusion potentially through activation of AMPK-endothelial nitric oxide synthase-mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.

Cardiac Implantable Electronic Device-Related Infection and Extraction Trends in the U.S.: LEAD INFECTION AND EXTRACTION TRENDS IN THE U.S.

Implantation of cardiac implanted electronic device (CIED) has surged lately. This resulted in a rise in cardiac device‐related infections (CDI) and inevitably, lead extractions. We examined the recent national trend in the incidence of CIED infections and lead extractions in hospitalized patients and associated mortality.

Five years of keeping a watch on the left atrial appendage—how has the WATCHMAN fared?

Left atrial appendage closure (LAAC) is a promising site-directed therapy for stroke prevention in patients with non-valvular atrial fibrillation (AF) who are ineligible or contraindicated for long-term oral anticoagulation. A variety of LAAC modalities are available, including percutaneous endocardial occluder devices such as WATCHMANTM (Boston Scientific Corp., Marlborough, MA, USA), and an ever-increasing body of evidence is helping to define the optimal use of each technique. Similarly increased experience with LAAC has revealed challenges such as device-related thrombi and peri-device leaks for which the long-term significance and appropriate management are areas of active investigation. We review the evolution and long-term outcomes with the WATCHMANTM device with particular emphasis on the nuances of its use and its role in the broader landscape of appendageology.

Impact of Radiofrequency Ablation of Atrial Fibrillation on Pulmonary Vein Cross Sectional Area: Implications for the Diagnosis of Pulmonary Vein Stenosis

IntroductionnRestoration of normal sinus rhythm by radiofrequency ablation (RFA) in atrial fibrillation (AF) patients can result in a reduction of left atrial (LA) volume and pulmonary vein (PV) dimensions. It is not clear if this PV size reduction represents a secondary effect of overall LA volume reduction or true PV stenosis. We assessed the relationship between LA volume reduction and PV orifice area pre- and post-RFA.nnnMethodsnA retrospective cohort study was conducted at a tertiary care academic hospital. Pre- and post-RFA cardiac computed tomography (CT) studies of 100 consecutive AF patients were reviewed. Studies identifying obvious segmental PV narrowing were excluded. Left atrial volumes and PV orifice cross-sectional areas (PVOCA) were measured using proprietary software from the CT scanner vendor (GE Healthcare, Waukesha, WI).nnnResultsnThe cohort had a mean age of 60 ± 8 years, 73% were male, and 90% were Caucasian. Non-paroxysmal AF was present in 76% of patients with a mean duration from diagnosis to RFA of 55 ± 54 months. Mean procedural time was 244 ± 70 min. AF recurred in 27% at 3 month follow-up. Pre-RFA LA volumes were 132 ± 60 ml and mean PVOCA was 2.89 ± 2.32 cm2. In patients with successful ablation, mean LA volume decreased by 10% and PVOCA decreased by 21%. PVOCA was significantly reduced in patients with successful RFA compared to those who had recurrence (2.18 ± 1.12 vs. 2.8 ± 1.9 cm2, p = 0.04) but reduction in LA volume between groups was not significant (118 ± 42 vs. 133 ± 54 ml, p=0.15).nnnConclusionsnThe study demonstrates that both PV orifice dimensions and LA volume are reduced after successful AF ablation. These data warrant a reassessment of criteria for diagnosing PV stenosis based on changes in PV caliber alone, ideally incorporating LA volume changes.

Left Atrial Appendage Closure for Stroke Prevention is Safe and Effective in Selected Patients with Atrial Fibrillation

The left atrial appendage (LAA) is implicated as a source of thrombus in the majority of patients with atrial fibrillation (AF) and embolic stroke. Therapeutic anticoagulation (AC) is the mainstay of treatment for stroke prophylaxis in AF. Despite adherence to AC, a significant number of patients are still subtherapeutic. In addition to this, several patients are ineligible for AC because of various reasons, including but not limited to high bleeding risk, ongoing bleeding, and non-compliance. These challenges associated with AC led to efforts looking at mechanical isolation of the LAA. Various endocardial and epicardial devices have been tried for mechanical isolation of the LAA, with variable success. The WATCHMANt (Boston Scientific, Maple Grove, MN) is the first endocardial device that received FDA approval as an alternative for warfarin for stroke prophylaxis in AF. The WATCHMANt (Boston Scientific) is not approved for AC-ineligible patients. The LARIAT (SentreHEART, Inc., Redwood City, CA) is an epicardially deployed device that has been proposed for AC-ineligible patients. Although not FDA approved, its safety and efficacy had been established in large prospective registries. The current review examines the current literature on AC and LAA exclusion devices in a comparative fashion. The protean effects of LARIAT (SentreHEART, Inc.) on rhythm and neurohormonal control are also reviewed. We conclude that LAA exclusion devices are an excellent alternative to AC for stroke prophylaxis in AC-eligible (WATCHMANt, Boston Scientific) and ineligible patients (LARIAT, SentreHEART).

Nitrite and Nitrate in Ischemia-Reperfusion Injury

There is a long and rich history of the use of nitrite for medical conditions. n n nNitrite has a number of essential functions in mammalian tissues. n n nNitrite is reduced to nitric oxide in blood and tissues, particularly in hypoxic or ischemic conditions. n n nNitrite protects from ischemia-reperfusion injury due to modulation of mitochondrial respiration. n n nNitrite has been shown in animal models to be beneficial in cardiovascular disease, cerebral, hepatic and renal I-R injury, effective for pulmonary disorders, peripheral artery disease and sickle cell disease. n n nVery low levels of nitrite are needed for protection. n n nThere are now a number of clinical trials for the use of nitrite in a number of disease conditions. n n nNitrite-based therapies may provide a safe and cost-effective strategy for conditions of NO insufficiency.