Barnabas Gellen

Calpastatin overexpression impairs postinfarct scar healing in mice by compromising reparative immune cell recruitment and activation

The activation of the calpain system is involved in the repair process following myocardial infarction (MI). However, the impact of the inhibition of calpain by calpastatin, its natural inhibitor, on scar healing and left ventricular (LV) remodeling is elusive. Male mice ubiquitously overexpressing calpastatin (TG) and wild-type (WT) controls were subjected to an anterior coronary artery ligation. Mortality at 6 wk was higher in TG mice (24% in WT vs. 44% in TG, P < 0.05) driven by a significantly higher incidence of cardiac rupture during the first week post-MI, despite comparable infarct size and LV dysfunction and dilatation. Calpain activation post-MI was blunted in TG myocardium. In TG mice, inflammatory cell infiltration and activation were reduced in the infarct zone (IZ), particularly affecting M2 macrophages and CD4(+) T cells, which are crucial for scar healing. To elucidate the role of calpastatin overexpression in macrophages, we stimulated peritoneal macrophages obtained from TG and WT mice in vitro with IL-4, yielding an abrogated M2 polarization in TG but not in WT cells. Lymphopenic Rag1(-/-) mice receiving TG splenocytes before MI demonstrated decreased T-cell recruitment and M2 macrophage activation in the IZ day 5 after MI compared with those receiving WT splenocytes. Calpastatin overexpression prevented the activation of the calpain system after MI. It also impaired scar healing, promoted LV rupture, and increased mortality. Defective scar formation was associated with blunted CD4(+) T-cell and M2-macrophage recruitment.

Apnea–hypopnea and desaturations in heart failure with reduced ejection fraction: Are we aiming at the right target?

BACKGROUND Sleep disordered breathing (SDB) is common in patients with heart failure with reduced ejection fraction (HFrEF). An increased apnea-hypopnea index (AHI) is associated with poor outcomes. We examined whether an analysis of nocturnal desaturations (NDs) can improve the risk stratification. METHODS Three-hundred seventy-six consecutive patients with stable chronic HFrEF and LVEF ≤ 45% were prospectively screened using polygraphy. Sleep apnea (SA) was defined as an AHI ≥ 15. The mean age was 59 ± 13 years, the mean LVEF was 30 ± 6%, and the median AHI was 18 [IQR: 9.33). The composite end-point of death, heart transplantation or LV assistance occurred in 98 patients (26%) within 3 years. Minimal oxygen saturation (MOS) during sleep, the number of desaturations <90%/h and the time spent with oxygen saturation <90% were significantly associated with adverse events (adjusted HR 1.25 [1.03-1.52], 1.25 [1.03-1.53], and 1.28 [1.04-1.59]), whereas the AHI was not (1.10 [0.86-1.39]). The best MOS cut-off value for poor outcomes was ≤ 88%. The patients with an MOS ≤ 88% had a significantly higher event rate (31.9%) than those with an MOS >88% (15.6%; p<0.01). The risk assessment using an MOS of ≤ 88% in addition to established prognostic markers yielded a net reclassification index (NRI) of nearly 6% and was particularly useful in the subgroup of patients with events (NRI: 8.4%). CONCLUSIONS In HFrEF patients, ND ≤ 88% appears to be predictive of adverse events, independent of the presence of SA. This suggests that the risk assessment in HFrEF should also include ND in top of AHI.

Left ventricular SERCA2a gene down‐regulation does not parallel ANP gene up‐regulation during post‐MI remodelling in rats

In most animal models of chronic hemodynamic overload of the left ventricle (LV) as well as in human end stage heart failure, the sarcoplasmic reticulum (SR) Ca2+‐ATPase (SERCA2a) mRNA levels are decreased in parallel with increased atrial natriuretic peptide (ANP) mRNA levels. The situation in the remote myocardium following myocardial infarction (MI) is unclear.

Comparison of Optical Coherence Tomography (OCT) and Intravascular Ultrasound (IVUS) for the early diagnosis of cardiac allograft vasculopathy in heart transplant patients

Introduction: Cardiac Allograft Vasculopathy (CAV) is one of the leading causes of death after cardiac transplantation. IntraVascular Ultrasound (IVUS) measures the increase in intima-media thickness (IMT) observed in CAV and is more sensitive for diagnosis of CAV than coronary angiography. Optical Coherence Tomography (OCT), a new intracoronary imaging technique, allows more precise measurement of IMT as compared to IVUS. Objective: Demonstrate that OCT is superior to IVUS for CAV detection in heart transplant patients. Methods: Comparison of OCT and IVUS in heart transplant patients with or without angiographic CAV, performed during their systematic follow-up coronary angiography. Results: Among ten heart transplant patients included with a median age of 53.5±12 years, 4 had angiographically significant CAV. No major adverse cardiac events occurred during the procedure. Twenty-two coronary arteries, divided into 105 segments, were analysed. IMT measured by IVUS and OCT was comparable (limits of agreement [-0.167 – 0.139]). The 4 patients with angiographic CAV had a thicker IMT than healthy patients as defined by IVUS (0.42±0.16 mm et 0.24±0.10 mm respectively, p < 0.001), and by OCT (0.41±0.16 mm and 0.27±0.12, p < 0.001). Only OCT allowed for separate measurement of intima and media. Intimal thickness was significantly increased in patients with CAV (0.28±0.15 mm vs. 0.16±0.09 mm, p < 0.001). Conclusion: OCT and IVUS are both reliable to measure IMT. However, only OCT can evaluate intimal thickening, the key feature of beginning CAV. OCT is therefore a promising tool in the early detection of CAV and may guide adjustment of immunosuppressive treatment aimed at reducing CAV progression.

Thromboaspiration Leading to Complete Coronary Artery Stripping in Acute Myocardial Infarction After Blast Injury

A54-year-old man without medical history was admitted in our hospital with hemorrhagic shock caused by left compressive hemothorax (Figure 1) after a suicidal gunshot. The entrance site of the projectile was in the 4th left intercostal space. Figure 1. Chest radiograph (posteroanterior view, white arrow shows the bullet). Surgical exploration performed within the 1st hour revealed dissection of the left internal mammary artery and multiple injuries of the lung parenchyma, which could be successfully repaired. Extensive superficial epicardial dilacerations were observed at the level of the mid left anterior descending coronary artery, without penetrating myocardial or coronary artery injury and without pericardial effusion. Coronary flow appeared to be preserved. On transfer into the intensive care unit of the sedated and mechanically ventilated patient, routine 12-lead ECG showed signs of anterior …

H022 FKBP12.6 overexpression in mouse cardiac myocytes offers minor protection against pressure overload-induced cardiac remodelling and failure

Alterations in RyR2 function is a hallmark of heart failure (HF). Decreased FKBP12.6 binding to RyR2 has been put forward to explain the diastolic SR Ca2+ leakage observed in this condition. Previous work in the mouse has shown that cardiac FKBP12.6 overexpression protects against the development of myocardial infarction-induced heart failure. Using a mouse model of conditional cardiac-specific FKBP12.6 overexpression, we tested the hypothesis that this overexpression protects against transverse aortic constriction (TAC)-induced cardiac remodelling and failure. Ten weeks after TAC, male transgenic (DT) and their littermates controls (Ctr) underwent heart catheterization. Ventricular expression of the hypertrophic gene program and calcium handling proteins were assessed by real-time PCR and Western blot, respectively.Ten weeks after TAC, the mortality rate was 23 % in Ctr and 13 % in DT (14/60 vs 5/39, ns). The percentage of mice with HF, based on pulmonary oedema, was 42 % in Ctr-TAC and 32 % in DT-TAC (15/36 vs 7/22, ns). Gravimetric and hemodynamic data are shown in the table: BNP mRNA level increased 2.8 fold in Ctr-TAC (P Conclusion Cardiac FKBP 12.6 overexpression offers weak protection if any against TAC-induced cardiac remodeling and failure in the mouse.