RyR2 C-terminal truncating variants identified in patients with arrhythmic phenotypes exert a dominant negative effect through formation of wildtype-truncation heteromers.

Gain-of-function missense variants in the cardiac ryanodine receptor (RyR2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), whereas RyR2 loss-of-function missense variants cause Ca2+ release deficiency syndrome (CRDS). Recently, truncating variants in RyR2 have also been associated with ventricular arrhythmias (VAs) and sudden cardiac death. However, there are limited insights into the potential clinical relevance and in vitro functional impact of RyR2 truncating variants. We performed genetic screening of patients presenting with syncope, VAs, or unexplained sudden death and in vitro characterization of the expression and function of RyR2 truncating variants in HEK293 cells. We identified two previously unknown RyR2 truncating variants (Y4591Ter and R4663Ter) and one splice site variant predicted to result in a frameshift and premature termination (N4717 + 15Ter). These 3 new RyR2 truncating variants and a recently reported RyR2 truncating variant, R4790Ter, were generated and functionally characterized in vitro. Immunoprecipitation and immunoblotting analyses showed that all 4 RyR2 truncating variants formed heteromers with the RyR2-wildtype (WT) protein. Each of these C-terminal RyR2 truncations was non-functional and suppressed [3H]ryanodine binding to RyR2-WT and RyR2-WT mediated store overload induced spontaneous Ca2+ release activity in HEK293 cells. The expression of these RyR2 truncating variants in HEK293 cells was markedly reduced compared with that of the full-length RyR2 WT protein. Our data indicate that C-terminal RyR2 truncating variants are non-functional and can exert a dominant negative impact on the function of the RyR2 WT protein through formation of heteromeric WT/truncation complex.

Jet length/velocity ratio: a new index for echocardiographic evaluation of chronic aortic regurgitation.

BACKGROUND: Management of aortic regurgitation depends on the assessment for severity. Echocardiography remains as the most widely available tool for evaluation of aortic regurgitation. In this manuscript, we describe a novel parameter, jet length/velocity ratio, for the diagnosis of severe aortic regurgitation. METHODS AND RESULTS: A total of 30 patients with aortic regurgitation were included to this study. Severity of aortic regurgitation was assessed with an aortic regurgitation index incorporating five echocardiographic parameters. Jet length/velocity ratio is calculated as the ratio of maximum jet penetrance to mean velocity of regurgitant flow. Jet length/velocity ratio was significantly higher in patients with severe aortic regurgitation (2.03 ± 0.53) compared to patients with less than severe aortic regurgitation (1.24 ± 0.32, P < 0.001). Correlation of jet length/velocity ratio with aortic regurgitation index was very good (r(2) = 0.86) and correlation coefficient was higher for jet length/velocity ratio compared to vena contracta, jet width/LVOT ratio and pressure half time. For a cutoff value of 1.61, jet length/velocity ratio had a sensitivity of 92% and specificity of 88%, with an AUC value of 0.955. CONCLUSIONS: Jet length/velocity ratio is a novel parameter that can be used to assess severity of chronic aortic regurgitation. Main limitation for usage of this novel parameter is jet impringement to left ventricular wall.

Tissue Doppler-derived isovolumic acceleration parameters in organic mitral regurgitation.

BACKGROUND AND AIM OF THE STUDY: New, quantitative, reliable and practical echocardiographic parameters are required for grading the severity of mitral regurgitation (MR). Thus, an investigation was made of tissue Doppler imaging (TDI) parameters in MR patients with a preserved left ventricular ejection fraction (LVEF). METHODS: Transthoracic echocardiography was performed in 96 consecutive patients with varying degrees of MR but with a preserved LVEF. In addition, TDI-derived systolic velocities of the mitral and tricuspid annulus were recorded. The results obtained were compared with those from 31 age- and gender-matched healthy controls. RESULTS: The study patients were classified according to MR severity: mild-moderate (n = 65) or severe (n = 31). Although isovolumic myocardial acceleration (IVA) and peak myocardial velocity during isovolumic contraction (IVV) showed similar values in all groups, the acceleration time (AT) was higher in the severe MR group than in mild or moderate MR patients (p < 0.001). The AT cut-off value to predict severe MR was 35 ms (sensitivity 74.2%, specificity 58.5%). CONCLUSION: AT has the potential to differentiate severe MR from non-severe MR in patients with a preserved LVEF. These findings suggest that TDI of the mitral annulus might serve as a novel method for assessing MR severity.

Acute aortic regurgitation with myocardial infarction: an important clue for aortic dissection.

BACKGROUND: Aortic dissection is an important cause of acute chest pain that should be rapidly diagnosed, as mortality increases with each hour this condition is left untreated. The diagnosis can be challenging, especially if concomitant myocardial infarction is present. Echocardiography is an important tool for the differential diagnosis. OBJECTIVES: To stress the importance of recognizing aortic regurgitation for the differentiation of myocardial infarction and aortic dissection. CASE REPORT: An 80-year-old woman was admitted to our hospital with chest pain that was diagnosed as inferior and lateral wall myocardial infarction based on electrocardiographic findings. The diagnosis was reevaluated when aortic regurgitation was detected on echocardiography. Closer inspection of the ascending aorta revealed a dissection flap as the cause of aortic regurgitation. CONCLUSION: Detection of aortic regurgitation in a patient with myocardial infarction and normal valves should prompt the search for a possible aortic dissection, whether or not the dissection flap can be visualized.

Incremental value of the signal-averaged ECG for diagnosing arrhythmogenic cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is currently diagnosed using a combination of clinical features, imaging, electrocardiography, and genetic investigations. An abnormal signal-averaged electrocardiogram (SAECG) is defined as a minor diagnostic criterion by the 2010 Task Force Criteria, but doubts remain about the value of this investigation. OBJECTIVE: We evaluated the utility of the SAECG in diagnosing ARVC using the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry, a population representative registry of probands with ARVC and relatives, less influenced by referral bias. METHODS: Probands with ARVC and family members from the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry underwent phenotype review. SAECG parameters were compared individually and in combination between those with varying degrees of ARVC severity and healthy controls (family members of probands with ARVC and unexplained sudden death, free of evidence of cardiac disease). RESULTS: A total of 196 patients with ARVC and 205 controls were included (mean age 44 ± 15 years; 186 of 401 men [46%]). SAECG abnormalities were seen in 83 of 205 controls (40%), 33 of 68 patients with ARVC and mild disease (51%), and 31 of 42 with severe disease (74%). The SAECG associated strongly with imaging abnormalities (major: odds ratio 3.0, 95% confidence interval 1.3-6.9; minor: odds ratio 3.5, 95% confidence interval 0.7-16.5) but not with other aspects of phenotype. Patients carrying pathogenic variants but with minimal phenotype had similar SAECGs to healthy controls (filtered QRS duration 111.2 ± 11.2 ms vs 111 ± 7.6 ms, P = .93; duration of low amplitude signals < 40 µV 32.3 ± 8.9 ms vs 34.2 ± 7.2 ms, P = .32; root mean square of the terminal 40 ms of the filtered QRS complex 43.1 ± 25.2 ms vs 38.2 ± 20.2 ms, P = .38). CONCLUSION: The SAECG appears to be a surrogate marker for structural abnormalities seen on imaging in those with ARVC. Great caution is required in interpreting SAECG findings in those without other corroborating evidence of an ARVC phenotype.

The Prevalence and Characteristics of Arrhythmic Mitral Valve Prolapse in Patients With Unexplained Cardiac Arrest.

BACKGROUND: There is growing evidence that mitral valve prolapse (MVP) is associated with otherwise unexplained cardiac arrest (UCA). However, reports are hindered by the absence of a systematic ascertainment of alternative diagnoses. OBJECTIVES: This study reports the prevalence and characteristics of MVP in a large cohort of patients with UCA. METHODS: Patients were enrolled following an UCA, defined as cardiac arrest with no coronary artery disease, preserved left ventricular ejection fraction, and no apparent explanation on electrocardiogram. A comprehensive evaluation was performed, and patients were diagnosed with idiopathic ventricular fibrillation (IVF) if no cause was found. Echocardiography reports were reviewed for MVP. Patients with MVP were divided into 2 groups: those with IVF (AMVP) and those with an alternative diagnosis (nonarrhythmic MVP). Patient characteristics were then compared. The long-term outcomes of AMVP were reported. RESULTS: Among 571 with an initially UCA, 34 patients had MVP (6%). The prevalence of definite MVP was significantly higher in patients with IVF than those with an alternative diagnosis (24 of 366 [6.6%] vs 5 of 205 [2.4%]; P = 0.03). Bileaflet prolapse was significantly associated with AMVP (18 of 23 [78%] vs 1 of 8 [12.5%]; P = 0.001; OR: 25.2). The proportion of patients with AMVP who received appropriate implantable cardioverter-defibrillator therapies over a median follow-up of 42 months was 21.1% (4 of 19). CONCLUSIONS: MVP is associated with otherwise UCA (IVF), with a prevalence of 6.6%. Bileaflet prolapse appears to be a feature of AMVP, although future studies need to ascertain its independent association. A significant proportion of patients with AMVP received appropriate implantable cardioverter-defibrillator therapies during follow-up.

Management of Inherited Arrhythmia Syndromes: A HiRO Consensus Handbook on Process of Care.

Inherited arrhythmia syndromes are rare genetic conditions that predispose seemingly healthy individuals to sudden cardiac arrest and death. The Hearts in Rhythm Organization is a multidisciplinary Canadian network of clinicians, researchers, patients, and families that aims to improve care for patients and families with inherited cardiac conditions, focused on those that confer predisposition to arrhythmia and sudden cardiac arrest and/or death. The field is rapidly evolving as research discoveries increase. A streamlined, practical guide for providers to diagnose and follow pediatric and adult patients with inherited cardiac conditions represents a useful tool to improve health system utilization, clinical management, and research related to these conditions. This review provides consensus care pathways for 7 conditions, including the 4 most common inherited cardiac conditions that confer predisposition to arrhythmia, with scenarios to guide investigation, diagnosis, risk stratification, and management. These conditions include Brugada syndrome, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy and related arrhythmogenic cardiomyopathies, and catecholaminergic polymorphic ventricular tachycardia. In addition, an approach to investigating and managing sudden cardiac arrest, sudden unexpected death, and first-degree family members of affected individuals is provided. Referral to specialized cardiogenetic clinics should be considered in most cases. The intention of this review is to offer a framework for the process of care that is useful for both experts and nonexperts, and related allied disciplines such as hospital management, diagnostic services, coroners, and pathologists, in order to provide high-quality, multidisciplinary, standardized care.

Les syndromes d'arythmie héréditaires sont des troubles génétiques rares qui prédisposent des personnes en apparence en bonne santé à un arrêt cardiaque soudain et à la mort. L'organisation Hearts in Rhythm Organization est un réseau multidisciplinaire canadien qui regroupe des cliniciens, des chercheurs ainsi que des patients et leurs proches dans le but d'améliorer les soins prodigués aux patients atteints de maladies cardiaques héréditaires et à leur famille, en particulier dans le cas des maladies qui entraînent une prédisposition à l'arythmie et à un arrêt cardiaque soudain et/ou à la mort. Puisque ce champ de recherche évolue rapidement, la mise au point d'un guide pratique et simple à l'intention des professionnels de la santé pour le diagnostic et le suivi des patients enfants et adultes présentant une maladie cardiaque héréditaire serait donc un outil intéressant pour améliorer l'utilisation du système de santé et la prise en charge clinique de ces maladies tout en orientant la recherche à ce propos. La présente synthèse expose les trajectoires de soins faisant l'objet d'un consensus pour sept maladies, dont les quatre maladies cardiaques héréditaires les plus courantes qui prédisposent à l'arythmie. Elle présente aussi des scénarios pour orienter les examens, le diagnostic, la stratification du risque et la prise en charge des patients. Ces maladies sont le syndrome de Brugada, le syndrome du QT long, la cardiomyopathie arythmogénique du ventricule droit et les cardiomyopathies arythmogènes associées, et la tachycardie ventriculaire polymorphe catécholaminergique. En outre, une approche pour la prise en charge de l'arrêt cardiaque soudain, de mort subite inattendue et des membres de la famille immédiate de la personne touchée est proposée. L'orientation vers des cliniques spécialisées en cardiogénétique doit être envisagée dans la plupart des cas. L'objectif est d'établir un cadre de soins qui soit utile pour les experts et les non-experts ainsi que pour les professionnels des domaines connexes, par exemple le personnel de l'administration hospitalière et des services diagnostiques, les coroners et les pathologistes, en vue d'offrir des soins multidisciplinaires normalisés de grande qualité.

Successful electrical cardioversion in a massive concentric hypertrophic cardiomyopathy with atrial fibrillation.

A 59-year-old man with a known history of nonobstructive hypertrophic cardiomyopathy and chronic atrial fibrillation was admitted to our clinic with weakness, palpitation, and exertional dyspnea. Electrocardiogram showed atrial fibrillation with high ventricular rate (120 beats per minute), intraventricular conduction delay, and left ventricular (LV) hypertrophy with ST-segment depression and inverted T waves. A transthoracic echocardiogram showed massive LV concentric hypertrophy. Although there was no gradient increase in the LV outflow tract, marked turbulent flow was seen in midventricular region by colored Doppler echocardiography. On the fourth day of admission, transesophageal echocardiography was done and showed no thrombus in the left atrium. Electrical cardioversion with 100 J was applied to the patient, and atrial fibrillation was returned to sinus rhythm. His control Doppler echocardiogram revealed peak systolic resting gradient of 54 mm Hg, with an increase to 84 mm Hg at Valsalva maneuver at the LV outflow. Cardiac magnetic resonance showed concentric LV hypertrophy with a 35-mm thickness in diastole, mild scar tissue in LV anterior wall midapical segments, and right ventricle wall thickness with a 10 mm in diastole. There was no bradycardia or tachycardia in 24-hour Holter and exercise electrocardiographic testing.

Iatrogenic Arteriovenous Fistula: A Rare Complication of Pacemaker Implantation.

Severe vascular complications associated with pacemaker implantation are rare. Typically, they are overt, and require immediate resolution. We present 2 patients with insidious presentation of arteriovenous fistulae due to pacemaker implantation that were recognized early post-implantation. Both were repaired endovascularly and had good outcomes post-repair. (Level of Difficulty: Intermediate.).

Impaired fasting glucose is associated with increased perioperative cardiovascular event rates in patients undergoing major non-cardiothoracic surgery.

BACKGROUND: Diabetes mellitus (DM) is a well-established risk factor for perioperative cardiovascular morbidity and mortality in patients undergoing noncardiac surgery. However, the impact of preoperative glucose levels on perioperative cardiovascular outcomes in patients undergoing nonemergent, major noncardiothoracic surgery is unclear. METHODS AND RESULTS: A total of 680 patients undergoing noncardiothoracic surgery were prospectively evaluated. Patients older than 18 years who underwent an elective, nonday case, open surgical procedure were enrolled. Electrocardiography and cardiac biomarkers were obtained 1 day before surgery, and on days 1, 3 and 7 after surgery. Preoperative risk factors and laboratory test results were measured and evaluated for their association with the occurrence of in-hospital perioperative cardiovascular events. Impaired fasting glucose (IFG) defined as fasting plasma glucose values of 100 to 125 mg/dl; DM was defined as fasting plasma glucose ≥ 126 mg/dl and/or plasma glucose ≥ 200 mg/dl or the current use of blood glucose-lowering medication, and glucose values below 100 mg/dl were considered normal. Plasma glucose levels were significantly higher in patients with perioperative cardiovascular events (n=80, 11.8%) in comparison to those without cardiovascular events (131 ± 42.5 vs 106.5 ± 37.5, p < 0.0001). Multivariate analysis revealed that patients with IFG and DM were at 2.1- and 6.4-fold increased risk of perioperative cardiovascular events, respectively. Every 10 mg/dl increase in preoperative plasma glucose levels was related to a 11% increase for adverse perioperative cardiovascular events. CONCLUSIONS: Not only DM but also IFG is associated with increased perioperative cardiovascular event rates in patients undergoing noncardiothoracic surgery.

Increased aortic stiffness can predict perioperative cardiovascular outcomes in patients undergoing noncardiac, nonvascular surgery.

BACKGROUND: Aortic stiffness is an early marker of arteriosclerosis and associated with cardiovascular mortality. However, the impact of aortic stiffness on perioperative cardiovascular outcomes in patients undergoing noncardiac surgery is unknown. METHODS: The study population was composed of 660 consecutive adults aged 18 years and over (mean age = 65.3 ± 14 years) who underwent intermediate-risk (nonvascular), noncardiac surgery between January 2010 and February 2011. Nonemergency, non-day-case, open surgical procedures were enrolled. Aortic stiffness indices were calculated from the aortic diameters measured by echocardiography. Electrocardiography and cardiac biomarkers were evaluated 1 day before surgery, and on days 1, 3, and 7 after surgery. RESULTS: Eighty patients (12.1%) experienced perioperative cardiovascular events (PCE). Preoperative aortic distensibility (AD) (2 ± 1.3 vs. 2.9 ± 1.1 cm2/dyn/10(3), P < 0.001) and aortic strain (AS) (4.4 ± 2.4 vs. 6.4 ± 1.9, P < 0.001) of the patients with PCE were significantly lower than in patients without PCE. Univariate analysis showed a significant association between age, diabetes mellitus (DM), coronary artery disease, preoperative atrial fibrillation, American Society of Anesthesiologists (ASA) status, Revised Cardiac Risk Index, left ventricle ejection fraction (LVEF), AD, aortic strain, and in-hospital PCE. However, on multivariate logistic regression analysis, only AD (OR: 1.94, 95% CI: 1.1-3.4; P = 0.02), AS (OR: 0.45, 95% CI: 0.3-0.6; P < 0.001), DM (OR: 2.28, 95% CI: 1.08-4.82; P = 0.03), and LVEF (OR: 0.96, 95% CI: 0.93-0.99; P = 0.03) remained as significant variables associated with PCE. CONCLUSION: Impaired elastic properties of the aorta are associated with increased PCE rates in patients undergoing noncardiac, nonvascular surgery.

Incidentally diagnosed unusual ascending aorta mass.

A 44-year-old female, with no medical history, was admitted to the cardiology department because of mild exertional dyspnea. Transthoracic and transesophageal echocardiography showed highly mobile, mass-like lesion in the aortic root. The patient was operated in the same week and a 1 cm × 6 cm soft tissue was excised from the ascending aorta. Pathological examination revealed a fibrin clot surrounded by a fibrous cap.

Aortic root abscess complicated by fistulization in a young patient with bicuspid aortic valve.

Aortic root abscess is a relatively common complication of aortic valve endocarditis. However, aortic root abscess and formation of a fistula from the aortic root to the right ventricular outflow tract in the setting of a native bicuspid aortic valve (BAV) is a rare event. We present consecutive echocardiographic images of unruptured periaortic abscess and fistulization of it to the right ventricle in 24 hours, in a patient with BAV and fever of unexplained origin.

Which is worst in patients undergoing primary angioplasty for acute myocardial infarction? Hyperglycaemia? Diabetes mellitus? Or both?

OBJECTIVE: The objective of this study was to evaluate the effect of admission hyperglycaemia and/or diabetes mellitus (DM) on the outcomes of primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). METHODS: 2482 consecutive patients with STEMI (mean age 56.5 +/- 11.9, years, 2064 men) undergoing primary PCI between October 2003 and March 2008 were retrospectively enrolled into the present study. Hyperglycaemia was defined as a venous plasma glucose level > or =200 mg/dl on admission. Patients were classified into four groups: non-diabetic/non-hyperglycaemic (NDNH, n=1806) patients; diabetic/non-hyperglycaemic (DNH, n=271) patients; non-diabetic/hyperglycaemic (NDH, n=64); and diabetic/hyperglycaemic (DH, n=341). RESULTS: In-hospital mortality was higher in NDH (12.5%) compared to DH (8.5%), DNH (6.3%), and NDNH (0.9%) patients (P < 0.001). The composite end points including death, reinfarction, and target-vessel revascularization (major adverse cardiac events [MACE]) in the hospital were also higher in NDH (18.8%) compared with other patients (DH, 13.8% vs. DNH, 10.3% vs. NDNH, 3.7%, P < 0.001). The median follow-up time was 21 months.The Kaplan-Meier survival plot for long-term cardiovascular death was worst for DH patients (log rank P < 0.001). After adjustment for potentially confounding factors, NDH (OR 3.04, 95% CI 1.06-8.73; P = 0.03), and DH (OR 2.3,95% CI 1.29-4.09; P = 0.005), but not DNH (OR 1.22,95% CI 0.57-2.6; P = 0.6) status, remained independent predictors of long-term cardiovascular mortality. CONCLUSIONS: STEMI patients with NDH represent the highest risk population for in-hospital mortality, and MACE. The worst outcomes for long-term cardiovascular mortality occur in DH patients.

Providing insights into atherosclerosis: A case of multivessel coronary artery disease with an anomalous straightforward vessel spared from atherosclerosis.

Atherosclerotic plaques tend to involve arterial localizations in which blood flow is not laminar due to arterial bends and bifurcations. A 49-year-old man was admitted to hospital with breathlessness and was subsequently diagnosed with left ventricular failure. Coronary angiography revealed three-vessel coronary artery disease and an anomalous extra left anterior descending artery taking off from the right sinus of Valsalva and spared from atherosclerosis. The absence of side branches and the relative lack of bends in arterial geometry were considered to be the cause of resistance to atherosclerosis. The present case identifies local flow conditions as an important factor determining the genesis of atherosclerosis in arterial segments.

Acute myocardial infarction and renal infarction in a bodybuilder using anabolic steroids.

A 41-year-old male bodybuilder was admitted with acute inferior myocardial infarction. The patient had been using oxymetholone and methenolone to increase his performance for 15 years and quitted smoking three years before. He underwent successful primary percutaneous coronary intervention (PCI) and bare metal stenting for total occlusion of the proximal right coronary artery. Angiography also showed a critical lesion in the left anterior descending (LAD) coronary artery. Five hours after primary PCI, the patient had severe right flank pain. Abdominal computed tomography showed a large renal infarction in the right kidney. Subcutaneous enoxaparin was added to dual antiplatelet treatment. Doppler renal ultrasound performed on the eighth day showed findings of reperfusion in the right kidney and normal-size kidneys. Transthoracic echocardiography demonstrated disappearance of previously detected thrombus remnant in the left ventricle and only mild hypokinesia around the apical and middle segments of the inferior and inferoseptal walls. The patient was discharged on the 10th day. Renal arteriography during elective LAD intervention 18 days after discharge showed complete revascularization, stent patency, and improved blood flow. This is the first case of renal infarction that developed in the early hours of primary PCI, despite effective anticoagulant and antiplatelet treatment. Intensive coronary artery and left ventricular thrombi may be explained by the use of anabolic steroids.