Cardiac Development and Factors Influencing the Development of Congenital Heart Defects (CHDs): Part I.

The traditional description of cardiac development involves progression from a cardiac crescent to a linear heart tube, which in the phase of transformation into a mature heart forms a cardiac loop and is divided with the septa into individual cavities. Cardiac morphogenesis involves numerous types of cells originating outside the initial cardiac crescent, including neural crest cells, cells of the second heart field origin, and epicardial progenitor cells. The development of the fetal heart and circulatory system is subject to regulatation by both genetic and environmental processes. The etiology for cases with congenital heart defects (CHDs) is largely unknown, but several genetic anomalies, some maternal illnesses, and prenatal exposures to specific therapeutic and non-therapeutic drugs are generally accepted as risk factors. New techniques for studying heart development have revealed many aspects of cardiac morphogenesis that are important in the development of CHDs, in particular transposition of the great arteries.

Successful ablation of Purkinje ectopy-triggered ventricular fibrillation storm in a patient with orthotopic heart transplantation and severe SARS-CoV-2 pneumonia: a case report.

Background: Catheter ablation is one of the most effective treatment options for patients with drug-refractory, scar-related monomorphic ventricular tachycardia (VT). In selected cases, catheter ablation also plays an important role in treatment of polymorphic VT (PMVT) and/or ventricular fibrillation (VF). Rarely, premature ventricular contractions (PVCs) originating from the Purkinje network can induce PMVT/VF. Ablation and elimination of these PVCs can prevent VF recurrences. Case summary: A 41-year-old patient with a history of orthotopic heart transplantation (HTX) 8 years before admission and newly diagnosed SARS-CoV-2 pneumonia was referred to our centre after experiencing several episodes of drug-refractory VF. An electrophysiological study showed ectopy-triggered VF originating from the anterior and posterior fascicles of the left bundle branch (LBB). Ablation of these PVCs from the LBB led to complete elimination of VF. A subcutaneous implantable cardioverter defibrillator was implanted as secondary prophylaxis. During the observation period of 6 months, no VF recurrence was observed. Conclusion: Identifying and eliminating the trigger (PVCs) can be life-saving and prevent VF in the specific cohort of HTX patients. High-density mapping using multipolar catheters with microelectrodes contributes significantly to our understanding of tachycardia mechanisms.

Pathogenesis and Surgical Treatment of Congenitally Corrected Transposition of the Great Arteries (ccTGA): Part III.

Congenitally corrected transposition of the great arteries (ccTGA) is an infrequent and complex congenital malformation, which accounts for approximately 0.5% of all congenital heart defects. This defect is characterized by both atrioventricular and ventriculoarterial discordance, with the right atrium connected to the morphological left ventricle (LV), ejecting blood into the pulmonary artery, while the left atrium is connected to the morphological right ventricle (RV), ejecting blood into the aorta. Due to this double discordance, the blood flow is physiologically normal. Most patients have coexisting cardiac abnormalities that require further treatment. Untreated natural course is often associated with progressive failure of the systemic right ventricle (RV), tricuspid valve (TV) regurgitation, arrhythmia, and sudden cardiac death, which occurs in approximately 50% of patients below the age of 40. Some patients do not require surgical intervention, but most undergo physiological repair leaving the right ventricle in the systemic position, anatomical surgery which restores the left ventricle as the systemic ventricle, or univentricular palliation. Various types of anatomic repair have been proposed for the correction of double discordance. They combine an atrial switch (Senning or Mustard procedure) with either an arterial switch operation (ASO) as a double-switch operation or, in the cases of relevant left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), intra-ventricular rerouting by a Rastelli procedure. More recently implemented procedures, variations of aortic root translocations such as the Nikaidoh or the half-turned truncal switch/en bloc rotation, improve left ventricular outflow tract (LVOT) geometry and supposedly prevent the recurrence of LVOTO. Anatomic repair for congenitally corrected ccTGA has been shown to enable patients to survive into adulthood.

Pathogenesis and Surgical Treatment of Dextro-Transposition of the Great Arteries (D-TGA): Part II.

Dextro-transposition of the great arteries (D-TGA) is the second most common cyanotic heart disease, accounting for 5-7% of all congenital heart defects (CHDs). It is characterized by ventriculoarterial (VA) connection discordance, atrioventricular (AV) concordance, and a parallel relationship with D-TGA. As a result, the pulmonary and systemic circulations are separated [the morphological right ventricle (RV) is connected to the aorta and the morphological left ventricle (LV) is connected to the pulmonary artery]. This anomaly is included in the group of developmental disorders of embryonic heart conotruncal irregularities, and their pathogenesis is multifactorial. The anomaly's development is influenced by genetic, epigenetic, and environmental factors. It can occur either as an isolated anomaly, or in association with other cardiac defects. The typical concomitant cardiac anomalies that may occur in patients with D-TGA include ventriculoseptal defects, patent ductus arteriosus, left ventricular outflow tract obstruction (LVOTO), mitral and tricuspid valve abnormalities, and coronary artery variations. Correction of the defect during infancy is the preferred treatment for D-TGA. Balloon atrial septostomy (BAS) is necessary prior to the operation. The recommended surgical correction methods include arterial switch operation (ASO) and atrial switch operation (AtrSR), as well as the Rastelli and Nikaidoh procedures. The most common postoperative complications include coronary artery stenosis, neoaortic root dilation, neoaortic insufficiency and neopulmonic stenosis, right ventricular (RV) outflow tract obstruction (RVOTO), left ventricular (LV) dysfunction, arrhythmias, and heart failure. Early diagnosis and treatment of D-TGA is paramount to the prognosis of the patient. Improved surgical techniques have made it possible for patients with D-TGA to survive into adulthood.

Third dose of the BNT162b2 vaccine in cardiothoracic transplant recipients: predictive factors for humoral response.

BACKGROUND: We report the results of a prospective study on the immunogenicity of a 3rd dose of BNT162b2 in thoracic organ recipients with no or minimal response following a two-dose BNT162b2 vaccination scheme. METHODS: A total of 243 transplant recipients received a homologue 3rd dose. Anti-SARS-CoV2-immunoglobulins (IgGs) were monitored immediately before (T1), 4 weeks (T2) as well as 2 and 4 months after the 3rd dose. Neutralizing antibody capacity (NAC) was determined at T2. To reveal predictors for detectable humoral response, patients were divided into a positive response group (n = 129) based on the combined criteria of IgGs and NAC above the defined cut-offs at T2-and a group with negative response (n = 114), with both, IgGs and NAC beyond the cut-offs. RESULTS: The 3rd dose induced a positive humoral response in 53% of patients at T2, 47% were still non-responsive. Sero-positivity was significantly stronger in patients who presented with weak, but detectable IgGs already prior to the booster (T1), when compared to those with no detectable response at T1. Multivariable analysis identified age > 55 years, a period since transplantation < 2 years, a reduced glomerular filtration rate, a triple immunosuppressive regimen, and the use of tacrolimus and of mycophenolate as independent risk factors for lack of humoral response. CONCLUSIONS: Our data indicate that a lack of immunogenicity is linked to the type and extent of maintenance immunosuppression. The necessity of the cumulative immunosuppressive regimen might individually be questioned and possibly be reduced to enhance the chance of an immune response following an additional booster dose.

The Role of Daily Implant-Based Multiparametric Telemonitoring in Patients with a Ventricular Assist Device.

The telemonitoring of heart failure (HF) patients is becoming increasingly important. This study aimed to evaluate the benefit of telemonitoring in end-stage HF patients with a ventricular-assistance device (VAD). A total of 26 HF-patients (66 ± 11 years, 88% male) on VAD therapy with an implantable cardioverter-defibrillator (ICD) or a cardiac resynchronization defibrillator (CRT-D) including telemonitoring function were enrolled. The long-term follow-up data (4.10 ± 2.58 years) were assessed. All the patients (n = 26, 100%) received daily ICD/CRT-D telemonitoring. In most of the patients (73%, n = 19), the telemedical center had to take action for a mean of three times. An acute alert due to sustained ventricular arrhythmias (VAs) occurred in 12 patients (63%) with 50% of them (n = 6) requiring ICD shock delivery. Eight patients (67%) were hospitalized due to symptomatic VAs. In 11 patients (92%), immediate medication adjustments were recommended. Relevant lead issues were revealed in thirteen patients (50%), with six patients (46%) undergoing consecutive lead revisions. Most of the events (83%) were detected within 24 h. Daily telemonitoring significantly reduced the number of in-hospital device controls by 44% (p < 0.01). The telemonitoring ensured that cardiac arrhythmias and device/lead problems were identified early, allowing pre-emptive and prompt interventions. In addition, the telemonitoring significantly reduced the number of in-hospital device controls in this cohort of HF patients.

Acute outcomes of MitraClip therapy for mitral regurgitation in high-surgical-risk patients: emphasis on adverse valve morphology and severe left ventricular dysfunction.

AIMS: We sought to assess the feasibility of catheter-based mitral valve repair using the MitraClip system in high-surgical-risk patients with mitral regurgitation (MR) > or =grade 3+. METHODS AND RESULTS: MitraClip therapy was performed in 51 consecutive patients [73 +/- 10 years; 34 (67%) men] with symptomatic functional [n = 35 (69%)] or organic MR [n = 16 (31%)]. Mean logistic EuroSCORE was 29 +/- 22%; Society of Thoracic Surgeons score was 15 +/- 11. Left ventricular (LV) ejection fraction was 36 +/- 17%. In 35 patients (69%), adverse mitral valve morphology and/or severe LV dysfunction were present. MitraClip implantation was successful in 49 patients (96%). Most patients [n = 34/49 (69%)] were treated with a single clip, whereas 14 patients (29%) received two clips and one patient received three clips. Mean device and fluoroscopy times were 105 +/- 65 min and 44 +/- 28 min, respectively. Procedure-related reduction in MR severity was one grade in 16 patients (31%), two grades in 24 patients (47%), and three grades in 9 patients (18%). Forty-four of the 49 successfully treated patients (90%) showed clinical improvement at discharge [NYHA functional class > or =III in 48 patients (98%) before and 16 patients (33%) after the procedure (P < 0.0001)]. There were no procedure-related major adverse events and no in-hospital mortality. CONCLUSION: Mitral valve repair using the MitraClip system was shown to be feasible in patients at high surgical risk primarily determined by an adverse mitral valve morphology and/or severe LV dysfunction.

Poor humoral and T-cell response to two-dose SARS-CoV-2 messenger RNA vaccine BNT162b2 in cardiothoracic transplant recipients.

AIMS: Immunocompromised patients have been excluded from studies of SARS-CoV-2 messenger RNA vaccines. The immune response to vaccines against other infectious agents has been shown to be blunted in such patients. We aimed to analyse the humoral and cellular response to prime-boost vaccination with the BNT162b2 vaccine (Pfizer-BioNTech) in cardiothoracic transplant recipients. METHODS AND RESULTS: A total of 50 transplant patients [1-3 years post heart (42), lung (7), or heart-lung (1) transplant, mean age 55 ± 10 years] and a control group of 50 healthy staff members were included. Blood samples were analysed 21 days after the prime and the boosting dose, respectively, to quantify anti-SARS-CoV-2 spike protein (S) immunoglobulin titres (tested by Abbott, Euroimmun and RocheElecsys Immunoassays, each) and the functional inhibitory capacity of neutralizing antibodies (Genscript). To test for a specific T-cell response, heparinized whole blood was stimulated with SARS-CoV-2 specific peptides, covering domains of the viral spike, nucleocapsid and membrane protein, and the interferon-γ release was measured (QuantiFERON Monitor ELISA, Qiagen). The vast majority of transplant patients (90%) showed neither a detectable humoral nor a T-cell response three weeks after the completed two-dose BNT162b2 vaccination; these results are in sharp contrast to the robust immunogenicity seen in the control group: 98% exhibited seroconversion after the prime dose already, with a further significant increase of IgG titres after the booster dose (average > tenfold increase), a more than 90% inhibition capability of neutralizing antibodies as well as evidence of a T-cell responsiveness. CONCLUSIONS: The findings of poor immune responses to a two-dose BNT162b2 vaccination in cardiothoracic transplant patients have a significant impact for organ transplant recipients specifically and possibly for immunocompromised patients in general. It urges for a review of future vaccine strategies in these patients.

Catheter ablation for atrial fibrillation in patients with end-stage heart failure and eligibility for heart transplantation.

AIMS: Timely referrals for transplantation and left ventricular assist device (LVAD) play a key role in favourable outcomes in patients with advanced heart failure (HF). The purpose of the Catheter Ablation for atrial fibrillation in patientS with end-sTage heart faiLure and Eligibility for Heart Transplantation (CASTLE-HTx) trial is to test the hypothesis that atrial fibrillation (AF) ablation has beneficial effects on mortality and morbidity during 'waiting time' for heart transplantation (HTx) or to prolong the time span until LVAD implantation. METHODS AND RESULTS: CASTLE-HTx is a randomized evaluation of ablative treatment of AF in patients with severe left ventricular dysfunction who are candidates and eligible for HTx. The primary endpoint is the composite of all-cause mortality, worsening of HF requiring a high urgent transplantation, or LVAD implantation. The secondary study endpoints are all-cause mortality, cardiovascular mortality, cerebrovascular accidents, worsening of HF requiring unplanned hospitalization, AF burden reduction, unplanned hospitalization due to cardiovascular reason, all-cause hospitalization, quality of life, number of delivered implantable cardioverter defibrillator therapies, time to first implantable cardioverter defibrillator therapy, number of device-detected ventricular tachycardia/ventricular fibrillation episodes, left ventricular function, exercise tolerance, and percentage of right ventricular pacing. Ventricular myocardial tissue will be obtained from patients who will undergo LVAD implantation or HTx to assess the effect of catheter ablation on human HF myocardium. CASTLE-HTx will randomize 194 patients over a minimum time period of 2 years. CONCLUSIONS: CASTLE-HTx will determine if AF ablation has beneficial effects on mortality in patients with end-stage HF who are eligible for HTx.

Donor-recipient risk assessment tools in heart transplant recipients: the Bad Oeynhausen experience.

AIMS: Some risk assessment tools have been developed to categorize mortality risk in heart transplant recipients, but it is unclear whether these tools can be used interchangeable in different transplant regions. METHODS AND RESULTS: We performed a retrospective single-centre study in 1049 adult German heart transplant recipients under jurisdiction of Eurotransplant. Univariable and multivariable Cox regression analysis was used to generate a risk scoring system. C-statistics were used to compare our score with a US score and a French score regarding their ability to discriminate between 1 year survivors and non-survivors within our study cohort. Of 38 parameters assessed, seven recipient-specific parameters [age, height, dilated cardiomyopathy (DCM), ischaemic cardiomyopathy (ICM), total bilirubin, extracorporeal membrane oxygenation (ECMO), and biventricular assist device/total artificial heart (BVAD/TAH) implant], one donor-specific parameter (cold ischaemic time), and one recipient-independent and donor-independent other parameter (late transplant era) were statistically significant in predicting 1 year mortality. The initial score was generated by using the regression coefficients from the multivariable analysis as follows: 1.70 * ln age - 4.0 * ln height - 0.9 * diagnosis (= 1 if diagnosis = DCM) - 0.67 * diagnosis (= 1 if diagnosis = ICM) + 0.33 * ln total bilirubin + 1.74 * ln cold ischaemic time + 0.98 * mechanical circulatory support (MCS) implant (= 1 if MCS implant = ECMO) + 0.47 * MCS implant (= 1 of MCS implant = BVAD/TAH) - 0.66 * transplant era (= 1 if transplant era = 2017-2018). The initial score was converted into the Bad Oeynhausen (BO) score as a positive integer variable by means of the following formula: BO score = (initial score + 8) * 3. In patients scoring 2 to <7 points (n = 112), 7 to <11 points (n = 580), 11 to <15 points (n = 339), and 15 to 20 points (n = 18), 1 year survival was 93.1%, 84.2%, 66.9%, and 27.8%, respectively. The c-index of our score was 0.73 [95% confidence interval (CI): 0.69-0.77]. Values were in our cohort for the US and French scores 0.66 (95% CI: 0.62-0.70) and 0.63 (95% CI: 0.59-0.67), respectively. CONCLUSIONS: Data indicate that our score, but also risk assessment tools from other transplant regions, may be used as a reliable support for risk-adjusted organ allocation and potentially help to improve outcomes in heart transplantation. Further developments will have to include as yet unaccounted risk factors for even more reliable predictions.

Non-invasive assessment of central venous pressure in heart failure: a systematic prospective comparison of echocardiography and Swan-Ganz catheter.

Assessing hemodynamics, especially central venous pressure (CVP), is essential in heart failure (HF). Right heart catheterization (RHC) is the gold-standard, but non-invasive methods are also needed. However, the role of 2-dimensional echocardiography (2DE) remains uncertain, and 3-dimensional echocardiography (3DE) is not always available. This study investigated standardized and breathing-corrected assessment of inferior vena cava (IVC) volume using echocardiography (2DE and 3DE) versus CVP determined invasively using RHC. Sixty consecutive HF patients were included (82% male, age 54 ± 11 years, New York Heart Association class 2.23 ± 0.8, ejection fraction 46 ± 18.4%, brain natriuretic peptide 696.93 ± 773.53 pg/mL). All patients underwent Swan-Ganz RHC followed by 2DE and 3DE, and IVC volume assessment. On 2DE, mean IVC size was 18.3 ± 5.5 mm and 13.8 ± 6 mm in the largest deflection and shortest distention, respectively. Mean CVP from RHC was 9.3 ± 5.3 mmHg. Neither 2DE nor 3DE showed acceptable correlation with invasively measured CVP; IVC volume acquisition showed optimal correlation with RHC CVP (0.64; 95% confidence interval 0.46-0.77), with better correlation when mitral valve early diastole E wave and right ventricular end-diastolic diameter were added. Using a CVP cut-point of 10 mmHg, receiver operating characteristic curve showed true positivity (specificity) of 0.90 and sensitivity of 62% for predicting CVP. A validation study confirmed these findings and verified the high predictive value of IVC volume assessment. Neither 2DE nor 3DE alone can reliably mirror CVP, but IVC volume acquisition using echocardiography allows non-invasive and adequate approximation of CVP. Correlation with invasively measured pressure was strongest when CVP is > 10 mmHg.

Noninvasive pulse contour analysis for determination of cardiac output in patients with chronic heart failure.

BACKGROUND: Determination of cardiac output (CO) is essential in diagnosis and management of heart failure (HF). The gold standard to obtain CO is invasive assessment via thermodilution (TD). Noninvasive pulse contour analysis (NPCA) is supposed as a new method of CO determination. However, a validation of this method in HF is pending and performed in the present study. METHODS: Patients with chronic-stable HF and reduced left ventricular ejection fraction (LVEF ≤ 45%; HF-REF) underwent right heart catheterization including TD. NPCA using the CNAP Monitor (V5.2.14, CNSystems Medizintechnik AG) was performed simultaneously. Three standardized TD measurements were compared with simultaneous auto-calibrated NPCA CO measurements. RESULTS: In total, 84 consecutive HF-REF patients were enrolled prospectively in this study. In 4 patients (5%), TD was not successful and for 22 patients (26%, 18 with left ventricular assist device), no NPCA signal could be obtained. For the remaining 58 patients, Bland-Altman analysis revealed a mean bias of + 1.92 L/min (limits of agreement ± 2.28 L/min, percentage error 47.4%) for CO. With decreasing cardiac index, as determined by the gold standard of TD, there was an increasing gap between CO values obtained by TD and NPCA (r = - 0.75, p < 0.001), resulting in a systematic overestimation of CO in more severe HF. TD-CI classified 52 (90%) patients to have a reduced CI (< 2.5 L/min/m2), while NPCA documented a reduced CI in 18 patients (31%) only. CONCLUSIONS: In HF-REF patients, auto-calibrated NPCA systematically overestimates CO with decrease in cardiac function. Therefore, to date, NPCA cannot be recommended in this cohort.

Comparison of low and high initial tacrolimus dosing in primary heart transplant recipients: a prospective European multicenter study.

BACKGROUND: The purpose of this prospective, randomized, open-label, phase II, multicenter study was to optimize the initial oral dose of tacrolimus. METHODS: A total of 113 patients were randomly assigned to initial low-dose (0.075 mg/kg/day, n=55) or high-dose (0.15 mg/kg/day, n=58) oral tacrolimus and followed for 3 months. Target whole-blood trough levels were 10 to 20 ng/mL. Prophylactic use of corticosteroids and azathioprine was identical in both groups, and antibody induction was mandatory. The primary endpoint was the time to and incidence of the initial oral tacrolimus dose adjustment because of toxicity or rejection, or withdrawal before initial dose change. Efficacy was assessed by the occurrence of biopsy-proven rejection (International Society for Heart and Lung Transplantation grade > or =1B). RESULTS: In the primary endpoint, no significant difference was observed between the low- and high-dose groups. After 3 months, there was no difference in freedom from initial oral tacrolimus dose change because of rejection, toxicity, or withdrawal (89.0% vs. 87.6%; not significant [NS]). In both groups, dose adjustments were mainly required to achieve and maintain target blood levels (80.0% vs. 82.8%; NS). Patient survival was 92.7% and 98.3% (NS). There was no significant difference between groups regarding freedom from biopsy-proven acute rejection (57.1% vs. 66.3%; NS). The overall safety profiles indicated a tendency toward better tolerability in the low-dose group. CONCLUSIONS: Although low-dose and high-dose tacrolimus had similar efficacy, low-dose tacrolimus was associated with a more favorable safety profile. Therefore we recommend starting tacrolimus therapy after antibody induction at 0.075 mg/kg and adjust dose according to whole-blood trough levels.

Levosimendan displays anti-inflammatory effects and decreases MPO bioavailability in patients with severe heart failure.

Treatment of decompensated heart failure often includes administration of levosimendan. Myeloperoxidase (MPO) is released during polymorphonuclear neutrophil (PMN) degranulation, and mediates dysregulation of vascular tone in heart failure. We evaluated the effects of levosimendan-treatment on MPO in patients with acute decompensation of chronic heart failure over a one week course. Plasma MPO levels were significantly decreased after levosimendan treatment (from 252.1 ± 31.1 pmol/l at baseline to 215.02 ± 27.96 pmol/l at 6 h, p < 0.05). Ex vivo incubation of whole blood with levosimendan decreased MPO release after PMN-stimulation (8.2 ± 1.4-fold increase at baseline vs. 6.0 ± 1.1-fold increase with levosimendan). MPO levels also significantly correlated with diastolic blood pressure over the time course. In a multivariate linear model, the main contributor to systolic, diastolic and mean blood pressure was level of PMN elastase. MPO contributed only in heparin-treated patients, suggesting a more significant role for endothelial-bound MPO than for circulating MPO or elastase with respect to blood pressure regulation. We here provide the first evidence that levosimendan treatment inhibits MPO release by PMNs in decompensated heart failure patients. This mechanism may regulate endothelial function and vascular tone in heart failure patients.

Antibody response after a single dose of an AS03-adjuvanted split-virion influenza A (H1N1) vaccine in heart transplant recipients.

BACKGROUND: Influenza A (H1N1) has emerged as a considerable threat for recipients of organ transplants. Vaccination against the novel influenza A (H1N1) virus has generally been advocated. There is limited experience with AS03-adjuvanted A/H1N1 pandemic influenza vaccines in immunosuppressed patients. METHODS: We conducted an observational, nonrandomized single-center study to assess antibody response and vaccine-related adverse effects in 47 heart transplant recipients (44 men; age, 56±13 years). The AS03-adjuvanted, inactivated split-virion A/California/7/2009 H1N1v pandemic vaccine was administered. Antibody titers were measured using hemagglutination inhibition; immunoglobulin G (IgG) response was assessed using a new pandemic influenza A IgG enzyme-linked immunosorbent assay (ELISA) test kit and compared with hemagglutination-inhibition titers. Adverse effects of vaccination were assessed by a questionnaire. RESULTS: Postvaccination antibody titers of greater than or equal to 1:40 were found in only 15 patients, corresponding to a seroprotection rate of 32% (95% confidence interval, 19%-47%). Sensitivity, specificity, positive predictive value, and negative predictive value of ELISA testing were 80.0%, 68.8%, 54.5%, and 88.0%, respectively. Age, time posttransplantation, and immunosuppressive regimen did not impact antibody response. Vaccination was well tolerated. CONCLUSIONS: Single-dose administration of an AS03-adjuvanted vaccine against the novel influenza A (H1N1) virus did not elicit seroprotective antibody concentrations in a substantial proportion of heart transplant recipients; the new pandemic influenza A IgG ELISA test kit proved to be of limited clinical use.

Echocardiographic and clinical outcomes of MitraClip therapy in patients not amenable to surgery.

OBJECTIVES: The aim of this study was to assess the outcomes of patients at prohibitive surgical risk undergoing MitraClip therapy (Abbott Vascular, Redwood City, California) for severe mitral regurgitation (MR). BACKGROUND: The safety of percutaneous mitral valve repair has been documented. However, midterm development of mitral valve function, ventricular remodeling, and clinical outcomes in patients not amenable to surgery are unknown. METHODS: A total of 104 consecutive patients (mean age 74 ± 9 years; 64 men; 49 and 54 with MR 3+ and 4+, respectively; 69 with functional MR; 59 and 45 in New York Heart Association classes III and IV, respectively) were followed for a median of 359 days. RESULTS: Device success was achieved in 96 patients (92%). In patients with successful index procedures, MR grade ≤2+ was present at follow-up in 82.5%, left ventricular end-diastolic and -systolic volumes were reduced, and forward stroke volumes were significantly increased. Improvements in New York Heart Association functional class were observed in 80% of patients, with 69% in class I or II; 75% improved in the 6-min walk test; and 74% reported improvements in quality of life. One-year estimates of mortality and rehospitalization were 22% and 31%, respectively. Forward stroke volume at discharge emerged as a predictor of event-free survival. CONCLUSIONS: MitraClip therapy improves clinical and echocardiographic outcomes at 1 year in about three-quarters of critically ill, elderly patients with moderate to severe MR not amenable to surgery.

[Atrial fibrillation in heart failure]. / Vorhofflimmern bei Herzinsuffizienz.

BACKGROUND: Atrial fibrillation is a common arrhythmia in patients with congestive heart failure caused by left ventricular dysfunction and is associated with significant morbidity and possibly increased mortality rates. It occurs with increasing frequency as the severity of heart failure increases. TREATMENT: As therapeutic options, two basic strategies are available: rhythm control with or without pharmacological manipulation to increase the chance of successful cardioversion and to maintain sinus rhythm, and rate control with anticoagulation. So far, a clear benefit of one of these two strategies over the other has not been demonstrated for patients with atrial fibrillation generally, nor have there been convincing data for the subgroup of heart failure patients. Traditionally, digoxin has been used in patients with heart failure and atrial fibrillation; however, it has no proven potential to restore sinus rhythm and is slow and not very effective in rate control requiring the addition of another rate-limiting agent, preferably a beta-blocker or calcium antagonist. Amiodarone has been evaluated in numerous clinical trials in patients with heart failure and appears to be safe and effective in terms of conversion to sinus rhythm, maintenance of sinus rhythm as well as control of ventricular rate. Dofetilide may be another option in patients with atrial fibrillation and heart failure, although a direct comparison with amiodarone is lacking. The problem with all antiarrhythmic drugs specifically in patients with heart failure is their toxicity. Because of their proarrhythmic effects, Class I antiarrhythmics are contraindicated in patients with heart failure. Torsades de pointes is the most serious adverse effect of sotalol and dofetilide. Amiodaron has less proarrhythmic risk but has numerous non-cardiac toxicities that require frequent monitoring. CONCLUSION: Overall, due to a low efficacy rate and high proarrhythmic risks, an ideal antiarrhythmic agent for patients with atrial fibrillation and heart failure does not exist, and drug selection should be highly individualized. In patients with chronic atrial fibrillation and heart failure, anticoagulation with warfarin for prevention of thromboembolic events is mandatory.

Reduction of cyclosporine after introduction of mycophenolate mofetil improves chronic renal dysfunction in heart transplant recipients--the IMPROVED multi-centre study.

AIMS: This comparative prospective multi-centre study evaluated efficacy and safety of cyclosporine A downtitration in heart transplant recipients with chronic renal dysfunction potentially attributable to cyclosporine (n=161). METHODS: In the intervention arm (n=109, recruited from 9 centres), mycophenolate mofetil was introduced de novo or substituting azathioprine, followed by cyclosporine reduction (target trough levels 2-4 microg/ml and 50 ng/ml, respectively). In controls (n=52, recruited from 1 centre), immunosuppression remained unchanged. Renal function was recorded twelve, six, and three months before, and throughout the eight-month study period. RESULTS: At study entry, cyclosporine trough levels and renal function parameters were comparable. At study end, mean+/-SD cyclosporine in the intervention arm was 57+/-24 vs. 116+/-36 ng/ml in controls. During the study, creatinine decreased by 23.3+/-50.7 micromol/l (P<0.0001) in the intervention arm but increased by 7.3+/-46.9 micromol/l (P=0.992) in controls (P=0.0001 for comparison between groups). A creatinine reduction of at least 20% was found in 35% of subjects of the intervention arm but only in 4% in the control arm (P<0.0001 for comparison between groups). Improvement in renal function was not weakened after adjustment for baseline characteristics in multiple regression analysis. Renal function improved in strata of creatinine entry values from 150 to 310 micromol/l, regardless of the presence of diabetes. Myocardial biopsies at target levels for cyclosporine and mycophenolate mofetil showed three reversible subclinical rejection episodes. CONCLUSIONS: Cyclosporine downtitration improved renal dysfunction in diabetic and non-diabetic heart transplant recipients across a wide range of creatinine levels. The long-term benefit of this strategy deserves further study.