Ulrik Dixen

Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation.

BACKGROUND Atrial fibrillation (AF) is the most common clinical arrhythmia and a major cause of cardiovascular morbidity and mortality. Among the gene defects previously associated with AF is a gain of function of the slowly activating delayed rectifier potassium current IKs, secondary to mutations in KCNQ1. Coexpression of KCNE5, the gene encoding the MiRP4 beta-subunit, has been shown to reduce IKs. OBJECTIVE The purpose of this study was to test the hypothesis that mutations in KCNE5 are associated with AF in a large cohort of patients with AF. METHODS One-hundred fifty-eight patients with AF were screened for mutations in the coding region of KCNE5. RESULTS A missense mutation involving substitution of a phenylalanine for leucine at position 65 (L65F) was identified in one patient. This patient did not have a history of familial AF, and neither KCNQ1 nor KCNE2 mutations were found. Transient transfection of Chinese hamster ovary (CHO) cells expressing IKs(KCNQ1+KCNE1) with KCNE5 suppressed the developing and tail currents of IKs in a concentration-dependent manner. Transient transfection with KCNE5-L65F failed to suppress IKs, yielding a current indistinguishable from that recorded in the absence of KCNE5. Developing currents recorded during a test pulse to +60 mV and tail currents recorded upon repolarization to -40 mV both showed a significant concentration-dependent gain of function in IKs with expression of KCNE5-L65F vs KCNE5-WT. CONCLUSION The results of this study suggest that a missense mutation in KCNE5 may be associated with nonfamilial or acquired forms of AF. The arrhythmogenic mechanism most likely is a gain of function of IKs.

New insights into cirrhotic cardiomyopathy

Cirrhotic cardiomyopathy designates a cardiac dysfunction, which includes reduced cardiac contractility with systolic and diastolic dysfunction, and presence of electrophysiological abnormalities in particular prolongation of the QT interval. Several pathophysiological mechanisms including reduced beta-receptor function seem involved in the autonomic and cardiac dysfunction. Cirrhotic cardiomyopathy can be revealed by tissue Doppler imaging but is best demasked by physical or pharmacological stress. Liver transplantation may revert cardiac dysfunction but surgery and shunt insertion may also aggravate the condition. Moreover, cirrhotic cardiomyopathy may contribute to heart failure after invasive procedures and to development of hepatic nephropathy as part of a cardiorenal syndrome. Whether beta-blockers have a deleterious effect in this clinical situation remains to be settled.

Raised Plasma Aldosterone and Natriuretic Peptides in Atrial Fibrillation

Background and Aims: During atrial fibrillation (AF), the renin-angiotensin-aldosterone system (RAAS) may be activated.In this study, our aim was to evaluate at a long-term follow-up visit the levels of plasma aldosterone and natriuretic peptides as markers of neurohormonal remodeling in patients with earlier, documented AF in relation to present heart rhythm, clinical data, and the left ventricular ejection fraction (LVEF). We hypothesized that increased levels of aldosterone and natriuretic peptides were significantly associated with present AF as markers of RAAS activation during the arrhythmia. Methods: We studied 158 patients with earlier ECG-documented AF followed by restored sinus rhythm (SR) attending a follow-up visit 2.6 years (mean) after primary inclusion. Results: At follow-up, 93 patients had SR. Heart rhythm at follow-up visit (SR/AF), plasma aldosterone, plasma N-terminal pro Brain Natriuretic Peptide (Nt- proBNP), plasma N-terminal pro Atrial Natriuretic Peptide (Nt-proANP), LVEF, medication, and clinical characteristics were recorded. Standard linear multiple regression analysis including age, sex, weight, hypertension, congestive heart failure, ischemic heart disease, present AF at follow-up, total duration of AF disease, ongoing medication, and the LVEF as explanatory variables showed that only ongoing treatment with diuretics was significantly associated (likelihood ratio test, p = 0.0057) with a raised log-transformed plasma aldosterone, although present AF at follow-up was related to a high aldosterone level (p = 0.09). For the natriuretic peptides, present AF at follow-up (p < 0.0001), age (p < 0.0001), female gender (p = 0.0047), ischemic heart disease (p = 0.0154), and ongoing treatment with sotalol (p = 0.0003) were all independently associated with high log-transformed plasma Nt-proANP. Likewise, present AF at follow-up (p = 0.0008) as well as age (p < 0.0001) were associated with high log-transformed plasma Nt-proBNP. Conclusions: In patients with earlier AF, AF at long-term follow-up visit was independently associated with raised levels of Nt-proANP and Nt-proBNP and to some extent with plasma aldosterone indicating neurohormonal activation during arrhythmia.

Diastolic dysfunction predicts new-onset atrial fibrillation and cardiovascular events in patients with acute myocardial infarction and depressed left ventricular systolic function: a CARISMA substudy

AIMS The aim of this study was to investigate the association between diastolic dysfunction and long-term occurrence of new-onset atrial fibrillation (AF) and cardiac events in patients with acute myocardial infarction (AMI) and left ventricular (LV) systolic dysfunction. METHODS AND RESULTS The study was performed as a substudy on the CARISMA study population. The CARISMA study enrolled 312 patients with an AMI and LV ejection fraction <or=40%. Patients were implanted with an implantable loop recorder and followed for 2 years. Sixty-two patients had a full echocardiographic assessment of the diastolic function using tissue Doppler analysis performed 6 weeks after the AMI. The endpoints were: (i) new-onset AF and (ii) major cardiovascular events (MACE) defined as re-infarction, stroke, or cardiovascular death. Twenty-four patients had diastolic dysfunction, whereas 38 patients had normal diastolic function. Diastolic dysfunction was associated with an increased risk of new-onset AF [HR = 5.30 (1.68-16.75), P = 0.005] and MACE [HR = 4.70 (1.25-17.75), P = 0.022] after adjustment for age, sex, NYHA class, and hypertension. CONCLUSION Diastolic dysfunction in post-MI patients with LV systolic dysfunction predisposes to new-onset AF and MACE.

The incidence and prognostic significance of new-onset atrial fibrillation in patients with acute myocardial infarction and left ventricular systolic dysfunction: A CARISMA substudy

BACKGROUND The incidence and risk associated with new-onset atrial fibrillation (AF) occurring after discharge in patients with acute myocardial infarction (MI) remains unknown. OBJECTIVE This study sought to describe the incidence and clinical risk associated with postdischarge new-onset AF in post-MI patients with left ventricular systolic dysfunction. METHODS The population included 271 post-MI patients with left ventricular ejection fraction ≤ 40% and no history of previous AF from the Cardiac Arrhythmias and Risk Stratification after Acute Myocardial Infarction (CARISMA) study. All patients were implanted with an implantable cardiac monitor and followed up every 3 months for 2 years. Major cardiovascular events were defined as reinfarction, stroke, hospitalization for heart failure, or death. RESULTS The risk of new-onset AF is highest during the first 2 months after the acute MI (16% event rate) and decreases until month 12 post-MI, after which the risk for new-onset AF is stable. The risk of major cardiovascular events was increased in patients with AF events ≥ 30 seconds (hazard ratio [95% CI] = 2.73 [1.35 to 5.50], P = .005), but not in patients with AF events lasting <30 seconds (hazard ratio [95% CI] = 1.17 [0.35 to 3.92], P = .80). More than 90% of all recorded AF events were asymptomatic. CONCLUSION Using an implantable cardiac monitor, the incidence of new-onset AF was found to be 4-fold higher than earlier reported. In the study population, in which treatment with beta-blockers was optimized, the vast majority of AF events were asymptomatic, emphasizing the importance of using continuous monitoring for studies concerning AF in heart failure patients. A duration of 30 seconds or more identified clinically important AF episodes documented by an implantable cardiac monitor.

Cardiovascular Autonomic Neuropathy and Subclinical Cardiovascular Disease in Normoalbuminuric Type 1 Diabetic Patients

Cardiovascular autonomic neuropathy (CAN) is associated with increased mortality in diabetes. Since CAN often develops in parallel with diabetic nephropathy as a confounder, we aimed to investigate the isolated impact of CAN on cardiovascular disease in normoalbuminuric patients. Fifty-six normoalbuminuric, type 1 diabetic patients were divided into 26 with (+) and 30 without (−) CAN according to tests of their autonomic nerve function. Coronary artery plaque burden and coronary artery calcium score (CACS) were evaluated using computed tomography. Left ventricular function was evaluated using echocardiography. Blood pressure and electrocardiography were recorded through 24 h to evaluate nocturnal drop in blood pressure (dipping) and pulse pressure. In patients +CAN compared with −CAN, the CACS was higher, and only patients +CAN had a CACS >400. A trend toward a higher prevalence of coronary plaques and flow-limiting stenosis in patients +CAN was nonsignificant. In patients +CAN, left ventricular function was decreased in both diastole and systole, nondipping was more prevalent, and pulse pressure was increased compared with −CAN. In multivariable analysis, CAN was independently associated with increased CACS, subclinical left ventricular dysfunction, and increased pulse pressure. In conclusion, CAN in normoalbuminuric type 1 diabetic patients is associated with distinct signs of subclinical cardiovascular disease.

A systematic review on the safety and efficacy of percutaneous edge-to-edge mitral valve repair with the MitraClip system for high surgical risk candidates

Background MitraClip implantation has emerged as a viable option in high surgical risk patients with severe mitral regurgitation (MR). We performed the present systematic review to assess the safety and efficacy of the MitraClip system for high surgical risk candidates with severe organic and/or functional MR. Methods Six electronic databases were searched for original published studies from January 2000 to March 2013. Two reviewers independently appraised studies, using a standard form, and extracted data on methodology, quality criteria, and outcome measures. All data were extracted and tabulated from the relevant articles’ texts, tables, and figures and checked by another reviewer. Results Overall 111 publications were identified. After applying selection criteria and removing serial publications with accumulating number of patients or increased length of follow-up, 12 publications with the most complete dataset were included for quality appraisal and data extraction. All 12 studies were prospective observational studies. Immediate procedural success ranged from 72–100%; 30 day mortality ranged from 0–7.8%. There was a significant improvement in haemodynamic profile and functional status after implantation. One year survival ranged from 75–90%. No long term outcomes have been reported for high surgical risk patients. Conclusions MitraClip implantation is an option in managing selected high surgical risk patients with severe MR. The current evidence suggests that MitraClip can be implanted with reproducible safety and feasibility profile in this subgroup of patients. Further prospective trials with mid- to long-term follow-up are required.

Assessment of left atrial volume and function in patients with permanent atrial fibrillation: comparison of cardiac magnetic resonance imaging, 320-slice multi-detector computed tomography, and transthoracic echocardiography

AIMS Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with substantial morbidity and mortality. AF is associated with enlargement of the left atrium (LA), and the LA volume has important prognostic implications for the disease. The objective of the study was to determine how measurements of LA volume and function obtained by transthoracic echocardiography (TTE), cardiac magnetic resonance (CMR), and 320-slice multi-detector computed tomography (MDCT) correlate in patients with permanent AF. METHODS AND RESULTS Thirty-four patients with permanent AF participated in the study. TTE, CMR, and 320-slice MDCT imaging procedures were performed within 7 ± 4 days. 320-slice MDCT overestimated maximal LA volume (LAmax) and minimal LA volume (LAmin) compared with CMR (LAmax: 80 vs. 73 mL/m(2), P = 0.0017; LAmin: 69 vs. 64 mL/m(2), P = 0.0217), whereas TTE underestimated these parameters compared with CMR (LAmax: 60 vs. 73 mL/m(2), P < 0.0001; LAmin: 50 vs. 64 mL/m(2), P < 0.0001), and also compared with MDCT (LAmax: 60 vs. 80 mL/m(2), P < 0.0001; LAmin: 50 vs. 69 mL/m(2), P < 0.0001). Measurements of LA volumes by MDCT and CMR closely correlated, and both MDCT and CMR had excellent intra- and inter-observer agreement with correlation coefficients of >0.90. The correlation between TTE-derived measurements and CMR/MDCT was fair to moderate. Intra- and inter-observer agreement for LA volume measurements by TTE were inferior to CMR and MDCT. CONCLUSION Measurements of LA volumes by CMR and 320-slice MDCT correlate closely in patients with permanent AF, and both modalities improve the reproducibility of measurements of LA volumes and function compared with 2D TTE.

Autonomic Dysfunction and New‐Onset Atrial Fibrillation in Patients With Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction: A CARISMA Substudy

Predicting New‐Onset AF. Background: Atrial fibrillation (AF) increases morbidity and mortality in patients with previous myocardial infarction and left ventricular systolic dysfunction. The purpose of this study was to identify patients with a high risk for new‐onset AF in this population using invasive and noninvasive electrophysiological tests.

Percutaneous atrial appendage occlusion for stroke prevention in patients with atrial fibrillation: a systematic review

This review aims to evaluate systematically the safety and efficacy of percutaneous left atrial appendage occlusion (PLAAO) in stroke prevention for patients with atrial fibrillation (AF). A systematic review of peer-reviewed journals on PLAAO before June 2011 was performed on three electronic databases. Fourteen studies were identified for evaluation. Overall, implantation was successful in 93% of all cases. Periprocedural mortality and stroke rates were 1.1% and 0.6%, respectively. The incidences of pericardial effusion/cardiac tamponade and device embolisation were 4% and 0.7%, respectively. At the time of the latest follow-up (up to 40 months), the overall incidence of stroke among all studies was 1.4% per annum. Existing evidence suggests that PLAAO is a relatively safe treatment for patients with AF. However, there is a need for further evaluation of its efficacy in the form of large and well-designed randomised controlled trials.