Inducible over-expression of cardiac Nos1ap causes short QT syndrome in transgenic mice.

Recent evidence demonstrated that alterations in the QT interval duration on the ECG are not only determined by mutations in genes for ion channels, but also by modulators of ion channels. Changes in the QT interval duration beyond certain thresholds are pathological and can lead to sudden cardiac death. We here focus on the ion channel modulator nitric oxide synthase 1 adaptor protein (Nos1ap). Whole-cell patch-clamp measurements of a conditional transgenic mouse model exhibiting cardiac-specific Nos1ap over-expression revealed a Nos1ap-dependent increase of L-type calcium channel nitrosylation, which led to increased susceptibility to ventricular tachycardias associated with a decrease in QT duration and shortening of APD90 duration. Survival was significantly reduced (60% after 12 weeks vs. 100% in controls). Examination of the structural features of the hearts of transgenic mice revealed constant heart dimensions and wall thickness without abnormal fibrosis content or BNP production after 3 months of Nos1ap over-expression compared to controls. Nos1ap over-expression did not alter cGMP production or ROS concentration. Our study showed that myocardial over-expression of Nos1ap leads to the shortening of the QT interval and reduces the survival rate of transgenic animals, perhaps via the development of ventricular arrhythmias. We conclude that Nos1ap overexpression causes targeted subcellular localization of Nos1 to the CaV1.2 with a subsequent decrease of ADP90 and the QT interval. This causes detrimental cardiac arrhythmias in transgenic mice.

Experimental Cardiorenal Syndrome Type 3: What Is Known so Far?

BACKGROUND: The concept of cardiorenal syndrome (CRS) has been established more than 10 years ago. Five distinct types of CRS have been defined. In CRS type 3, acute kidney injury (AKI) induces cardiac complications such as ventricular decompensation due to arrhythmias, myocardial ischemia, or fluid retention with or without arterial hypertension. The risk of cardiovascular events in AKI has been known for many years, even long before the introduction of the CRS concept. However, epidemiological and clinical studies published in recent years increasingly emphasized CRS type 3 (and the remaining four types also) as separate entity which requires particular therapeutic attention in an interdisciplinary manner. However, only a limited number of experimental studies specifically addressed CRS type 3 so far. Our review aims to summarize experimental studies on the pathological mechanisms in CRS type 3. METHODS: The following search criteria were employed in order to identify articles published on the topic: "cardiorenal syndrome 3" OR "cardiorenal syndrome type 3" OR "CRS type 3" OR "CRS 3" AND "experimental" OR "mouse" OR "mice" OR "rats" OR "animals"; additional criteria were "myocardium" AND "ischemia" AND "kidney" OR "renal". By applying the search criteria mentioned earlier, 10 references were finally selected. RESULTS: By applying the search strategy, 10 experimental studies were finally selected. All included cardiac outcome analysis in AKI animals. The data clearly provide evidence for cardiac complications that evolve independently from excretory kidney dysfunction. Pathological processes that emerge in the heart of animals subjected to renal ischemia involve inflammation, a dysbalance of redox components, pro-apoptotic processes, and mitochondrial dysfunction. CONCLUSION: The findings may explain why AKI increases the risk of acute cardiac complications even if dialysis treatment has been initiated.

Senescent murine femoral arteries undergo vascular remodelling associated with accelerated stress-induced contractility and reactivity to nitric oxide.

This work explored the mechanism of augmented stress-induced vascular reactivity of senescent murine femoral arteries (FAs). Mechanical and pharmacological reactivity of young (12-25 weeks, y-FA) and senescent (>104 weeks, s-FAs) femoral arteries was measured by wire myography. Expression and protein phosphorylation of selected regulatory proteins were studied by western blotting. Expression ratio of the Exon24 in/out splice isoforms of the regulatory subunit of myosin phosphatase, MYPT1 (MYPT1-Exon24 in/out), was determined by polymerase chain reaction (PCR). While the resting length-tension relationship showed no alteration, the stretch-induced-tone increased to 8.3 ± 0.9 mN in s-FA versus only 4.6 ± 0.3 mN in y-FAs. Under basal conditions, phosphorylation of the regulatory light chain of myosin at S19 was 19.2 ± 5.8% in y-FA versus 49.2 ± 12.6% in s-FA. Inhibition of endogenous NO release raised tone additionally to 10.4 ± 1.2 mN in s-FA, whereas this treatment had a negligible effect in y-FAs (4.8 ± 0.3 mN). In s-FAs, reactivity to NO donor was augmented (pD2  = -4.5 ± 0.3 in y-FA vs. -5.2 ± 0.1 in senescent). Accordingly, in s-FAs, MYPT1-Exon24-out-mRNA, which is responsible for expression of the more sensitive to protein-kinase G, leucine-zipper-positive MYPT1 isoform, was increased. The present work provides evidence that senescent murine s-FA undergoes vascular remodelling associated with increases in stretch-activated contractility and sensitivity to NO/cGMP/PKG system.

Secondary Prevention of Potentially Life-Threatening Arrhythmia Using Implantable Cardioverter Defibrillators in Patients with Biopsy-Proven Viral Myocarditis and Preserved Ejection Fraction.

BACKGROUND: Arrhythmia and sudden cardiac death (SCD) are known complications of acute viral myocarditis, regardless of ejection fraction (EF) at presentation. Whether such complications confer long-term risk is unknown, especially in those who present with preserved left ventricular (LV) function. No guidelines exist to the long-term reduction of arrhythmic death in such patients. METHOD: In this retrospective study, we analyzed the long-term results of implantable cardioverter defibrillator (ICD) treatment in patients after an acute phase of myocarditis with life-threatening arrhythmia. RESULTS: We identified 51 patients who had ICDs implanted following life-threatening arrhythmia presentation of confirmed acute viral myocarditis, despite preserved LVEF. Overall, 72.5% of patients had a clinical history of chest pain and viral infection with fever. Viral myocarditis was confirmed by cardiac magnetic resonance imaging (all had late enhancement) plus endomyocardial biopsies (most frequent were Epstein-Barr virus 29.4%, adenovirus 17.6%, and Coxsackie 17.6%), and 88.2% were discharged on anti-arrhythmic drugs. Overall, 12 patients (23.5%) required ICD intervention within the first 3 months, a further 7 patients (37.3% overall) between 3 and 12 months, and a further 12 patients (60.8% overall) until 58 months. During the follow-up, 3 of 51 patients (5.9%) died-deaths were due to cardiac events (n = 1), fatal infection (n = 1), and car accidents (n = 1). Of the 31 patients who had ventricular tachycardias after the acute phase of myocarditis, 11 needed radiofrequency ablation due to a high number of events or electrical storm. No baseline variables were identified that would serve as a basis for risk stratification. CONCLUSION: Malignant arrhythmic events due to viral myocarditis are potential predictors of future SCD in patients not only with a reduced but also with a preserved EF.

Nuclear calcineurin is a sensor for detecting Ca2+ release from the nuclear envelope via IP3R.

In continuously beating cells like cardiac myocytes, there are rapid alterations of cytosolic Ca2+ levels. We therefore hypothesize that decoding Ca2+ signals for hypertrophic signaling requires intracellular Ca2+ microdomains that are partly independent from cytosolic Ca2+. Furthermore, there is a need for a Ca2+ sensor within these microdomains that translates Ca2+ signals into hypertrophic signaling. Recent evidence suggested that the nucleus of cardiac myocytes might be a Ca2+ microdomain and that calcineurin, once translocated into the nucleus, could act as a nuclear Ca2+ sensor. We demonstrate that nuclear calcineurin was able to act as a nuclear Ca2+ sensor detecting local Ca2+ release from the nuclear envelope via IP3R. Nuclear calcineurin mutants defective for Ca2+ binding failed to activate NFAT-dependent transcription. Under hypertrophic conditions Ca2+ transients in the nuclear microdomain were significantly higher than in the cytosol providing a basis for sustained calcineurin/NFAT-mediated signaling uncoupled from cytosolic Ca2+. Measurements of nuclear and cytosolic Ca2+ transients in IP3 sponge mice showed no increase of Ca2+ levels during diastole as we detected in wild-type mice. Nuclei, isolated from ventricular myocytes of mice after chronic Ang II treatment, showed an elevation of IP3R2 expression which was dependent on calcineurin/NFAT signaling and persisted for 3 weeks after removal of the Ang II stimulus. These data provide an explanation how Ca2+ and calcineurin might regulate transcription in cardiomyocytes in response to neurohumoral signals independently from their role in cardiac contraction control. KEY MESSAGES: • Calcineurin acts as an intranuclear Ca2+ sensor to promote NFAT activity. • Nuclear Ca2+ in cardiac myocytes increases via IP3R2 upon Ang II stimulation. • IP3R2 expression is directly dependent on calcineurin/NFAT.