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Concept: Cardiac anatomy

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The heartbeat originates within the sinoatrial node (SAN), a small structure containing <10,000 genuine pacemaker cells. If the SAN fails, the ∼5 billion working cardiomyocytes downstream of it become quiescent, leading to circulatory collapse in the absence of electronic pacemaker therapy. Here we demonstrate conversion of rodent cardiomyocytes to SAN cells in vitro and in vivo by expression of Tbx18, a gene critical for early SAN specification. Within days of in vivo Tbx18 transduction, 9.2% of transduced, ventricular cardiomyocytes develop spontaneous electrical firing physiologically indistinguishable from that of SAN cells, along with morphological and epigenetic features characteristic of SAN cells. In vivo, focal Tbx18 gene transfer in the guinea-pig ventricle yields ectopic pacemaker activity, correcting a bradycardic disease phenotype. Myocytes transduced in vivo acquire the cardinal tapering morphology and physiological automaticity of native SAN pacemaker cells. The creation of induced SAN pacemaker (iSAN) cells opens new prospects for bioengineered pacemakers.

Concepts: Gene, Cardiology, Heart, Cardiac electrophysiology, Cardiac anatomy, Cardiac pacemaker, Sinoatrial node, Artificial pacemaker

28

A 50-year-old Chinese woman, non-smoker, presented with a 6-month history of increased sweating on the right side of her face, exertional chest tightness and breathlessness. Although the patient presented with increased sweating on the right, further history and examination revealed unilateral, left-sided anhidrosis, left partial ptosis and miosis consistent with Horner’s syndrome. The patient was subsequently investigated with thoracic CT to assess for an apical lung mass (Pancoast tumour). A CT chest ruled out a mediastinal tumour, however, it revealed a large 60×41 mm soft tissue mass arising from the left atrium, protruding across the mitral valve into the left ventricle, suspicious of an intracardiac tumour. The patient was referred urgently for cardiothoracic assessment at a tertiary referral centre and successful open resection was performed. Histology confirmed an atrial myxoma. The patient developed postoperative atrial fibrillation but otherwise made a full recovery.

Concepts: Blood, Heart, Ventricle, Left ventricle, Cardiac anatomy, Miosis, Pancoast tumor, Horner's syndrome

27

The aim of the study is to determine the impact of the underlying etiology (Barlow’s disease or fibroelastic deficiency) on left ventricular function in patients with degenerative mitral valve disease and severe mitral regurgitation.

Concepts: Heart, Mitral valve, Left ventricle, Mitral regurgitation, Mitral valve prolapse, Cardiac anatomy, Regurgitation, Diastole

27

-Risks associated with pediatric reconstructive heart surgery include injury of the sinoatrial node (SAN) and atrioventricular node (AVN), requiring cardiac rhythm management using implantable pacemakers. These injuries are result of difficulties in identifying nodal tissues intraoperatively. Here, we describe an approach based on confocal microscopy and extracellular fluorophores to quantify tissue microstructure and identify nodal tissue.

Concepts: Cardiology, Heart, Cardiac anatomy, Identification, Cardiac pacemaker, Sinoatrial node, Atrioventricular node, Electrical conduction system of the heart

27

KCNE genes encode for a small family of Kv channel ancillary subunits that form heteromeric complexes with Kv channel alpha subunits to modify their functional properties. Mutations in KCNE genes have been found in patients with cardiac arrhythmias such as the long QT syndrome and/or atrial fibrillation. However, the precise molecular pathophysiology that leads to these diseases remains elusive. In previous studies the electrophysiological properties of the disease causing mutations in these genes have mostly been studied in heterologous expression systems and we cannot be sure if the reported effects can directly be translated into native cardiomyocytes. In our laboratory we therefore use a different approach. We directly study the effects of KCNE gene deletion in isolated cardiomyocytes from knockout mice by cellular electrophysiology - a unique technique that we describe in this issue of the Journal of Visualized Experiments. The hearts from genetically engineered KCNE mice are rapidly excised and mounted onto a Langendorff apparatus by aortic cannulation. Free Ca(2+) in the myocardium is bound by EGTA, and dissociation of cardiac myocytes is then achieved by retrograde perfusion of the coronary arteries with a specialized low Ca(2+) buffer containing collagenase. Atria, free right ventricular wall and the left ventricle can then be separated by microsurgical techniques. Calcium is then slowly added back to isolated cardiomyocytes in a multiple step comprising washing procedure. Atrial and ventricular cardiomyocytes of healthy appearance with no spontaneous contractions are then immediately subjected to electrophysiological analyses by patch clamp technique or other biochemical analyses within the first 6 hours following isolation.

Concepts: DNA, Genetics, Blood, Heart, Cardiac muscle, Cardiac electrophysiology, Ventricle, Cardiac anatomy

27

The risk factors for aortic and mitral valve diseases that require surgical repair such as congenital bicuspid aortic valve (BAV) and mitral valve prolapse include acquired clinical factors and genetic influences. Whether race affects the prevalence of certain valvular diseases has not been sufficiently investigated. Through the Cleveland Clinic’s Cardiovascular Information Registry, we evaluated the data from 40,419 patients who had undergone aortic valve surgery, mitral valve surgery, and/or coronary artery bypass grafting from 1993 to 2007. Of these patients, 38,366 were white and 2,053 were black. The prospective evaluation of valvular disease was coded, identifying the etiology and morphology by echocardiographic, surgical, and pathologic inspection. At baseline, compared to white patients, the black patients were younger, more often women, had a greater body mass index, and a greater prevalence of hypertension, diabetes, tobacco use, and renal disease. The prevalence of congenital BAV and mitral valve prolapse was considerably lower in blacks than in whites (9% vs 25%, p <0.001, and 27% vs 52%, p <0.001, respectively), as was the presence of calcific aortic stenosis (14% vs 28%; p <0.001), pathologically determined aortic valve calcium (50% vs 67%; p <0.001), and mitral valve chordal rupture (13% vs 31%; p <0.001). In conclusion, in the present large surgical series, the valve etiologies and morphology differed among blacks and whites. Despite an adverse cardiovascular risk profile, blacks had a significantly lower prevalence of valvular calcium and degeneration than did the whites and a lower prevalence of congenital BAV and mitral valve prolapse. Our findings offer insight into the influence of race on the development of mitral valve disease and congenital BAV.

Concepts: Atherosclerosis, Heart, Left ventricle, Mitral valve prolapse, Cardiac anatomy, Aortic valve, Valvular heart disease, Bicuspid aortic valve

25

Dual aortic and ventricular thrombi are rare following myocardial infraction. We report the case of a 56-year-old man who initially denied primary percutaneous coronary intervention as a result of psychological phobia. Initial pharmacological management by thrombolysis and heparin was followed by multiple arterial thromboses including those of the left ventricle and right iliac artery with a subsequent diagnosis of heparin-induced thrombocytopaenia. Ensuing surgical management revealed the unanticipated finding of an additional aortic sinus thrombosis that was excised. The left ventricular thrombus was removed endoscopically to prevent ventricular incisions. This case emphasizes the technical advantages of video-endoscopic management of intracardiac thrombi and highlights the unexpected nature of multiple thromboses associated with heparin-induced thrombocytopaenia.

Concepts: Blood, Myocardial infarction, Heart, Thrombosis, Artery, Cardiovascular system, Left ventricle, Cardiac anatomy

10

Single-vessel, intracoronary infusion of stem cells under stop-flow conditions has proven safe but achieves only limited myocardial coverage. Continuous flow intracoronary delivery to one or more coronary vessels may achieve broader coverage for treating cardiomyopathy, but has not been investigated. Using nonocclusive coronary guiding catheters, we infused allogeneic cardiosphere-derived cells (CDCs) either in a single vessel or sequentially in all three coronary arteries in porcine ischemic cardiomyopathy and used magnetic resonance imaging (MRI) to assess structural and physiological outcomes. Vehicle-infused animals served as controls. Single-vessel stop-flow and continuous-flow intracoronary infusion revealed equivalent effects on scar size and function. Sequential infusion into each of the three major coronary vessels under stop-flow or continuous-flow conditions revealed equal efficacy, but less elevation of necrotic biomarkers with continuous-flow delivery. In addition, multi-vessel delivery resulted in enhanced global and regional tissue function compared to a triple-vessel placebo-treated group. The functional benefits after global cell infusion were accompanied histologically by minimal inflammatory cellular infiltration, attenuated regional fibrosis and enhanced vessel density in the heart. Sequential multi-vessel non-occlusive delivery of CDCs is safe and provides enhanced preservation of left ventricular function and structure. The current findings provide preclinical validation of the delivery method currently undergoing clinical testing in the Dilated cardiomYopathy iNtervention With Allogeneic MyocardIally-regenerative Cells (DYNAMIC) trial of CDCs in heart failure patients.

Concepts: Cardiology, Cardiomyopathy, Heart, Magnetic resonance imaging, Artery, Coronary circulation, Cardiovascular system, Cardiac anatomy

8

Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle characterized by otherwise unexplained thickening of the left ventricle. Left ventricular outflow tract (LVOT) obstruction is present in approximately two-thirds of patients and substantially increases the risk of disease complications. Invasive treatment with septal myectomy or alcohol septal ablation can improve symptoms and functional status, but currently available drugs for reducing obstruction have pleiotropic effects and variable therapeutic responses. New medical treatments with more targeted pharmacology are needed, but the lack of preclinical animal models for HCM with LVOT obstruction has limited their development. HCM is a common cause of heart failure in cats, and a subset exhibit systolic anterior motion of the mitral valve leading to LVOT obstruction. MYK-461 is a recently-described, mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve LVOT obstruction in feline HCM. We evaluated mixed-breed cats in a research colony derived from a Maine Coon/mixed-breed founder with naturally-occurring HCM. By echocardiography, we identified five cats that developed systolic anterior motion of the mitral valve and LVOT obstruction both at rest and under anesthesia when provoked with an adrenergic agonist. An IV MYK-461 infusion and echocardiography protocol was developed to serially assess contractility and LVOT gradient at multiple MYK-461 concentrations. Treatment with MYK-461 reduced contractility, eliminated systolic anterior motion of the mitral valve and relieved LVOT pressure gradients in an exposure-dependent manner. Our findings provide proof of principle that acute reduction in contractility with MYK-461 is sufficient to relieve LVOT obstruction. Further, these studies suggest that feline HCM will be a valuable translational model for the study of disease pathology, particularly LVOT obstruction.

Concepts: Disease, Cardiology, Heart, Ventricle, Hypertrophic cardiomyopathy, Mitral valve, Left ventricle, Cardiac anatomy

7

In patients with hypertrophic cardiomyopathy and left ventricular outflow tract (LVOT) obstruction, but without basal septal hypertrophy, we sought to identify mitral valve (MV) and papillary muscle (PM) abnormalities that predisposed to LVOT obstruction, using echo and cardiac magnetic resonance.

Concepts: Cardiology, Heart, Hypertrophic cardiomyopathy, Mitral valve, Left ventricle, Papillary muscle, Cardiac anatomy, Chordae tendineae