The role of Matrix Metalloproteinase-2 and Galectin-3 as predictive biomarkers for all-cause mortality in patients undergoing transfemoral transcatheter aortic valve implantation.

BACKGROUND: Currently available risk scores fail to accurately predict morbidity and mortality in patients with severe symptomatic aortic stenosis who undergo transcatheter aortic valve implantation (TAVI). In this context, biomarkers like matrix metalloproteinase-2 (MMP-2) and Galectin-3 (Gal-3) may provide additional prognostic information. METHODS: Patients with severe aortic stenosis undergoing consecutive, elective, transfemoral TAVI were included. Baseline demographic data, functional status, echocardiographic findings, clinical outcomes and biomarker levels were collected and analysed. RESULTS: The study cohort consisted of 89 patients (age 80.4 ± 5.1 years, EuroScore II 7.1 ± 5.8%). During a median follow-up period of 526 d, 28 patients (31.4%) died. Among those who died, median baseline MMP-2 (alive: 221.6 [170.4; 263] pg/mL vs. deceased: 272.1 [225; 308.8] pg/mL, p < 0.001) and Gal-3 levels (alive: 19.1 [13.5; 24.6] pg/mL vs. deceased: 25 [17.6; 29.5] pg/mL, p = 0.006) were higher than in survivors. In ROC analysis, MMP-2 reached an acceptable level of discrimination to predict mortality (AUC 0.733, 95% CI [0.62; 0.83], p < 0.001), but the predictive value of Gal-3 was poor (AUC 0.677, 95% CI [0.56; 0.79], p = 0.002). Kaplan-Meier and Cox regression analyses showed that patients with MMP-2 and Gal-3 concentrations above the median at baseline had significantly impaired long-term survival (p = 0.004 and p = 0.02, respectively). CONCLUSIONS: In patients with severe aortic stenosis undergoing transfemoral TAVI, MMP-2 and to a lesser extent Gal-3, seem to have additive value in optimizing risk prediction and streamlining decision-making.

Sex difference in appropriate shocks but not mortality during long-term follow-up in patients with implantable cardioverter-defibrillators.

AIMS: Implantable cardioverter-defibrillators (ICDs) have been shown to improve survival, although a considerable number of patients never receive therapy. Implantable cardioverter-defibrillators are routinely implanted regardless of sex. There is continuing controversy whether major outcomes differ between men and women. METHODS AND RESULTS: In this retrospective single-centre study, 1151 consecutive patients (19% women) undergoing ICD implantation between 1998 and 2010 were followed for mortality and first appropriate ICD shock over 4.9 ± 2.7 years. Sex-related differences were investigated using multivariable Cox models adjusting for potential confounders. During follow-up, 318 patients died, a rate of 5.9% per year among men and 4.6% among women (uncorrected P = 0.08); 266 patients received a first appropriate ICD shock (6.3% per year among men vs. 3.6% among women, P = 0.002). After multivariate correction, independent predictors of all-cause mortality were age (hazard ratio, HR = 1.04 per year of age, 95% confidence interval (CI) [1.03-1.06], P < 0.001), left ventricular ejection fraction (HR = 0.98 per %, 95% CI [0.97-1.00], P = 0.025), renal function (HR = 0.99 per mL/min/1.73 m(2), 95% CI [0.99-1.00], P = 0.009), use of diuretics (HR = 1.81, 95% CI [1.29-2.54], P = 0.0023), peripheral arterial disease (HR = 2.21, 95% CI [1.62-3.00], P < 0.001), and chronic obstructive pulmonary disease (HR = 1.48, 95% CI [1.13-1.94], P = 0.029), but not sex. Female sex (HR = 0.51, 95% CI [0.33-0.81], P = 0.013), older age (HR = 0.98, 95% CI [0.97-0.99], P < 0.001), and primary prophylactic ICD indication (HR = 0.69, 95% CI [0.52-0.93], P = 0.043) were independent predictors for less appropriate shocks. CONCLUSION: Women receive 50% less appropriate shocks than men having similar mortality in this large single-centre population. These data may pertain to individually improved selection of defibrillator candidates using risk factors, e.g. sex as demonstrated in this study.

Transient hypoglycemia as a rare cause of recurring transient loss of consciousness: a case report.

BACKGROUND: Syncopes and transient loss of consciousness affect a large number of patients. Determining the underlying mechanism of a syncope is key to effectively treating and preventing future events. However, given the broad differential diagnosis of transient loss of consciousness, it can be challenging to determine the exact etiology. CASE PRESENTATION: This case presents a 42-year-old Caucasian female patient with recurrent transient loss of consciousness due to a hitherto undiagnosed impaired glucose tolerance and hyperinsulinism. The patient had been thoroughly tested for all typical causes of syncope without finding any causal explanation. An oral glucose tolerance test confirmed rapidly dropping blood glucose levels associated with rapidly fading consciousness as the underlying cause of transient loss of consciousness. Further diagnostic workup revealed that the patient suffered from impaired glucose tolerance and subsequent hyperinsulinism without overt diabetes mellitus. Nutritional counseling including reduction of glucose intake and frequently eating smaller meal portions led to a significant reduction in the frequency of transient loss of consciousness and overall improvement in quality of life. CONCLUSIONS: The current European Society of Cardiology (ESC) guideline on syncope does not list hypoglycemia as a cause of transient loss of consciousness. However, this case report stresses that metabolic dysregulation can indeed lead to self-limited transient loss of consciousness. Thus, in the case of recurrent syncope with an unclear underlying mechanism, physicians should consider transient hypoglycemia and metabolic workup as a possible differential diagnosis.

Empagliflozin inhibits Na+ /H+ exchanger activity in human atrial cardiomyocytes.

AIMS: Recent clinical trials have proven gliflozins to be cardioprotective in diabetic and non-diabetic patients. However, the underlying mechanisms are incompletely understood. A potential inhibition of cardiac Na+ /H+ exchanger 1 (NHE1) has been suggested in animal models. We investigated the effect of empagliflozin on NHE1 activity in human atrial cardiomyocytes. METHODS AND RESULTS: Expression of NHE1 was assessed in human atrial and ventricular tissue via western blotting. NHE activity was measured as the maximal slope of pH recovery after NH4 + pulse in isolated carboxy-seminaphtarhodafluor 1 (SNARF1)-acetoxymethylester-loaded murine ventricular and human atrial cardiomyocytes. NHE1 is abundantly expressed in human atrial and ventricular tissue. Interestingly, compared with patients without heart failure (HF), atrial NHE1 expression was significantly increased in patients with HF with preserved ejection fraction and atrial fibrillation. The largest increase in atrial and ventricular NHE1 expression, however, was observed in patients with end-stage HF undergoing heart transplantation. Importantly, acute exposure to empagliflozin (1 µmol/L, 10 min) significantly inhibited NHE activity to a similar extent in human atrial myocytes and mouse ventricular myocytes. This inhibition was also achieved by incubation with the well-described selective NHE inhibitor cariporide (10 µmol/L, 10 min). CONCLUSIONS: This is the first study systematically analysing NHE1 expression in human atrial and ventricular myocardium of HF patients. We show that empagliflozin inhibits NHE in human cardiomyocytes. The extent of NHE inhibition was comparable with cariporide and may potentially contribute to the improved outcome of patients in clinical trials.

Empagliflozin reduces Ca/calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes.

AIMS: The EMPA-REG OUTCOME study showed reduced mortality and hospitalization due to heart failure (HF) in diabetic patients treated with empagliflozin. Overexpression and Ca2+ -dependent activation of Ca2+ /calmodulin-dependent kinase II (CaMKII) are hallmarks of HF, leading to contractile dysfunction and arrhythmias. We tested whether empagliflozin reduces CaMKII- activity and improves Ca2+ -handling in human and murine ventricular myocytes. METHODS AND RESULTS: Myocytes from wild-type mice, mice with transverse aortic constriction (TAC) as a model of HF, and human failing ventricular myocytes were exposed to empagliflozin (1 µmol/L) or vehicle. CaMKII activity was assessed by CaMKII-histone deacetylase pulldown assay. Ca2+ spark frequency (CaSpF) as a measure of sarcoplasmic reticulum (SR) Ca2+ leak was investigated by confocal microscopy. [Na+ ]i was measured using Na+ /Ca2+ -exchanger (NCX) currents (whole-cell patch clamp). Compared with vehicle, 24 h empagliflozin exposure of murine myocytes reduced CaMKII activity (1.6 ± 0.7 vs. 4.2 ± 0.9, P < 0.05, n = 10 mice), and also CaMKII-dependent ryanodine receptor phosphorylation (0.8 ± 0.1 vs. 1.0 ± 0.1, P < 0.05, n = 11 mice), with similar results upon TAC. In murine myocytes, empagliflozin reduced CaSpF (TAC: 1.7 ± 0.3 vs. 2.5 ± 0.4 1/100 µm-1  s-1 , P < 0.05, n = 4 mice) but increased SR Ca2+ load and Ca2+ transient amplitude. Importantly, empagliflozin also significantly reduced CaSpF in human failing ventricular myocytes (1 ± 0.2 vs. 3.3 ± 0.9, P < 0.05, n = 4 patients), while Ca2+ transient amplitude was increased (F/F0 : 0.53 ± 0.05 vs. 0.36 ± 0.02, P < 0.05, n = 3 patients). In contrast, 30 min exposure with empagliflozin did not affect CaMKII activity nor Ca2+ -handling but significantly reduced [Na+ ]i . CONCLUSIONS: We show for the first time that empagliflozin reduces CaMKII activity and CaMKII-dependent SR Ca2+ leak. Reduced Ca2+ leak and improved Ca2+ transients may contribute to the beneficial effects of empagliflozin in HF.

The contractile adaption to preload depends on the amount of afterload.

AIMS: The Frank-Starling mechanism (rapid response (RR)) and the secondary slow response (SR) are known to contribute to increases contractile performance. The contractility of the heart muscle is influenced by pre-load and after-load. Because of the effect of pre-load vs. after-load on these mechanisms in not completely understood, we studied the effect in isolated muscle strips. METHODS AND RESULTS: Progressive stretch lead to an increase in shortening/force development under isotonic (only pre-load) and isometric conditions (pre- and after-load). Muscle length with maximal function was reached earlier under isotonic (Lmax-isotonic ) compared with isometric conditions (Lmax-isometric ) in nonfailing rabbit, in human atrial and in failing ventricular muscles. Also, SR after stretch from slack to Lmax-isotonic was comparable under isotonic and isometric conditions (human: isotonic 10 ± 4%, isometric 10 ± 4%). Moreover, a switch from isotonic to isometric conditions at Lmax-isometric showed no SR proving independence of after-load. To further analyse the degree of SR on the total contractile performance at higher pre-load muscles were stretched from slack to 98% Lmax-isometric under isotonic conditions. Thereby, the SR was 60 ± 9% in rabbit and 51 ± 14% in human muscle strips. CONCLUSIONS: This work shows that the acute contractile response largely depends on the degree and type of mechanical load. Increased filling of the heart elevates pre-load and prolongs the isotonic part of contraction. The reduction in shortening at higher levels of pre-load is thereby partially compensated by the pre-load-induced SR. After-load shifts the contractile curve to a better 'myofilament function' by probably influencing thin fibers and calcium sensitivity, but has no effect on the SR.

Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy.

The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~107 primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (ΔGG). Surprisingly, ΔGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation-independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway.

Longevity of implantable cardioverter-defibrillators in a single-center population.

BACKGROUND OR PURPOSE: Real-life comparative data of implantable cardioverter-defibrillator (ICD) longevity are needed to identify the best possible device longevity for optimal patient comfort and to minimize risk for multiple replacements. METHODS: We retrospectively studied ICD longevity in a large single-center population. At our institution, 1272 consecutive patients were implanted with 1665 ICD or cardiac resynchronization therapy with defibrillator (CRT-D) devices between 1998 and 2010. Device data and follow-up were retrieved from the continuous ICD clinic documentation, and generator replacements were verified from the hospital charts. Kaplan-Meier event probabilities for the time to generator replacement were calculated according to device type, pacing percentage (sum of atrial, right and left ventricular pacing, if applicable) and right ventricular pacing threshold, incidence of ICD shocks, and manufacturer. Multivariate Cox proportional hazards regression was performed in addition. RESULTS: A total of 470 devices were replaced for elective replacement indicator. These occurred after 5.4 years (95% confidence interval, 5.1 to 5.6 years) in 175 of 625 implanted Boston Scientific or Guidant devices, after 5.7 years (5.5 to 5.9 years) in 266 of 883 Medtronic devices, and 5.2 years (5.0 to 5.4 years) in 29 of 157 Biotronik devices, respectively. Differences between manufacturers remained significant upon multivariate analysis (Medtronic vs. Boston Scientific: P = 0.01; both vs. Biotronik: P < 0.01) as did differences of device type (single- and dual-chamber ICD vs. CRT-D, P < 0.01) and pacing percentage (P < 0.01). Pacing output and ICD shocks did not influence battery longevity. CONCLUSION: ICD longevity differed significantly between manufacturers, independent of device type or pacing parameters.

Daptomycin for treatment of methicillin-resistant Staphylococcus epidermidis saphenectomy wound infection after coronary artery bypass graft operation (CABG): a case report.

We report a case of successful treatment of postoperative saphenectomy wound infection of the upper left leg with the antibiotic drug Daptomycin.