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Background: Implementation of guideline-directed cholesterol management remains low despite definitive evidence establishing such measures reduce cardiovascular (CV) events, especially in high atherosclerotic CV disease (ASCVD) risk patients. Modern electronic resources now exist that may help improve health care delivery. While electronic medical records (EMR) allow for population health screening, the potential for coupling EMR screening to remotely delivered algorithmic population-based management has been less studied as a way of overcoming barriers to optimal cholesterol management.Methods: In an academically affiliated healthcare system, using EMR screening, we sought to identify 1,000 high ASCVD risk patients not meeting guideline-directed low-density lipoprotein-cholesterol (LDL-C) goals within specific system-affiliated primary care practices. Contacted patients received cholesterol education and were offered a remote, guideline-directed, algorithmic cholesterol management program executed by trained but non-licensed "navigators" under professional supervision. Navigators used telephone, proprietary software and internet resources to facilitate algorithm-driven, guideline-based medication initiation/titration, and laboratory testing until patients achieved LDL-C goals or exited the program. As a clinical effectiveness program for cholesterol guideline implementation, comparison was made to those contacted patients who declined program-based medication management, and received education only, along with their usual care.Results: 1021 patients falling into guideline-defined high ASCVD risk groups warranting statin therapy (ASCVD, type 2 diabetes, LDL ≥ 190 mg/dL, calculated 10-year ASCVD risk ≥7.5%) and not achieving guideline-defined target LDL-C levels and/or therapy were identified and contacted. Among the 698 such patients who opted for program medication management, significant LDL-C reductions occurred in the total cohort (mean -65.4 mg/dL, 45% decrease), and each high ASCVD risk subgroup: ASCVD (-57.2 mg/dL, -48.0%); diabetes mellitus (-53.1 mg/dL, -40.0%); severe hypercholesterolemia (-76.3 mg/dL, -45.7%); elevated ASCVD 10-year risk (-62.8 mg/dL, -41.1%) (P<0.001 for all), without any significant complications. Among 20% of participants with reported statin intolerance, average LDL-C decreased from baseline 143 mg/dL to 85 mg/dL using mainly statins and ezetimibe, with limited PCSK9 inhibitor use. In comparison, eligible high ASCVD risk patients who were contacted but opted for education only, a 17% LDL-C decrease occurred over a similar timeframe, with 80% remaining with an LDL-C over 100 mg/dL.Conclusions: A remote, algorithm-driven, navigator-executed cholesterol management program successfully identified high ASCVD risk undertreated patients using EMR screening and was associated with significantly improved guideline-directed LDL-C control, supporting this approach as a novel strategy for improving health care access and delivery. [ABSTRACT FROM AUTHOR]

Missense mutations in alpha tropomyosin, cardiac troponin T and B cardiac myosin heavy chain (MHC) cause familial hypertrophic cardiomyopathy (FHC) indicating that FHC affects the sarcomere. A non-missense mutation in cardiac troponin T which is similar to a splice donor mutation functioning as a null allele also causes FHC. Imbalance of sarcomeric proteins can also cause cardiac hypertrophy.

Despite increasing ability to understand and correct molecular derangements in disease, genomics and novel phenotypic assays are unevenly deployed in clinical practice. This has hampered translational research and our ability to identify clinically actionable subtypes of disease. Historic examples illustrate how the perspectives of stakeholders across the healthcare ecosystem can influence adoption of innovations in healthcare. Consideration of these factors, from discovery to implementation, can accelerate adoption of new molecular and digital phenotypes in a 'learning' healthcare ecosystem. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease.Methods: A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype.Conclusions: The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained. [ABSTRACT FROM AUTHOR]

Background: Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. The etiology of DCM is genetically heterogeneous. Objectives: We sought to define the prevalence of mutations in the RNA splicing protein RBM20 in a large cohort with DCM and to determine whether genetic variation in RBM20 is associated with clinical outcomes. Methods: Subjects included in the Genetic Risk Assessment of Defibrillator Events (GRADE) study were aged at least 18 years, had an ejection fraction of ≤30%, and an implantable cardioverter-defibrillator (ICD). The coding region and splice junctions of RBM20 were screened in subjects with DCM; 2 common polymorphisms in RBM20, rs942077 and rs35141404, were genotyped in all GRADE subjects. Results: A total of 1465 subjects were enrolled in the GRADE study, and 283 with DCM were screened for RBM20 mutations. The mean age of subjects with DCM was 58 ± 13 years, 64% were males, and the mean follow-up time was 24.2 ± 17.1 months after ICD placement. RBM20 mutations were identified in 8 subjects with DCM (2.8%). Mutation carriers had a similar survival, transplantation rate, and frequency of ICD therapy compared with nonmutation carriers. Three of 8 subjects with RBM20 mutations (37.5%) had atrial fibrillation (AF), whereas 19 subjects without mutations (7.4%) had AF (P = .02). Among all GRADE subjects, rs35141404 was associated with AF (minor allele odds ratio = 0.62; 95% confidence interval = 0.44–0.86; P = .006). In the subset of GRADE subjects with DCM, rs35141404 was associated with AF (minor allele odds ratio = 0.58; P = .047). Conclusions: Mutations in RBM20 were observed in approximately 3% of subjects with DCM. There were no differences in survival, transplantation rate, and frequency of ICD therapy in mutation carriers. [ABSTRACT FROM AUTHOR]

Background: The angiotensin-converting enzyme (ACE) gene contains a common polymorphism based on the insertion (I) or deletion (D) of a 287-bp intronic DNA fragment. The D allele is associated with higher ACE activity and thus higher angiotensin II levels. Angiotensin II stimulates cardiac fibrosis and conduction heterogeneity. Objective: The purpose of this study was to determine whether the ACE I/D polymorphism modulates cardiac electrophysiology. Methods: Three different cohorts of patients were studied: 69 patients with paroxysmal lone atrial fibrillation (AF), 151 patients with structural heart disease and no history of AF, and 161 healthy subjects without cardiovascular disease or AF. Patients taking drugs that affect cardiac conduction were excluded from the study. ECG parameters during sinus rhythm were compared among the ACE I/D genotypes. Results: The ACE I/D polymorphism was associated with the PR interval and heart block in the lone AF cohort. In multivariable linear regression models, the D allele was associated with longer PR interval in the lone AF and heart disease cohorts (12.0-ms and 7.1-ms increase per D allele, respectively). P-wave duration showed a similar trend, with increase in PR interval across ACE I/D genotypes in the lone AF and heart disease cohorts. Conclusion: The ACE D allele is associated with electrical remodeling in patients with lone AF and in those with heart disease, but not in control subjects. ACE activity may play a role in cardiac remodeling after the development of AF and heart disease. [Copyright &y& Elsevier]

Background: Mutations in several ion channel genes have been reported to cause rare cases of familial atrial fibrillation (AF). Objective: The purpose of this study was to determine the genetic basis for AF in a family with autosomal dominant AF. Methods: Family members were evaluated by 12-lead ECG, echocardiogram, signal-averaged P-wave analysis, and laboratory studies. Fourteen family members in AF-324 were studied. Six individuals had AF, with a mean age at onset of 32 years (range 16–59 years). Results: Compared with unaffected family members, those with AF had a longer mean QRS duration (100 vs 86 ms, P = .015) but no difference in the corrected QT interval (423 ± 15 ms vs 421 ± 21 ms). The known loci for AF and other cardiovascular diseases were evaluated. Evidence of linkage was obtained with marker D11S4088 located within KCNQ1, and a highly conserved serine in the third transmembrane region was found to be mutated to a proline (S209P). Compared to the wild-type channel, the S209P mutant activates more rapidly, deactivates more slowly, and has a hyperpolarizing shift in the voltage activation curve. A fraction of the mutant channels are constitutively open at all voltages, resulting in a net increase in IKs current. Conclusion: We identified a family with lone AF due to a mutation in the highly conserved S3 domain of KCNQ1, a region of the channel not previously implicated in the pathogenesis of AF. [Copyright &y& Elsevier]

Abstract: Over the last decade the zebrafish has emerged as a major genetic model organism. While stimulated originally by the utility of its transparent embryos for the study of vertebrate organogenesis, the success of the zebrafish was consolidated through multiple genetic screens, sequencing of the fish genome by the Sanger Center, and the advent of extensive genomic resources. In the last few years the potential of the zebrafish for in vivo cell biology, physiology, disease modeling and drug discovery has begun to be realized. This review will highlight work on cardiac electrophysiology, emphasizing the arenas in which the zebrafish complements other in vivo and in vitro models; developmental physiology, large-scale screens, high-throughput disease modeling and drug discovery. Much of this work is at an early stage, and so the focus will be on the general principles, the specific advantages of the zebrafish and on future potential. [Copyright &y& Elsevier]

Background: Mutations in the sodium channel SCN5A have been implicated in many cardiac disorders, including the long QT syndrome, Brugada syndrome, conduction system disease, and dilated cardiomyopathy with atrial arrhythmias. Objective: In view of the pleiotropic effects of SCN5A mutations, the purpose of this study was to examine a cohort of patients with familial atrial fibrillation (AF) for mutations in the SCN5A gene. Methods: Probands with AF were enrolled in the study between June 1, 2001 and February 10, 2004. Each patient underwent a standardized evaluation, which included an interview, physical examination, ECG, echocardiogram, and blood sample for genetic analysis. Direct sequencing of the coding region of SCN5A was used to screen for mutations in genomic DNA. Results: One hundred eighty-nine patients with AF were enrolled during the study period. From this cohort, a subset of 57 probands with a family history of AF in at least one first-degree relative was studied. Forty-seven subjects were men (82%); 45 had paroxysmal AF (79%). Echocardiography revealed ejection fraction 62% ± 6.4 % and left atrial dimension 40 ± 6.9 mm. A single mutation (N1986K) was observed in one family but was not present in more than 600 control chromosomes. Expression of the N1986K mutant in Xenopus oocytes revealed a hyperpolarizing shift in channel steady-state inactivation. Conclusion: In a cohort with familial AF, a single SCN5A mutation causing the arrhythmia in one kindred was identified. These data extend the range of phenotypes observed with SCN5A mutations and suggest that variation in the SCN5A gene is not a major cause of familial AF. [Copyright &y& Elsevier]

Atrial fibrillation is the most common, significant clinical arrhythmia, yet relatively little is known about the primary etiology of this condition and it remains difficult to treat or prevent. Atrial fibrillation induces remodeling of atrial myocytes that in turn helps to sustain the arrhythmia and increases susceptibility to recurrence. Recent work suggests that atrial fibrillation is a heterogeneous syndrome but subsets with specific etiologies are beginning to be uncovered. Identification of the discrete causes of atrial fibrillation will enable the development of targeted strategies for the prevention and treatment of this morbid disorder. [Copyright &y& Elsevier]

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and challenges the capacity of health care systems globally. Atherosclerosis is the underlying pathophysiological entity in two-thirds of patients with CVD. When considering that atherosclerosis develops over decades, there is potentially great opportunity for prevention of associated events such as myocardial infarction and stroke. Subclinical atherosclerosis has been identified in its early stages in young individuals; however, there is no consensus on how to prevent progression to symptomatic disease. Given the growing burden of CVD, a paradigm shift is required—moving from late management of atherosclerotic CVD to earlier detection during the subclinical phase with the goal of potential cure or prevention of events. Studies must focus on how precision medicine using imaging and circulating biomarkers may identify atherosclerosis earlier and determine whether such a paradigm shift would lead to overall cost savings for global health. [Display omitted] • Early-stage subclinical atherosclerosis can be identified in young individuals, but evidence-based strategies are needed to prevent progression of disease and clinical events. • Precision medicine using imaging and circulating biomarkers could facilitate early identification of atherosclerosis and the development of curative interventions. • A paradigm shift based on these principles could reduce the global burden of CVD with enormous implications for population health. [ABSTRACT FROM AUTHOR]

Examines the genetic heterogeneity of familial atrial myxoma syndromes. Incidence; Transmission; Signs and symptoms; Isolation of genomic DNA; Importance of gene identification; Cause of familial atrial myxomas.

As the number of potential chemical warfare agents grows and as the diversity of potential threat scenarios expands with nonstate actors, so a need for innovative approaches to countermeasure development has emerged. In the last few years, the utility of the zebrafish as a model organism that is amenable to high-throughput screening has become apparent and this system has been applied to the unbiased discovery of chemical warfare countermeasures. This review summarizes the in vivo screening approaches that have been used in the countermeasure discovery arena, and highlights the successes to date as well as the potential challenges in moving the field forward. Importantly, the zebrafish platform for countermeasure discovery offers a rapid response system for the development of antidotes to the continuous stream of emerging chemical warfare agents. [ABSTRACT FROM AUTHOR]

Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disorder characterized by the early appearance of ventricular arrhythmias often out of proportion to the degree of ventricular remodeling and dysfunction. ACM typically presents in adolescence or early adulthood. It accounts for 10% of sudden cardiac deaths in individuals under the age of 18 years. Although there has been significant progress in recognizing the genetic determinants of ACM, how specific gene mutations cause the disease remains poorly understood. Here, we review insights gained from studying the human disease as well as in vivo and in vitro experimental models. These observations have advanced our understanding of the molecular mechanisms underlying the pathogenesis of ACM and may lead to development of new mechanism-based therapies. [ABSTRACT FROM AUTHOR]

The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide- induced tumor necrosis factor-a factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed inHEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression downregulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressedNEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation ofNEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca21 and Na1 homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation. [ABSTRACT FROM AUTHOR]

Background: Arrhythmogenic cardiomyopathy (ACM) is a variably penetrant disease increasingly identified in young patients.Objectives: This study sought to describe the diverse phenotype, genotype, and outcomes in pediatric and adolescent patients.Methods: Records from 1999 to 2016 were reviewed for individuals age <21 years with a consistent personal or family history. Patients were categorized by right ventricular (RV), left dominant (LD), or biventricular subtypes using 2010 Task Force Criteria or proposed features of LD disease, encompassing electrocardiographic, structural, histological, and arrhythmic characteristics. Genetic variants classified as pathogenic and/or likely pathogenic by 2015 American College of Medical Genetics and Genomics criteria in recognized disease-associated genes were included.Results: Manifest disease was evident in 32 patients (age 15.1 ± 3.8 years), of whom 22 were probands, including 16 RV, 7 LD, and 9 biventricular ACM. Nondiagnostic features were seen in 5 of 15 family members. RV disease was associated with cardiac arrest and ventricular tachycardia (p = 0.02) and prevalence of PKP2 variants (p < 0.01), whereas biventricular disease was associated with a younger age of onset (p = 0.02). LD ACM was associated with variants in DSP and LMNA, and biventricular ACM with more a diverse etiology in desmosomal genes. Cardiac arrest was observed in 5 probands (age 15.3 ± 1.9 years) and ventricular tachycardia in 10 (age 16.6 ± 2.7 years), 6 probands, and 4 family members. Features suggestive of myocardial inflammation were seen in 6 patients, with ventricular tachycardia and/or cardiac arrest in 3 patients. Cardiac transplantation was performed in 10 patients. There were no deaths. In RV and biventricular disease, electrocardiographic preceded imaging features, whereas the reverse was seen in LD disease.Conclusions: ACM in the young has highly varied phenotypic expression incorporating life-threatening arrhythmia, heart failure, and myocardial inflammation. Increased awareness of early onset, aggressive disease has important implications for patient management and familial screening. [ABSTRACT FROM AUTHOR]

The QT interval is an important diagnostic feature on surface electrocardiograms because it reflects the duration of the ventricular action potential. A previous genome-wide association study has reported a significant linkage between a single-nucleotide polymorphism ~11.7 kb downstream of the gene encoding the RING finger ubiquitin ligase rififylin (RFFL) and variability in the QT interval. This, along with results in animal studies, suggests that RFFL may have effects on cardiac repolarization. Here, we sought to determine the role of RFFL in cardiac electrophysiology. Adult rabbit cardiomyocytes with adenovirus-expressed RFFL exhibited reduced rapid delayed rectifier current (IKr). Neonatal rabbit cardiomyocytes transduced with RFFL-expressing adenovirus exhibited reduced total expression of the potassium channel ether-a-go-go-related gene (rbERG). Using transfections of 293A cells and Western blotting experiments, we observed that RFFL and the core-glycosylated Form of the human ether-a-go-go-related gene (hERG) potassium channel interact. Furthermore, RFFL overexpression led to increased polyubiquitination and proteasomal degradation of hERG protein and to an almost complete disappearance of IKr, which depended on the intact RING domain of RFFL. Blocking the ER-associated degradation (ERAD) pathway with a dominant-negative form of the ERAD core component, valosin-containing protein (VCP), in 293A cells partially abolished RFFL-mediated hERG degradation. We further substantiated the link between RFFL and ERAD by showing an interaction between RFFL and VCP in vitro. We conclude that RFFL is an important regulator of voltage-gated hERG potassium channel activity and therefore cardiac repolarization and that this ubiquitination-mediated regulation requires parts of the ERAD pathway. [ABSTRACT FROM AUTHOR]

Background: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized.Objectives: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences.Methods: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed.Results: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = -3.2; 95% CI: -6.4 to -0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90).Conclusions: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions. [ABSTRACT FROM AUTHOR]

Background Aortic root dimension (ARD), an echocardiographic marker of aortopathy, has recently been associated with intracranial aneurysm eccentricity, suggesting a common underlying pathophysiology between intracranial aneurysm and aortopathy. Objective To identify specific intracranial aneurysm-related parameters that independently correlate with ARD in patients with subarachnoid hemorrhage. Methods Clinical and aneurysm-related parameters obtained from 151 patients with ruptured intracranial aneurysms, and who also underwent echocardiography with ARD measured, were examined. Univariate and multivariate analysis were performed to determine correlation of these parameters with ARD. Results 151 patients who were evaluated from 2008 to 2013 were analyzed. Multivariate linear regression revealed that male gender and fusiform aneurysms were correlated with higher ARD ( P < 0.01 and P = 0.041, respectively) after adjustment for other morphological and clinical variables. Conclusions Fusiform aneurysms are correlated with larger ARD than saccular aneurysms, suggesting a shared pathophysiologic mechanism with aortopathy. [ABSTRACT FROM AUTHOR]

Summary Some organisms, such as adult zebrafish and newborn mice, have the capacity to regenerate heart tissue following injury. Unraveling the mechanisms of heart regeneration is fundamental to understanding why regeneration fails in adult humans. Numerous studies have revealed that nerves are crucial for organ regeneration, thus we aimed to determine whether nerves guide heart regeneration. Here, we show using transgenic zebrafish that inhibition of cardiac innervation leads to reduction of myocyte proliferation following injury. Specifically, pharmacological inhibition of cholinergic nerve function reduces cardiomyocyte proliferation in the injured hearts of both zebrafish and neonatal mice. Direct mechanical denervation impairs heart regeneration in neonatal mice, which was rescued by the administration of neuregulin 1 (NRG1) and nerve growth factor (NGF) recombinant proteins. Transcriptional analysis of mechanically denervated hearts revealed a blunted inflammatory and immune response following injury. These findings demonstrate that nerve function is required for both zebrafish and mouse heart regeneration. [ABSTRACT FROM AUTHOR]

Two recent studies (Newton-Cheh, C. et al. (2009) Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. 41, 399-406 and Pfeufer, A. et al. (2009) Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat. Genet. 41, 407- 414) identified an association, with genome-wide significance, between a single nucleotide polymorphism within the gene encoding RING finger protein 207 (RNF207) and the QT interval. We sought to determine the role of RNF207 in cardiac electrophysiology. Morpholino knockdown of RNF207 in zebrafish embryos resulted in action potential duration prolongation, occasionally a 2:1 atrioventricular block, and slowing of conduction velocity. Conversely, neonatal rabbit cardiomyocytes infected with RNF207-expressing adenovirus exhibited shortened action potential duration. Using transfections of U-2 OS and HEK293 cells, Western blot analysis and immunocytochemistry data demonstrate that RNF207 and the human ether-a-go-go-related gene (HERG) potassium channel interact and colocalize. Furthermore, RNF207 overexpression significantly elevated total and membrane HERG protein and HERG-encoded current density by ~30 -50%, which was dependent on the intact N-terminal RING domain of RNF207. Finally, coexpression of RNF207 and HSP70 increased HERG expression compared with HSP70 alone. This effect was dependent on the C terminus of RNF207. Taken together, the evidence is strong that RNF207 is an important regulator of action potential duration, likely via effects on HERG trafficking and localization in a heat shock protein-dependent manner. [ABSTRACT FROM AUTHOR]

The likelihood of success of conservative management of obstructive hypertrophic cardiomyopathy (HC) and the predictors of failure of conservative therapy are not known. We therefore evaluated the efficacy of an algorithm for the management of symptoms and predictors of failed conservative therapy in 249 consecutive symptomatic patients with obstructive HC referred to a dedicated HC program for management in general or for septal reduction therapy (SRT) in particular. There was considerable practice variation in the extent to which conservative therapy was optimized before referral for SRT. Over 3.7 ± 2.9-year follow-up, symptoms resolved with addition of or increase in dosage of a β blocker, calcium channel blocker, or disopyramide in 16%, 10%, and 10% of patients, respectively. Pacing with short atrioventricular delay controlled symptoms in 4 of 9 patients. In 63% of patients, conservative measures failed to control symptoms. Multivariate predictors of failure of conservative therapy were presence of New York Heart Association class III or IV symptoms (hazard ratio 2.0, 95% confidence interval 1.4 to 2.9, p = 0.001) and greater septal wall thickness (hazard ratio 1.06, 95% confidence interval 1.02 to 1.10, p = 0.003) at presentation. At time of presentation, 93 patients (37%) were already on optimal therapy and were referred for SRT. Of the remaining 156 patients who did not require immediate SRT, 93 (60%) were free from a recommendation for SRT at the end of the follow-up period. In conclusion, in symptomatic patients with obstructive HC, conservative therapy is successful in >1/3 of referred patients at 3.7-year follow-up, obviating SRT in these patients. Clinicians in programs offering SRT should optimize conservative therapy before recommending SRT. [ABSTRACT FROM AUTHOR]

Abstract: Altered mechanical loading of the heart leads to hypertrophy, decompensated heart failure and fatal arrhythmias. However, the molecular mechanisms that link mechanical and electrical dysfunction remain poorly understood. Growing evidence suggest that ventricular electrical remodeling (VER) is a process that can be induced by altered mechanical stress, creating persistent electrophysiological changes that predispose the heart to life-threatening arrhythmias. While VER is clearly a physiological property of the human heart, as evidenced by “T wave memory”, it is also thought to occur in a variety of pathological states associated with altered ventricular activation such as bundle branch block, myocardial infarction, and cardiac pacing. Animal models that are currently being used for investigating stretch-induced VER have significant limitations. The zebrafish has recently emerged as an attractive animal model for studying cardiovascular disease and could overcome some of these limitations. Owing to its extensively sequenced genome, high conservation of gene function, and the comprehensive genetic resources that are available in this model, the zebrafish may provide new insights into the molecular mechanisms that drive detrimental electrical remodeling in response to stretch. Here, we have established a zebrafish model to study mechano-electrical feedback in the heart, which combines efficient genetic manipulation with high-precision stretch and high-resolution electrophysiology. In this model, only 90 min of ventricular stretch caused VER and recapitulated key features of VER found previously in the mammalian heart. Our data suggest that the zebrafish model is a powerful platform for investigating the molecular mechanisms underlying mechano-electrical feedback and VER in the heart. [Copyright &y& Elsevier]

Abstract: The molecular pathways by which newly formed, immature endothelial cell tubes remodel to form a mature network of vessels supported by perivascular mural cells are not well understood. The zebrafish iguana (igu) genetic mutant has a mutation in the daz-interacting protein 1 (dzip1), a member of the hedgehog signaling pathway. Loss of dzip1 results in decreased size of the cranial dorsal aortae, ultrastructural defects in perivascular mural cell recruitment and subsequent hemorrhage. Although hedgehog signaling is disrupted in igu mutants, we find no defects in vessel patterning or artery–vein specification. Rather, we show that the loss of angiopoietin1 (angpt1) expression in ventral perivascular mesenchyme is responsible for vascular instability in igu mutants. Over-expression of angpt1 or partial down-regulation of the endogenous Angpt1 antagonist angpt2 rescues hemorrhage. This is the first direct in vivo link between hedgehog signaling and the induction of vascular stability by recruitment of perivascular mural cells through angiopoietin signaling. [Copyright &y& Elsevier]

We report on the long QT syndrome occurring in conjunction with nontoxic multinodular goiter and sensorineural deafness in several siblings of a large family. Autosomal and X-linked recessive and dominant modes of inheritance are possible for the different phenotypes. The affected family members had various phenotype combinations, suggesting variable expressivity and incomplete penetrance. [Copyright &y& Elsevier]

Summary: Hemodynamic responses that control blood pressure and the distribution of blood flow to different organs are essential for survival. Shear forces generated by blood flow regulate hemodynamic responses, but the molecular and genetic basis for such regulation is not known. The transcription factor KLF2 is activated by fluid shear stress in cultured endothelial cells, where it regulates a large number of vasoactive endothelial genes. Here, we show that Klf2 expression during development mirrors the rise of fluid shear forces, and that endothelial loss of Klf2 results in lethal embryonic heart failure due to a high-cardiac-output state. Klf2 deficiency does not result in anemia or structural vascular defects, and it can be rescued by administration of phenylephrine, a catecholamine that raises vessel tone. These findings identify Klf2 as an essential hemodynamic regulator in vivo and suggest that hemodynamic regulation in response to fluid shear stress is required for cardiovascular development and function. [Copyright &y& Elsevier]