Long-Term Results of Patch Repair in Destructive Valve Endocarditis.

OBJECTIVES: Treatment of destructive endocarditis with abscess formation is a surgical challenge and associated with significant morbidity and mortality. A root replacement is often performed in case of an annular abscess. This retrospective study was designed to assess the long-term outcome of extensive debridement and patch reconstruction as an alternative approach. METHODS: Between November 2007 and November 2016, a selected group of 79 patients (29.6% of all surgical endocarditis cases) with native valve endocarditis (NVE, 53.2%) or prosthetic valve endocarditis (PVE, 46.8%) valve endocarditis underwent surgical therapy with extensive annular debridement and patch reconstruction. Their postoperative course, freedom from recurrent endocarditis, and survival at 1, 5, and 7 years were evaluated. RESULTS: About two-thirds of patients were in a stable condition, one-third of patients were in a critical state. The median logistic EuroSCORE I was 17%. Infected tissue was removed, and defect closure was performed, either with autologous pericardium for small defects, or with bovine pericardium for larger defects. Overall, in-hospital mortality was 11.3% (NVE: 9.7%, PVE: 13.2%; p = 0.412). In single valve endocarditis survival at 1, 5, and 7 years was 81, 72, 72%, respectively for NVE, and 80, 57, 57%, respectively for PVE (p = 0.589), whereas in multiple valve endocarditis survival at 1, 5, and 7 years was 82, 82, 82% for NVE, and 61, 61, and 31%, respectively for PVE (p = 0.132). Confirmed late reinfection was very low. CONCLUSION: Surgical treatment of destructive endocarditis with abscess formation using patch repair techniques offers acceptable early and long-term results. The relapse rate was low. PVE and involvement of multiple valves were associated with worse outcomes.

Enhanced CaMKII-Dependent Late INa Induces Atrial Proarrhythmic Activity in Patients With Sleep-Disordered Breathing.

RATIONALE: Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased CaMKII (Ca/calmodulin-dependent protein kinase II) activity has been previously implicated in atrial arrhythmogenesis. OBJECTIVE: We hypothesized that CaMKII-dependent dysregulation of Na current (INa) may contribute to atrial proarrhythmic activity in patients with SDB. METHODS AND RESULTS: We prospectively enrolled 113 patients undergoing elective coronary artery bypass grafting for cross-sectional study and collected right atrial appendage biopsies. The presence of SDB (defined as apnea-hypopnea index ≥15/h) was assessed with a portable SDB monitor the night before surgery. Compared with 56 patients without SDB, patients with SDB (57) showed a significantly increased level of activated CaMKII. Patch clamp was used to measure INa. There was a significantly enhanced late INa, but reduced peak INa due to enhanced steady-state inactivation in atrial myocytes of patients with SDB consistent with significantly increased CaMKII-dependent cardiac Na channel phosphorylation (NaV1.5, at serine 571, Western blotting). These gating changes could be fully reversed by acute CaMKII inhibition (AIP [autocamtide-2 related inhibitory peptide]). As a consequence, we observed significantly more cellular afterdepolarizations and more severe premature atrial contractions in atrial trabeculae of patients with SDB, which could be blocked by either AIP or KN93 (N-[2-[[[(E)-3-(4-chlorophenyl)prop-2-enyl]-methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide). In multivariable linear regression models incorporating age, sex, body mass index, existing atrial fibrillation, existing heart failure, diabetes mellitus, and creatinine levels, apnea-hypopnea index was independently associated with increased CaMKII activity, enhanced late INa and correlated with premature atrial contraction severity. CONCLUSIONS: In atrial myocardium of patients with SDB, increased CaMKII-dependent phosphorylation of NaV1.5 results in dysregulation of INa with proarrhythmic activity that was independent from preexisting comorbidities. Inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02877745. Visual Overview: An online visual overview is available for this article.

Diagnostic value of FDG PET/CT imaging in patients with surgically managed infective endocarditis: results of a retrospective analysis at a tertiary center.

BACKGROUND: We assessed the diagnostic value of FDG PET/CT in a real-world cohort of patients with surgically managed infective endocarditis (IE). METHODS: We performed a retrospective analysis of all patients hospitalized in a tertiary IE referral medical center from January 2014 to October 2018 fulfilling the following criteria: ICD-10 code for IE and OPS code for both, heart surgery and FDG PET/CT. RESULTS: Final analysis included 29 patients, whereof 28 patients had surgically proven IE. FDG PET/CT scan was true-positive in 15 patients (sensitivity (SEN) 56%) and false-negative in 12 patients. Combination of Duke criteria (DC) with FDG PET/CT scan resulted in gain of SEN for all patients with confirmed IE (SEN of DC 79% vs SEN of combination DC and FDG PET/CT 89%), driven by a relevant gain in PVE patients only (SEN of DC 78% vs SEN of combination DC and FDG PET/CT 94%). Interestingly, higher prosthesis age was observed in patients with false-negative scans. CONCLUSIONS: We found a SEN of 56% for FDG PET/CT in a real-world cohort of patients with surgically proven IE which was associated with a 16% gain of IE diagnosis in patients with PVE when combined with DC.

Multi-organ dysfunction syndrome in patients undergoing extracorporeal life support.

BACKGROUND: Multiple organ failure is a common complication in patients undergoing ECLS significantly affecting patient outcomes. Gaining knowledge about the mechanisms of onset, clinical course, risk factors, and potential therapeutic targets is highly desirable. METHODS: Data of 354 patients undergoing ECLS with one-, two, three-, and four organ failures were retrospectively analyzed. Incidence of multiple organ dysfunction (MODS), its impact on survival, risk factors for its occurrence, and the impact of proinflammatory mediators on the occurrence of MODS in patients undergoing ECLS were investigated. RESULTS: The median follow-up was 66 (IQR 6; 820) days. 245 (69.2%) patients could be weaned from ECLS, 30-day survival and 1-year survival were 194 (54.1%) and 157 (44.4%), respectively. The duration of mechanical support was 4 (IQR 2; 7) days in the median. Increasing severity of MODS resulted in significant prolongation of mechanical circulatory support and worsening of the outcome. Liver dysfunction had the strongest impact on patient mortality (OR = 2.5) and survival time (19 vs 367 days). The serum concentration of analyzed interleukins rose significantly with each, additional organ affected by dysfunction (p < 0.001). All analyzed proinflammatory cytokines showed significant predictivity relative to the occurrence of MODS with interleukin 8 serum level prior to ECLS showing the strongest predictive potential for the occurrence of MODS (AUC 0.78). CONCLUSION: MODS represents a frequent complication in patients undergoing ECLS with a significant impact on survival. Proinflammatory cytokines show prognostic capacity regarding the occurrence and severity of multi-organ dysfunction.

25 Years' Experience with Redo Operations in Cardiac Surgery-Third-Time Sternotomy Procedures.

BACKGROUND: Over the years, open heart surgery has become more complex, and especially reoperative surgery, more demanding. The risk of third-time or more sternotomy procedures is unclear. METHODS: We reviewed our institutional experience of 25 years based on two generations of cardiac surgeons in a German university medical center to document frequency, outcome, and complications of the various types of open heart procedures. RESULTS: Overall, we included 104 patients with a mean age of 64 ± 13 years. The EuroSCORE II (European System for Cardiac Operative Risk Evaluation) calculated an average mortality risk of 15.7 ± 15.4%. Subgroup comparison of isolated coronary artery bypass grafting (CABG), aortic valve replacement, and mitral valve replacement procedures did not delineate significantly different risk profiles except for the incidence of acute myocardial infarction, which was present in every second patient (53.3%) scheduled for CABG surgery. The time interval to previous surgery was 4.7 ± 6.3 years on average. Most frequent surgical procedures were valve operations, which were accomplished in 72 patients (69.2%), whereas coronary bypass surgery was performed in 23 patients (22.1%) only. Combined procedures were performed in 27 patients. Complex aortic arch replacement with a frozen elephant trunk procedure was necessary in six patients. Overall, 30-day survival was 81.7%. CONCLUSION: In conclusion, third-time and more sternotomy procedures offer acceptable outcome and should therefore be considered in appropriate patients.

Dantrolene reduces CaMKIIδC-mediated atrial arrhythmias.

AIMS: In atrial fibrillation (AF), an increased diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) mediated by calcium/calmodulin-dependent-protein-kinaseIIδC (CaMKII) can serve as a substrate for arrhythmia induction and persistence. Dantrolene has been shown to stabilize the cardiac ryanodine-receptor. This study investigated the effects of dantrolene on arrhythmogenesis in human and mouse atria with enhanced CaMKII activity. METHODS AND RESULTS: Human atrial cardiomyocytes (CMs) were isolated from patients with AF. To investigate CaMKII-mediated arrhythmogenesis, atrial CMs from mice overexpressing CaMKIIδC (TG) and the respective wildtype (WT) were studied using confocal microscopy (Fluo-4), patch-clamp technique, and in vivo atrial catheter-based burst stimulations. Dantrolene potently reduced Ca2+ spark frequency (CaSpF) and diastolic SR Ca2+ leak in AF CMs. Additional CaMKII inhibition did not further reduce CaSpF or leak compared to dantrolene alone. While the increased SR CaSpF and leak in TG mice were reduced by dantrolene, no effects could be detected in WT. Dantrolene also potently reduced the pathologically enhanced frequency of diastolic SR Ca2+ waves in TG without having effects in WT. As an increased diastolic SR Ca2+ release can induce a depolarizing transient inward current, we could demonstrate that the incidence of afterdepolarizations in TG, but not in WT, mice was significantly diminished in the presence of dantrolene. To translate these findings into an in vivo situation we could show that dantrolene strongly suppressed the inducibility of AF in vivo in TG mice. CONCLUSION: Dantrolene reduces CaMKII-mediated atrial arrhythmogenesis and may therefore constitute an interesting antiarrhythmic drug for treating patients with atrial arrhythmias driven by an enhanced CaMKII activity, such as AF.

The impact of interleukin serum levels on the prognosis of patients undergoing venoarterial extracorporeal membrane oxygenation.

Extracorporeal life support is increasingly used in the treatment of patients presenting with cardiogenic shock or in need of cardiopulmonary resuscitation. Identifying therapeutic targets and factors associated with the prognosis are highly desirable. The present study analyzed the impact of interleukin 6 and 8 on the outcome of patients undergoing venoarterial extracorporeal membrane oxygenation (VA ECMO). Interleukin 6 and 8 serum levels of 329 patients were analyzed prior to, on days 1 and 5 of VA ECMO therapy. Interleukin 6 and 8 serum levels of surviving and nonsurviving patients were compared. At time points with significant differences, receiver operating characteristics and cutoff levels were analyzed to determine the prognostic value of interleukin serum levels. Survival analysis was performed to compare patients above and below cutoff levels. Interleukin 6 serum levels were significantly elevated in nonsurviving patients prior to VA ECMO initiation. Interleukin 6 and 8 serum levels in nonsurviving patients were significantly elevated on day 1 of VA ECMO. Receiver operating characteristics analysis revealed significant prognostic impact of interleukin 6 and 8 on day 1 of VA ECMO (AUC 0.70 and 0.72). Survival analysis comparing patients above and below the cutoff showed a 1-year survival of 32.6% for IL6 and 20.8% for IL8 above, as well as 66.9% for IL6 and 61.9% for IL8 below the cutoff (P < .05). Interleukin 6 and 8 serum levels demonstrated prognostic value early in VA ECMO therapy. The technical applicability of interleukin reduction raises interest in interleukins 6 and 8 as therapeutic targets.

Pericardiectomy for Constrictive Pericarditis: An Institution's 21 Years Experience.

BACKGROUND: The aim of this retrospective study was to evaluate our experience with the surgical pericardiectomy procedure for patients suffering from isolated severe constrictive pericarditis. METHODS: From 1995 to 2016, 39 patients underwent isolated pericardiectomy for constrictive pericarditis. Fifteen patients were excluded because of concomitant surgery. There were 31 male (79.5%) patients and 8 female (20.5%) patients, 28 to 76 years old (mean, 56.6 ± 13.6 years). The underlying etiologies were idiopathic pericarditis (74.5%), infection (10%), rheumatic disorders (8%), status post cardiac surgery (2.5%), tuberculosis (2.5%), and status post mediastinal irradiation (2.5%). RESULTS: Pericardiectomy was performed through midline sternotomy in all cases. Sixteen patients (41%) underwent pericardiectomy electively employing cardiopulmonary bypass with the heart beating, and 23 patients (59%) had surgery without extracorporeal circulation (ECC). The overall 30-day mortality rate was 50% if cardiopulmonary bypass was used (13.8% since 2007). If surgery was performed without a heart-lung machine, mortality was 0%. On-pump patients had a significantly longer intensive care unit (ICU) stay (12 ± 9 vs. 4 ± 4 days, p = 0.013). Likewise, the duration of mechanical ventilation was much longer (171 ± 246 vs. 21 ± 40 hours, p = 0.04). The hospital stay was comparable with 28 ± 10 and 24 ± 18 days (p = 0.21). CONCLUSION: The present study demonstrates that pericardiectomy, without the use of cardiopulmonary bypass as treatment for constrictive pericarditis, is a safe procedure with an excellent outcome in critically ill patients.

Impact of Elevated Donor Troponin I as Predictor of Adverse Outcome in Adult Heart Transplantation: A Single-center Experience.

BACKGROUND: Due to globally increasing donor organ shortage, investigation of previously described risk factors for utilizing marginal donor hearts is needed. The aim of this study was to determine the impact of elevated donor serum troponin I (TnI) levels on outcome after heart transplantation (HTx). METHODS: Between January 1996 and August 2013, 161 patients were reviewed for donor TnI serum levels (>0.3 ng/mL was considered elevated), postoperative outcome parameters, 30-day mortality, and 1-, 3-, and 5-year survival. RESULTS: TnI levels were elevated in 45 (28.0%) donors. Recipients of hearts with elevated TnI had higher incidence of postoperative systolic dysfunction, prolonged inotropic support, prolonged mechanical ventilation, and longer intensive care unit (ICU) stay (p < 0.001). This group had higher 30-day mortality (22.2% vs 8.6%, p = 0.03) and lower 1-, 3-, and 5-year survival (56%, 53%, and 50% versus 82%, 76%, and 69%, p = 0.032). Elevated TnI was the only independent risk factor for 30-day mortality (odds ratio [OR] 3.63, 95% confidence interval [CI] 1.28-10.27, p = 0.015). CONCLUSIONS: Elevated donor TnI serum concentration seems to be a marker for adverse outcome and increased short- and long-term mortality after HTx. Nevertheless, many other perioperative variables and parameters can be associated with outcome.

Existence of circulating anti-endothelial cell antibodies after heart transplantation is associated with post-transplant acute allograft rejection.

Anti-endothelial cell antibodies (AECA) may be involved in the development of heart allograft rejection. Its detection might be a cheap and noninvasive method to identify high-risk patients. An indirect immunofluorescence method on human umbilical vein endothelial cells was used to investigate the presence of AECAs in 260 pre- and post-transplant serum samples sequentially collected from 34 patients within the first year after heart transplantation (HTX). The presence of AECAs before (23.5 %) and early after HTX (14.7 %) was associated with a significantly increased risk of early acute rejection (75 and 60 %, respectively) compared to 33 % in AECA-negative patients (p = 0.049). Moreover, rejections from AECA-positive patients were more severe (p = 0.057) with a significantly increased incidence of multiple (p = 0.025). The mean number of the sum of rejection episodes was significantly higher in AECA-positive patients (p ≤ 0.05). Patients free of AECAs mainly received mycophenolate mofetil as primary immunosuppression (p = 0.067). Nevertheless, the presence of AECAs did not affect long-term outcome and mortality of HTX patients. Despite a low number of patient samples, the detection of AECAs before and early after HTX could be used as a biomarker for an increased risk of early acute rejection in high-risk patients. This easy method might be a valuable tool to support screening procedures to improve individualized immunosuppressive therapy.

Veno-arterial extracorporeal membrane oxygenation support for severe cardiac failure in a pediatric patient with intracranial hemorrhage after spontaneous aneurysmatic rupture.

INTRODUCTION: Extracorporeal life support in adult patients with extended intracranial hemorrhage is controversial. In pediatric patients, it has traditionally been considered a contraindication as systemic anticoagulation may worsen the hemorrhage and neurological outcome. CASE HISTORY: We present a nine-year-old female patient who was admitted with extended intracranial hemorrhage after spontaneous rupture of an aneurysm. On day four after the emergency craniotomy, she required veno-arterial extracorporeal membrane oxygenation for septic shock. Using an adapted anticoagulation protocol aimed at lower activated partial thromboplastin time target values, we did not observe any new bleeding or clotting complications during systemic anticoagulation and the patient had good neurological recovery. CONCLUSION: Extracorporeal life support with low dose systemic anticoagulation can be considered as a treatment option in pediatric patients after craniotomy for intracranial aneurysmatic hemorrhage.

Single-center experience with extracorporeal life support in 103 nonpostcardiotomy patients.

Extracorporeal membrane oxygenation (ECMO) has been successfully used to support patients with cardiac arrest failing to respond to conventional cardiopulmonary resuscitation (CPR). Preimplant factors being indicative for success are unknown up to now. The study describes single center experience with special focus on differences between survivors and nonsurvivors. Between 2002 and 2009, 103 patients were supported within the scope of CPR by means of ECMO. Besides primary diagnosis, duration, and outcome, pH, lactate, mean arterial pressure, aspartate aminotransferase, bilirubin, catecholamine dosage, and oxygenation ratio before ECMO, after 2 h, 1 day, and at explantation were analyzed. One hundred three patients (51.2 ± 16 years, 35 women, 68 men) were analyzed. Primary cardiac failure led to CPR in 54%. Duration of support was 4.8 ± 0.6 days. Twenty-nine (28.1%) patients survived to hospital discharge. On ECMO support, pH, lactate, and mean arterial pressure improved significantly. Catecholamine dosage was significantly reduced after ECMO implantation. Demographic data and primary diagnosis revealed no significant influence on outcome. pH, lactate, creatinine, and bilirubin differed significantly between survivors and nonsurvivors in the course of ECMO support. ECMO support during CPR reliably improves the circulatory and respiratory situation. Considering observed survival critical patient selection is mandatory. Although there are several significant differences between surviving patients and patients with fatal outcome, patient selection turns out to be difficult as clinically relevant factors show only limited predictive value. Future research should focus on better defining a population that may be best of all suited for the use of ECMO support in CPR.

Reduced 30-day mortality in men after elective coronary artery bypass surgery with minimized extracorporeal circulation-a propensity score analysis.

BACKGROUND: Impact of minimized extracorporeal circulation (MECC) for coronary surgery on mortality remains controversial and gender significantly influence outcome. METHODS: We analyzed 3,139 male patients undergoing elective coronary surgery between 01/2004 and 05/2009. Using propensity score matching after binary logistic regression, 1,005 patients (from 1,119 patients) undergoing surgery with MECC could be matched with 1,005 patients (from 2,020 patients) undergoing surgery with conventional extracorporeal circulation (CECC). Primary outcome was 30-day mortality. RESULTS: Unadjusted 30-day mortality was 2.7% in patients with CECC and 0.8% in those with MECC (mean difference -1.9%; p < 0.001). The adjusted mean difference (average treatment effect of the treated) after matching was -1.5% (95% confidence interval (CI) -2.6 to -0.4; p = 0.006). Postoperative hospital stay was shorter in patients operated with minimized systems (adjusted mean difference -0.8 days; 95% CI -1.46 to -0.09; p = 0.03) and incidence of postoperative neurocognitive dysfunction was also lower (adjusted mean difference -1.3%; 95% CI -2.2 to -0.4; p = 0.001). Chest tube drainage (adjusted mean difference +22 mL; 95% CI -47 to 91; p = 0.5) and risk for acute kidney injury, kidney injury and failure according to RIFLE criteria (adjusted mean difference -1.0%; 95% CI -2.5 to 0.6; p = 0.24) proved to be insignificant between both groups. Apart from reduced 30-day mortality, however, average treatment effects for intensive care unit stay, postoperative hospital stay, chest tube drainage and kidney injury did not significantly differ. CONCLUSION: Using propensity score analysis, we observed an association between MECC and reduced 30-day mortality in men, but our results call for further analysis.

Temporary right heart assist: a minimally invasive approach.

A surgical method for the implantation of a mechanical right ventricular assist device which avoids resternotomy/thoracotomy and related complications at the time of explantation is presented. In order to support the failing right heart, a Dacron vascular graft was sewn to the pulmonary artery. For venous drainage, a cannula was inserted into the right atrium via the femoral vein. Explantation of the system, after the right heart resumed its function, was accomplished by retracting and compressing the venous cannula in the groin as well as by retracting the arterial cannula from the Dacron vascular graft followed by suturing without opening the chest. Between 2006 and 2011, this system was used in 12 patients. The median duration of right heart support was 10.5 days. Seven patients were successfully weaned from the system, six patients survived. In all cases, explantation was free of complications. The technique described is a safe method to support the right heart and allows explantation without the risks and complications of reopening the thorax.

A decade of surgical therapy in an all-comer cohort with type A aortic dissection.

BACKGROUND: We reported on a decade of aortic surgery for type A aortic dissection to assess surgical techniques employed and outcomes over time in an all-comer analysis of a mid-size university cardiosurgical center. METHODS: From 2009 to 2018, 283 patients (189 males and 94 females, mean age 62 years, range 30-85 years), who underwent surgical therapy for type A aortic dissection in our institution were included in a retrospective statistical analysis. RESULTS: Among all the patients, 55.5% of them were hemodynamically stable, 10.3% came in intubated. A neurological deficit was present in 18.9% of cases, extremity malperfusion was noted in 17.4%, and abdominal malperfusion detected in 8.2%. The extent of the aortic dissection corresponded to DeBakey type I in 88% of cases, a thoracoabdominal involvement was seen in 64%. In 51.9% of patients, only the ascending aorta replaced, another 40.6% of patients had proximal arch replacement too. A separate stent placement into the descending aorta was achieved in 13.4% of patients, during surgery (5.7%) or thereafter (7.7%). Overall survival to discharge was 79.5%. Most frequent complications were stroke and paralysis (15.2%), but only visceral malperfusion (OR 9.0) and heart failure mandating ECMO therapy (OR 29.5) were associated with significantly increased mortality. CONCLUSIONS: Surgery for type A aortic dissection is still challenging. Along with the refinement of surgical techniques, the indication for the various procedures has moved from a simplified general strategy to a more individualized concept.

Female Patients With Sleep-Disordered Breathing Display More Frequently Heart Failure With Preserved Ejection Fraction.

Objective: Sleep-disordered breathing (SDB) is a widespread disease that is often associated with heart failure (HF) with preserved ejection fraction (HFpEF). HFpEF is more frequent in women than in men, but detailed pathomechanisms remain unclear. We investigated HFpEF in women and men in a high-risk cohort with SDB monitoring. Methods and Results: Three hundred twenty-seven patients (84.4% men) undergoing elective coronary artery bypass grafting were prospectively subjected to SDB monitoring, and an apnea-hypopnea index (AHI) ≥15/h defined SDB. HF was classified according to current guidelines. HFpEF was significantly more frequent in SDB patients compared to those without SDB (28 vs. 17%, P = 0.016). This distribution was driven by an increased frequency of HFpEF in female SDB patients (48% vs. only 25% in male, P = 0.022). In accordance, female patients with SDB exhibited significantly more impaired diastolic left ventricular filling compared to men (echocardiographic E/e'). In contrast to men, in women, minimum oxygen saturation (O2min, measured by polygraphy, R 2 = 0.470, P < 0.001) and time of oxygen saturation <90% (R 2 = 0.165, P = 0.044) were significantly correlated with E/e'. Moreover, the correlation between O2min and E/e' was significantly different in women compared to men (P < 0.001). Intriguingly, this association remained independent of clinical covariates in women [age, body mass index, systolic contractile dysfunction, diabetes mellitus, and glomerular filtration rate (GFR), R 2 = 0.534, P = 0.042, multivariate regression analysis]. Since angiotensin II signaling has been mechanistically linked to HF, we measured protein expression of its cleavage enzyme ACE2 in human right atrial appendage biopsies (Western blot). Intriguingly, we found a significantly decreased ACE2 expression preferentially in women with SDB (2.66 ± 0.42 vs. 4.01 ± 2.47 in men with SDB, P = 0.005). In accordance, left ventricular mass index was significantly increased in women with SDB compared to women without SDB. Conclusion: In patients with SDB, HFpEF and diastolic dysfunction were more frequent in women compared to men. In contrast to men, the severity of SDB was associated with the degree of diastolic dysfunction in women. These insights might help to find sex-specific therapies for patients with sleep-disordered breathing and heart failure. Clinical Trial Registration: Unique identifier: NCT02877745, URL: http://www.clinicaltrials.gov.

Depression and disease severity as correlates of everyday physical activity in heart transplant candidates.

It is unclear to what extent patients awaiting heart transplantation (HTx) engage in physical activities. We examined the everyday physical activity and its associations with depressive symptoms and disease severity in 318 patients newly registered for HTx in the multi-site study 'Waiting for a New Heart' (aged 53.5 +/- 11.4 years, 18% female patients). Participants completed questionnaires assessing depressive symptomatology and physical activity (number of physical activities, caloric expenditure associated with each activity), and estimated the distance they were able to walk without a break. Medical parameters at the time of listing [e.g. peak oxygen consumption (peakVO(2)); the German Transplant Society Score (GTSS)] were provided by Eurotransplant. Almost 50% of patients engaged in activities of daily living (housework, walking), but <10% engaged in regular exercise. All physical activity measures correlated significantly with peakVO(2) (Ps < 0.01). Elevated depression scores were present in 39% of patients. Controlling for confounding variables (e.g. peakVO(2), diastolic blood pressure, GTSS, age), depressive symptomatology accounted for additional variance in all physical activity measures (Ps < 0.05). The association of depressive symptoms with reduced physical activity suggests two important perspectives: attempts to increase physical activity (especially in the area of daily living) might benefit from targeting depression, and increased physical activity might also help to reduce depressive symptoms.

The oral Ca/calmodulin-dependent kinase II inhibitor RA608 improves contractile function and prevents arrhythmias in heart failure.

AIMS: Excessive activation of Ca/calmodulin-dependent kinase II (CaMKII) is of critical importance in heart failure (HF) and atrial fibrillation. Unfortunately, lack of selectivity, specificity, and bioavailability have slowed down development of inhibitors for clinical use. We investigated a novel CaMKIIδ/CaMKIIÉ£-selective, ATP-competitive, orally available CaMKII inhibitor (RA608) on right atrial biopsies of 119 patients undergoing heart surgery. Furthermore, we evaluated its oral efficacy to prevent deterioration of HF in mice after transverse aortic constriction (TAC). METHODS AND RESULTS: In human atrial cardiomyocytes and trabeculae, respectively, RA608 significantly reduced sarcoplasmic reticulum Ca leak, reduced diastolic tension, and increased sarcoplasmic reticulum Ca content. Patch-clamp recordings confirmed the safety of RA608 in human cardiomyocytes. C57BL6/J mice were subjected to TAC, and left ventricular function was monitored by echocardiography. Two weeks after TAC, RA608 was administered by oral gavage for 7 days. Oral RA608 treatment prevented deterioration of ejection fraction. At 3 weeks after TAC, ejection fraction was 46.1 ± 3.7% (RA608) vs. 34.9 ± 2.6% (vehicle), n = 9 vs. n = 12, P < 0.05, ANOVA, which correlated with significantly less CaMKII autophosphorylation at threonine 287. Moreover, a single oral dose significantly reduced inducibility of atrial and ventricular arrhythmias in CaMKIIδ transgenic mice 4 h after administration. Atrial fibrillation was induced in 6/6 mice for vehicle vs. 1/7 for RA608, P < 0.05, 'n - 1' χ2 test. Ventricular tachycardia was induced in 6/7 for vehicle vs. 2/7 for RA608, P < 0.05, 'n - 1' χ2 test. CONCLUSIONS: RA608 is the first orally administrable CaMKII inhibitor with potent efficacy in human myocytes. Moreover, oral administration potently inhibits arrhythmogenesis and attenuates HF development in mice in vivo.

Pumpless extracorporeal interventional lung assist in patients with acute respiratory distress syndrome: a prospective pilot study.

INTRODUCTION: Pumpless interventional lung assist (iLA) is used in patients with acute respiratory distress syndrome (ARDS) aimed at improving extracorporeal gas exchange with a membrane integrated in a passive arteriovenous shunt. In previous studies, feasibility and safety of the iLA system was demonstrated, but no survival benefit was observed. In the present pilot study we tested the hypothesis that timely initiation of iLA using clear algorithms and an improved cannulation technique will positively influence complication rates and management of lung protective ventilation. METHODS: iLA was implemented in 51 patients from multiple aetiologies meeting ARDS-criteria (American-European Consensus) for more than 12 hours. Initiation of iLA followed an algorithm for screening, careful evaluation and insertion technique. Patients with cardiac insufficiency or severe peripheral vascular disease were not considered suitable for iLA. Arterial and venous cannulae were inserted using a new strategy (ultrasound evaluation of vessels by an experienced team, using cannulae of reduced diameter). The incidence of complications and the effects on tidal volumes and inspiratory plateau pressures were primary outcome parameters, while oxygenation improvement and carbon dioxide removal capabilities were secondary study parameters. RESULTS: Initiation of iLA resulted in a marked removal in arterial carbon dioxide allowing a rapid reduction in tidal volume (