Effects of MitraClip on cognitive and psychological function in heart failure patients: the sicker the better

Purpose: Cognitive impairment and reduced quality of life is a common condition in patients with heart failure (HF). Percutaneous mitral valve repair using (PMVR) MitraClip (MC) has emerged as a promising interventional tool, reducing all-cause mortality and hospitalization as well as increasing cognitive functioning and quality of life. However, the benefit of HF patients with severely depressed cognitive functioning remains unknown. Methods: We assessed cognitive functioning (figural memory—FGT, executive function—TOL, TMT B), psychosocial functioning (depression—PHQ-9, quality of life—SF36), and clinical parameters (echocardiography, 6-min walk test distance, and cardiac biomarkers) 1 day before (t0) and 6 weeks after (t1) MC intervention in HF patients (n = 40). First, paired sample t tests were conducted to uncover improvements in cognitive functioning post-MC intervention. Second, the COGBAT Norm-sample, a representative age-matched healthy sample, was used to compare participants’ individual scores. Third, bivariate linear regressions were calculated for all key predictors of the detected improvements in cognitive functioning post-MC intervention (t1–t0). Results: Following the MC intervention, we found significant improvements in figural memory, executive functioning, and psychosocial functioning. Most of the patients with depressed executive functioning before the MC intervention showed post-intervention test scores within the normal range (> 50th percentile; t0 22.5% vs. t1 60%) as compared to the normative COGBAT sample. Regression analyses revealed that lower baseline scores in planning ability before the MC intervention (t0) were associated with greater planning ability (TOL; B = − 0.78, 95% CI − 1.04 to − 0.53), figural memory (FGT; B = − 0.26, 95% CI − 0.44 to − 0.07), and cognitive flexibility (TMT B; B = − 0.36, 95% CI − 0.50 to − 0.23) improvement post-MC intervention (t1–t0). Psychosocial functioning and age were not associated with these improvements. Conclusions: Patients with depressed executive functioning showed the greatest benefit from the MC intervention regarding cognitive functioning. Age and psychological functioning seem less important for cognitive performance improvements post-MC intervention. Hence, severely depressed cognitive functioning in patients is not a contraindication for PMVR using MitraClip

CaMKII activation participates in doxorubicin cardiotoxicity and is attenuated by moderate GRP78 overexpression.

The clinical use of the chemotherapeutic doxorubicin (Dox) is limited by cardiotoxic side-effects. One of the early Dox effects is induction of a sarcoplasmic reticulum (SR) Ca2+ leak. The chaperone Glucose regulated protein 78 (GRP78) is important for Ca2+ homeostasis in the endoplasmic reticulum (ER)-the organelle corresponding to the SR in non-cardiomyocytes-and has been shown to convey resistance to Dox in certain tumors. Our aim was to investigate the effect of cardiac GRP78 gene transfer on Ca2+ dependent signaling, cell death, cardiac function and survival in clinically relevant in vitro and in vivo models for Dox cardiotoxicity.By using neonatal cardiomyocytes we could demonstrate that Dox induced Ca2+ dependent Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activation is one of the factors involved in Dox cardiotoxicity by promoting apoptosis. Furthermore, we found that adeno-associated virus (AAV) mediated GRP78 overexpression partly protects neonatal cardiomyocytes from Dox induced cell death by modulating Ca2+ dependent pathways like the activation of CaMKII, phospholamban (PLN) and p53 accumulation. Most importantly, cardiac GRP78 gene therapy in mice treated with Dox revealed improved diastolic function (dP/dtmin) and survival after Dox treatment. In conclusion, our results demonstrate for the first time that Ca2+ dependent CaMKII activation fosters Dox cardiomyopathy and provide additional insight into possible mechanisms by which GRP78 overexpression protects cardiomyocytes from Doxorubicin toxicity

Successful support of biventricular heart failure patients by new EXCOR® Adult pumps with bileaflet valves: a prospective study

AIMS The Berlin Heart EXCORAdult biventricular assist device (BiVAD) is an approved mechanical circulatory support for patients with end-stage biventricular heart failure. In this prospective post-market clinical follow-up study, we present the first clinical experience of the new EXCORAdult pump with bileaflet (BL) valves in Europe. METHODS AND RESULTS After CE-mark approval in August 2014, a total of 12 patients were enrolled with a mean age of 44 years ± 11 (range 21-58 years). The majority of patients (n = 11) were in INTERMACS level 1 or 2. Eight patients had a median pre-operative extracorporeal life support (ECLS) of 6 days (range 1-37 days). Primary end point was survival, either to heart transplantation (HTx), recovery or alive at 12 months on device, whichever occurred first. Secondary end point was the number of adverse events throughout EXCORBiVAD support. Median support time up to last follow-up on EXCORBiVAD device was 248 days (range 57-381 days) and patient survival at 1 year was 92%. Half of the EXCORBiVAD patients (n = 6) were transplanted and five patients were still on support at 1 year post-implantation. Complications during EXCORBiVAD support were thoracic bleeding, exit site infection and ischemic cerebrovascular incidents in three cases, respectively. CONCLUSION The new EXCORAdult pump with BL provides pulsatile high cardiac output with excellent outcome and successful bridging to HTx, particularly in critically ill patients with INTERMACS level 1 or 2 at the time of implantation

Prognostic relevance of hemodialysis for short-term survival in patients after LVAD implantation

End-stage heart failure (HF) is associated with renal failure (RF). This study aimed to determine the prognostic influence of RF and post-operative hemodialysis on short-term survival following left ventricular assist device (LVAD) implantation. This retrospective study includes 68 patients undergoing LVAD treatment. Kidney function was recorded prior to LVAD implantation, immediately afterwards and after 30 days, noting the need for hemodialysis. Median pre-operative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) classification was 3.47 +/- 1.08. 30 days after implantation there was a significant improvement of estimated glomerular filtration rate (eGFR) and reduction of blood urea nitrogen (BUN). Of pre-operative RF parameters, BUN was associated with increased mortality and need for early post-operative hemodialysis. Post-operative hemodialysis was associated with significantly lower short-term survival, while pre-operative hemodialysis did not impact mortality. Post-operative acute kidney injury (AKI) requiring hemodialysis can be regarded as a strong negative prognostic marker for short-term survival. The absence of a clear correlation between most routine RF parameters and survival or the need for early post-operative hemodialysis calls into question the predictive value of pre-operative RE. The negative association of only post-operative hemodialysis on short-term survival emphasises the impact of the occurrence of AKI

Myocardial Ablation of G Protein-Coupled Receptor Kinase 2 (GRK2) Decreases Ischemia/Reperfusion Injury through an Anti-Intrinsic Apoptotic Pathway

Studies from our lab have shown that decreasing myocardial G protein-coupled receptor kinase 2 (GRK2) activity and expression can prevent heart failure progression after myocardial infarction. Since GRK2 appears to also act as a pro-death kinase in myocytes, we investigated the effect of cardiomyocyte-specific GRK2 ablation on the acute response to cardiac ischemia/reperfusion (I/R) injury. To do this we utilized two independent lines of GRK2 knockout (KO) mice where the GRK2 gene was deleted in only cardiomyocytes either constitutively at birth or in an inducible manner that occurred in adult mice prior to I/R. These GRK2 KO mice and appropriate control mice were subjected to a sham procedure or 30 min of myocardial ischemia via coronary artery ligation followed by 24 hrs reperfusion. Echocardiography and hemodynamic measurements showed significantly improved post-I/R cardiac function in both GRK2 KO lines, which correlated with smaller infarct sizes in GRK2 KO mice compared to controls. Moreover, there was significantly less TUNEL positive myocytes, less caspase-3, and -9 but not caspase-8 activities in GRK2 KO mice compared to control mice after I/R injury. Of note, we found that lowering cardiac GRK2 expression was associated with significantly lower cytosolic cytochrome C levels in both lines of GRK2 KO mice after I/R compared to corresponding control animals. Mechanistically, the anti-apoptotic effects of lowering GRK2 expression were accompanied by increased levels of Bcl-2, Bcl-xl, and increased activation of Akt after I/R injury. These findings were reproduced in vitro in cultured cardiomyocytes and GRK2 mRNA silencing. Therefore, lowering GRK2 expression in cardiomyocytes limits I/R-induced injury and improves post-ischemia recovery by decreasing myocyte apoptosis at least partially via Akt/Bcl-2 mediated mitochondrial protection and implicates mitochondrial-dependent actions, solidifying GRK2 as a pro-death kinase in the heart

Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction

G-protein-coupled receptor kinase 2 (GRK2) is a primary regulator of β-adrenergic signaling in the heart. G-protein-coupled receptor kinase 2 ablation impedes heart failure development, but elucidation of the cellular mechanisms has not been achieved, and such elucidation is the aim of this study

G protein–coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure

Myocardial G protein-coupled receptor kinase 2 (GRK2) is a critical regulator of cardiac β-adrenergic receptor (βAR) signaling and cardiac function. Its upregulation in heart failure (HF) may further depress cardiac function and contribute to mortality in this syndrome. Preventing GRK2 translocation to activated βAR with a GRK2-derived peptide that binds G(βγ) (βARKct) has benefited some models of HF, but the precise mechanism is uncertain, as GRK2 is still present and βARKct has other potential effects. We generated mice in which cardiac myocyte GRK2 expression was normal during embryonic development, but was ablated after birth (αMHC-Cre × GRK2 fl/fl), or only after administration of tamoxifen (αMHC-MerCreMer×GRK2 fl/fl) and examined the consequences of GRK2 ablation before and after surgical coronary artery ligation on cardiac adaptation after myocardial infarction. Absence of GRK2 prior to coronary artery ligation prevented maladaptive post-infarction remodeling and preserved βAR responsiveness. Strikingly, GRK2 ablation initiated 10 days after infarction increased survival, enhanced cardiac contractile performance, and halted ventricular remodeling. These results demonstrate a specific causal role for GRK2 in post-infarction cardiac remodeling and HF and support therapeutic approaches of targeting GRK2 or restoring βAR signaling by other means to improve outcomes in HF