Juvenile-onset multifocal atrial arrhythmias, atrial standstill and compound heterozygosity of genetic variants in TAF1A: sentinel event for evolving dilated cardiomyopathy-a case report.

Background: Juvenile onset of extensive atrial electromechanical failure, including atrial standstill, is a rare disease entity that may precede ventricular cardiomyopathy. Genetic variants associated with early-onset atrioventricular (AV) cardiomyopathy are increasingly recognized. Case summary: A 16-year-old patient presented with atrial brady- and tachyarrhythmias and concomitant impaired atrial electromechanical function (atrial standstill). The atrial phenotype preceded the development of a predominantly right-sided AV dilated cardiomyopathy with pronounced myocardial fibrosis. A His-bundle pacemaker was installed for high-degree AV conduction block and sinus arrest. Using familial-based whole-exome sequencing, a missense mutation and a copy number variant deletion (compound heterozygosity) of the TAF1A gene (involved in ribosomal RNA synthesis) were identified. Discussion: Juvenile onset of severe atrial electromechanical failure with atrial arrhythmias should prompt deep pheno- and genotyping and calls for vigilance for downstream cardiomyopathic deterioration.

Development and implementation of a cardiac resynchronisation therapy care pathway: improved process and reduced resource use.

BACKGROUND: Cardiac resynchronisation therapy (CRT) requires intensive, complex and multidisciplinary care to maximize the clinical benefit. In current practice this is typically a task for highly specialised physicians. We report on a novel multidisciplinary, standardised CRT care pathway (CRT-CPW). Experienced clinicians developed a CPW with simple and broadly applicable aids based on clinical evidence and identified shortcomings in the current CRT care. The resulting CPW was implemented at the Maastricht University Medical Center, aiming at a transfer from heterogeneous physician-led care to standardized nurse-led care. METHODS: Two CRT patient cohorts were compared in this analysis. The benchmarked usual care cohort (2012-2014, 122 patients) was compared with the CRT-CPW cohort (2015-2017, 115 patients). The primary outcomes were process-related: number of physician consultations, nurse consultations, length of stay (LOS) at implantation and total hospitalisation days during 1-year follow-up, and referral-to-treatment time. Clinical outcomes were assessed to adress non-inferiority of quality of care. RESULTS: Patients in the CRT-CPW cohort consulted nurses and technicians significantly more often than patients in the usual care cohort (2.4±1.5 vs 1.7±2.0, p<0.0001 and 4.3±2.5 vs 3.7±1.5, p=0.063, respectively). Patients with CRT-CPW consulted physicians significantly less often (1.7±1.4 vs 2.6±2.1, p<0.001). Referral to treatment time was significantly reduced in the CRT-CPW group (23.6±18.4 vs 37.0±26.3 days, p=0.002). LOS at implantation and total hospitalisation days were significantly reduced in the CRT-CPW group (1.1±1.2 vs 1.5±0.7 days, p<0.0001 and 2.4±4.8 vs 4.8±9.3, p<0.0001, respectively). Clinical outcome analyses showed no significant difference in 12-month all-cause mortality and heart failure hospitalisations. CONCLUSION: The introduction of a novel CRT-CPW resulted in a successful transition of physician-led to nurse-led care, with a significantly reduced resource use and equal clinical outcomes. Future evaluations will focus on impact on outcomes versus costs, to evaluate cost-effectiveness of the CRT-CPW.

Polygenic Score for ß-Blocker Survival Benefit in European Ancestry Patients With Reduced Ejection Fraction Heart Failure.

BACKGROUND: ß-Blockers (BBs) are mainstay therapy for heart failure with reduced ejection fraction. However, individual patient responses to BB vary, which may be partially due to genetic variation. The goal of this study was to derive and validate the first polygenic response predictor (PRP) for BB survival benefit in heart failure with reduced ejection fraction patients. METHODS: Derivation and validation analyses were performed in n=1436 total HF patients of European descent and with ejection fraction <50%. The PRP was derived in a random subset of the Henry Ford Heart Failure Pharmacogenomic Registry (n=248) and then validated in a meta-analysis of the remaining patients from Henry Ford Heart Failure Pharmacogenomic Registry (n=247), the TIME-CHF (Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure; n=431), and HF-ACTION trial (Heart Failure: a Controlled Trial Investigating Outcomes of Exercise Training; n=510). The PRP was constructed from a genome-wide analysis of BB×genotype interaction predicting time to all-cause mortality, adjusted for Meta-Analysis Global Group in Chronic Heart Failure score, genotype, level of BB exposure, and BB propensity score. RESULTS: Five-fold cross-validation summaries out to 1000 single-nucleotide polymorphisms identified optimal prediction with a 44 single-nucleotide polymorphism score and cutoff at the 30th percentile. In validation testing (n=1188), greater BB exposure was associated with reduced all-cause mortality in patients with low PRP score (n=251; hazard ratio, 0.19 [95% CI, 0.04-0.51]; P=0.0075) but not high PRP score (n=937; hazard ratio, 0.84 [95% CI, 0.53-1.3]; P=0.448)-a difference that was statistically significant (P interaction, 0.0235). Results were consistent regardless of atrial fibrillation, ejection fraction (≤40% versus 41%-50%), or when examining cardiovascular death. CONCLUSIONS: Among patients of European ancestry with heart failure with reduced ejection fraction, a PRP distinguished patients who derived substantial survival benefit from BB exposure from a larger group that did not. Additional work is needed to prospectively test clinical utility and to develop PRPs for other population groups and other medications.

Contemporary use of devices in chronic heart failure in the Netherlands.

AIMS: Despite previous surveys regarding device implantation rates in heart failure (HF), insight into the real-world management with devices is scarce. Therefore, we investigated device implantation rates in HF with reduced left ventricular ejection fraction (LVEF) in 34 Dutch centres. METHODS AND RESULTS: A cross-sectional outpatient registry was conducted in 6666 patients with LVEF < 50% and with information about device implantation available [74 (66-81) years of age; 64% male]. Patients were classified into conventional pacemakers (PM, n = 562), implantable cardioverter defibrillators (ICD, n = 1165), and cardiac resynchronization therapy with defibrillator function (CRT-D, n = 885) or pacemaker function only (CRT-P, n = 248), or no device (n = 3806). Centres were divided into ICD-implanting and CRT-implanting and referral centres. Overall, 17.5% had an ICD, 13.3% CRT-D, 3.7% CRT-P, and 8.4% PM. Of those with LVEF ≤ 30%, 42.5% had ICD or CRT-D therapy. A large variation in implantation rates existed between centres: 3-51% for ICD therapy, 0.3-44% for CRT-D therapy, 0-11% for CRT-P therapy, and 0-25% PM therapy. Implantation centres showed higher implantation rates of ICD, CRT-D, and CRT-P compared with referral centres [36% vs. 25% for defibrillators (ICD or CRT-D) and 17% vs. 9% for CRT devices (CRT-D or CRT-P), respectively, P < 0.001], independently of other factors. A large number of clinical factors were predictive for device usage. Among other, LVEF < 40% and male sex were independent positive predictors for ICD/CRT-D use [odds ratio (OR) = 3.33, P < 0.001; OR = 1.87, P = 0.019, respectively]. Older age was independently associated with less ICD/CRT-D (OR = 0.96 per year, P < 0.001) and more CRT-P/PM use (OR = 1.03 per year, P = 0.006). CONCLUSIONS: In this large Dutch HF registry, less than half of the patients with reduced LVEF received an ICD or CRT, even if LVEF was ≤30%, and a large variation between centres existed. Patients from implantation centres had more often ICD or CRT. More uniformity regarding guideline-based use of device therapy in clinical practice is needed.

Pre-clinical diabetic cardiomyopathy: prevalence, screening, and outcome.

AIMS: Diabetic cardiomyopathy, characterized by left ventricular (LV) dysfunction and LV hypertrophy independent of myocardial ischaemia and hypertension, could contribute to the increased life-time risk of congestive heart failure seen in patients with diabetes. We assessed prospectively the prevalence, effectiveness of screening methods [brain natriuretic peptide (BNP) and C-reactive protein in combination with clinical parameters], and outcome of pre-clinical diabetic cardiomyopathy. METHODS AND RESULTS: We studied 100 adults (mean age 57.4 +/- 10.2 years, 44% females) with diabetes and no previous evidence of structural heart disease. By echocardiography, diabetic cardiomyopathy was present in 48% of patients. Screening with combinations of clinical parameters (gender, systolic blood pressure, and body mass index), but not BNP, resulted in high negative predictive values for diabetic cardiomyopathy. During a mean follow-up of 48.5 +/- 9.0 months, in the groups with and without diabetic cardiomyopathy, 12.5 vs. 3.9% (P < 0.2) patients died or experienced cardiovascular events and 37.5 vs. 9.6% (P < 0.002) had a deterioration in NYHA functional class. Overall event-free survival was 54 vs. 87% (P = 0.001) in the groups with and without diabetic cardiomyopathy, respectively. Brain natriuretic peptide was an independent predictor of events [odds ratio 3.5 (1.1-10.9), P = 0.02]. CONCLUSION: Pre-clinical diabetic cardiomyopathy is common. Screening with combinations of simple clinical parameters, but not BNP, can be useful to identify those patients needing further evaluation. Patients with pre-clinical diabetic cardiomyopathy are at increased risk for functional deterioration and possibly cardiovascular events during follow-up. Brain natriuretic peptide was shown to be an independent predictor of future events.

Mitral annuloplasty in patients with ischemic versus dilated cardiomyopathy.

OBJECTIVE: Mitral regurgitation is a frequent finding in patients with end-stage cardiomyopathy predicting poor survival. Conventional treatment consists medical treatment or cardiac transplantation. However, despite severely decreased left ventricular function, mitral annuloplasty may improve survival and reduce the need for allografts. METHODS: From January 1996 to July 2002, 121 patients with severe end-stage dilated (DCM) or ischemic cardiomyopathy (ICM), mitral regurgitation > or =2, and left ventricular ejection fraction < or =30% underwent mitral valve annuloplasty using a flexible posterior ring. DCM was diagnosed in 30 patients (25%), whereas ICM was found in 91 patients (75%). Concomitant tricuspid valve repair was performed in 14 (46.6%) patients in the DCM, and in 11 (12%) in the ICM group (P=0.0001), coronary artery bypass grafting in three (10%) in the DCM, and in 78 patients (86%) in the ICM group (P<0.00001). The mean follow-up time was 567+/-74 days in the DCM and 793+/-63 days in the ICM group (ns). RESULTS: Early mortality was 6.6% (8/121), and was equal for both groups. Improvement in NYHA class (DCM 3.3+0.1-1.8+/-0.16; ICM from 3.2+0.04 to 1.7+/-0.07) were equal between groups after 1 year. Seventeen (15%) late deaths occurred during the follow-up period. There was no difference in the 2-year actuarial survival between groups (DCM/ICM 0.93/0.85). Risk factors for mitral reconstruction failure, defined as regurgitation > or =2 after 1 year, were preoperative NYHA IV in the DCM group (P=0.03), a preoperative posterior infarction (P=0.025), decreased left ventricular function (P=0.043), larger ring size (P=0.026) and preoperative renal failure (P=0.05) in the ICM group. Risk factors for death were larger ring size (P=0.02) and an increased LVEDD (P=0.027) in the DCM group and the postoperative use of IABP (P=0.002), renal failure (P=0.001), and a larger preoperative LVESD (P=0.035) in the ICM group. CONCLUSION: Mitral reconstruction with a posterior annuloplasty using a flexible ring is effective in patients with severely depressed left ventricle function and has an acceptable operative mortality. Mid-term results are superior to medical treatment alone and comparable to cardiac transplantation.

Technical details with the use of cryopreserved arterial allografts for aortic infection: influence on early and midterm mortality.

PURPOSE: In situ repair with cryopreserved vascular allografts improves the results in the surgical treatment of aortic infection. This study evaluated the technical pitfalls with the use of allografts that influence early and midterm mortality. METHODS: Between 1990 and 1999, 49 patients, 21 (43%) with a mycotic aneurysm and 28 (57%) with a prosthetic graft infection of the thoracic and abdominal aorta including pelvic and groin vessels, underwent in situ repair with cryopreserved arterial allografts. Seventeen patients (35%) had aortobronchial, aortoesophageal, or aortoenteric fistulas. RESULTS: Allograft-related technical problems occurred in eight patients (16%) in this series, and they included: intraoperative rupture caused by allograft friability; allograftenteric fistula from ligated allograft side branches rupturing 8, 18, and 48 months after implantation; anastomotic failure caused by inappropriate mechanical stress; anastomotic stricture after partial replacement of infected prosthetic grafts; allograft failure caused by inappropriate wound drainage; and recurrence of infection after inappropriate duration of antifungal treatment. Seven of the eight technical problems (87%) occurred in the first 10 patients (80%) in this series. There was one technical failure in the remaining 39 patients (2.6%; P =.0002) because of various technical adaptations, such as critical selection of allografts, use of allograft strips supporting large anastomoses, sealing with antibiotic-impregnated fibrin glue, and change in technique of allograft side-branch ligature. The 30-day mortality rate was 6% for the whole series; however, it was 2.6% for last 39 patients, with no recurrence of infection or allograft-related late death. CONCLUSIONS: In situ repair with cryopreserved arterial allografts achieves excellent early and late results in the treatment of aortic infection. However, distinct allograft-related technical problems had to be overcome to improve the outcome of patients with major vascular infections.