Left Atrial Volume Index Is Associated With Cardioembolic Stroke and Atrial Fibrillation Detection After Embolic Stroke of Undetermined Source.

Background and Purpose- Left atrial enlargement has been shown to be associated with ischemic stroke, but the association with embolic stroke mechanisms remains unknown. We aim to study the associations between left atrial volume index (LAVI) and embolic stroke subtypes and atrial fibrillation (AF) detection on cardiac event monitoring in patients with embolic stroke of unknown source. Methods- Data were collected from a prospective cohort of consecutive patients with ischemic stroke admitted to a comprehensive stroke center over 18 months. Stroke subtype was classified into cardioembolic stroke, noncardioembolic stroke of determined mechanism (NCE), or embolic stroke of undetermined source (ESUS). Univariate and prespecified multivariable analyses were performed to assess associations between LAVI and stroke subtype and AF detection in patients with ESUS. Results- Of 1224 consecutive patients identified during the study period, 1020 (82.6%) underwent transthoracic echocardiography and had LAVI measurements. LAVI was greater in patients with cardioembolic stroke than NCE (41.4 mL/m2±18.0 versus 28.6 mL/m2±12.2; P<0.001) but not in ESUS versus NCE (28.9 mL/m2±12.6 versus 28.6 mL/m2±12.2; P=0.61). In multivariable logistic regression models, LAVI was greater in cardioembolic stroke versus NCE (adjusted odds ratio per mL/m2, 1.07; 95% CI, 1.05-1.09; P<0.001) but not in ESUS versus NCE (adjusted odds ratio per mL/m2, 1.00; 95% CI, 0.99-1.02; P=0.720). Among 99 patients with ESUS who underwent cardiac monitoring, 18.2% had AF detected; LAVI was independently associated with AF detection in ESUS (adjusted odds ratio per mL/m2, 1.09; 95% CI, 1.02-1.15; P=0.007). Conclusions- LAVI is associated with cardioembolic stroke as well as AF detection in patients with ESUS, 2 subsets of ischemic stroke that benefit from anticoagulation therapy. Patients with increased LAVI may be a subgroup where anticoagulation may be tested for stroke prevention.

Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.

Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM.

The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion.

Natural models of heart regeneration in lower vertebrates such as zebrafish are based on invasive surgeries causing mechanical injuries that are limited in size. Here, we created a genetic cell ablation model in zebrafish that facilitates inducible destruction of a high percentage of cardiomyocytes. Cell-specific depletion of over 60% of the ventricular myocardium triggered signs of cardiac failure that were not observed after partial ventricular resection, including reduced animal exercise tolerance and sudden death in the setting of stressors. Massive myocardial loss activated robust cellular and molecular responses by endocardial, immune, epicardial and vascular cells. Destroyed cardiomyocytes fully regenerated within several days, restoring cardiac anatomy, physiology and performance. Regenerated muscle originated from spared cardiomyocytes that acquired ultrastructural and electrophysiological characteristics of de-differentiation and underwent vigorous proliferation. Our study indicates that genetic depletion of cardiomyocytes, even at levels so extreme as to elicit signs of cardiac failure, can be reversed by natural regenerative capacity in lower vertebrates such as zebrafish.

Optical mapping in the developing zebrafish heart.

Understanding the developmental basis of cardiac electrical activity has proven technically challenging, largely as a result of the inaccessible nature of the heart during cardiogenesis in many organisms. The emergence of the zebrafish as a model organism has availed the very earliest stages of heart formation to experimental exploration. The zebrafish also offers a robust platform for genetic and chemical screening. These tools have been exploited in screens for modifiers of cardiac electrophysiologic phenotypes and in screens for novel drugs.

Novel Use of a Rotating Mechanical Dilator Sheath for S-ICD Lead Extraction.

A 53-year-old man with a subcutaneous implantable cardioverter-defibrillator (S-ICD) presented with inappropriate shocks. He underwent device extraction, and the lead was freed using a rotating mechanical dilator sheath. As patients with S-ICDs get older, extractions will become more complicated and more common. We have described a novel method of S-ICD lead extraction. (Level of Difficulty: Advanced.).

The genetics of atrial fibrillation.

PURPOSE OF REVIEW: A substantial genetic contribution to the etiology of atrial fibrillation has emerged in the last decade, and has bolstered links between this arrhythmia and other forms of heart disease. In this article, we will summarize the work that has defined the inherited diathesis toward atrial fibrillation, outline the genetic studies to date, and characterize the roadblocks to a complete mechanistic understanding of this common arrhythmia. RECENT FINDINGS: Clinical genetic work has demonstrated a large heritable contribution in atrial fibrillation, with studies in lone forms of the arrhythmia suggesting a traditional monogenic syndrome with reduced penetrance. Several Mendelian loci for typical forms of atrial fibrillation have been identified but the genes have not yet been cloned. Rare forms of familial atrial fibrillation are caused by mutations in potassium channel genes, and there are single families with mutations in a nuclear pore and a natriuretic peptide gene, respectively. Common loci with small effects are now being identified in genome-wide association (GWA) studies, including a locus on chromosome 4q25. These loci explain less than 10% of the inherited contribution to the arrhythmia, suggesting there are major contributions that have not yet been uncovered. SUMMARY: Although great strides have been made in exploring the genetics of atrial fibrillation, the paroxysmal and asymptomatic nature of the phenotype challenges investigators as they seek the mechanistic basis of the arrhythmia.

Kruppel-like factors in muscle health and disease.

Kruppel-like factors (KLF) are zinc-finger DNA-binding transcription factors that are critical regulators of tissue homeostasis. Emerging evidence suggests that KLFs are critical regulators of muscle biology in the context of cardiovascular health and disease. The focus of this review is to provide an overview of the current state of knowledge regarding the physiologic and pathologic roles of KLFs in the three lineages of muscle: cardiac, smooth, and skeletal.

Saphenous vein graft aneurysm presenting as abdominal pain.

Aneurysmal dilation of a saphenous vein aortocoronary graft remains a rare complication. We report a patient with saphenous vein graft aneurysm who presented with abdominal pain due to compression of the adjacent liver 43 years after the coronary bypass operation.

Chamber identity programs drive early functional partitioning of the heart.

The vertebrate heart muscle (myocardium) develops from the first heart field (FHF) and expands by adding second heart field (SHF) cells. While both lineages exist already in teleosts, the primordial contributions of FHF and SHF to heart structure and function remain incompletely understood. Here we delineate the functional contribution of the FHF and SHF to the zebrafish heart using the cis-regulatory elements of the draculin (drl) gene. The drl reporters initially delineate the lateral plate mesoderm, including heart progenitors. Subsequent myocardial drl reporter expression restricts to FHF descendants. We harnessed this unique feature to uncover that loss of tbx5a and pitx2 affect relative FHF versus SHF contributions to the heart. High-resolution physiology reveals distinctive electrical properties of each heart field territory that define a functional boundary within the single zebrafish ventricle. Our data establish that the transcriptional program driving cardiac septation regulates physiologic ventricle partitioning, which successively provides mechanical advantages of sequential contraction.

Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish.

The vertebrate heart is one of the first organs to form, and its early function and morphogenesis are crucial for continued embryonic development. Here we analyze the effects of loss of Heart adaptor protein 1 (Hadp1), which we show is required for normal function and morphogenesis of the embryonic zebrafish heart. Hadp1 is a pleckstrin homology (PH)-domain-containing protein whose expression is enriched in embryonic cardiomyocytes. Knockdown of hadp1 in zebrafish embryos reduced cardiac contractility and altered late myocyte differentiation. By using optical mapping and submaximal levels of hadp1 knockdown, we observed profound effects on Ca(2+) handling and on action potential duration in the absence of morphological defects, suggesting that Hadp1 plays a major role in the regulation of intracellular Ca(2+) handling in the heart. Hadp1 interacts with phosphatidylinositol 4-phosphate [PI4P; also known as PtdIns(4)P] derivatives via its PH domain, and its subcellular localization is dependent upon this motif. Pharmacological blockade of the synthesis of PI4P derivatives in vivo phenocopied the loss of hadp1 in zebrafish. Collectively, these results demonstrate that hadp1 is required for normal cardiac function and morphogenesis during embryogenesis, and suggest that hadp1 modulates Ca(2+) handling in the heart through its interaction with phosphatidylinositols.