The CnB1 p.D102A variant is linked to dilated cardiomyopathy via impaired Calcineurin activity.

BACKGROUND: The role of calcineurin (protein phosphatase 2B (PP2B)) in the pathogenesis of human dilated cardiomyopathy (DCM) has not been fully elucidated. We determined the potential involvement of calcineurin in the pathogenesis of DCM caused by mutations in CnB1, a subunit of calcineurin. METHODS: By whole-exome sequencing, we identified a new CnB1 variant in a Han Chinese proband with cardiomyopathy from a 3-generation family with 2 normal individuals and 3 individuals with familial dilated cardiomyopathy. The potential pathogenic variant was validated by Sanger sequencing. We performed functional and mechanistic experiments in a CnB1-knockin (KI) mouse model and at the cellular level. RESULTS: We detected a rare heterozygous CnB1 variant (p.D102A) in a proband with dilated cardiomyopathy. This variant was localized to the EF hand 3 region of CnB1, where no variants have been previously reported. KI mice harboring the p.D102A variant exhibited decreased cardiac function and cardiac dilatation. Immunoblotting, RT-PCR and immunofluorescence results showed decreased cardiomyocyte size and heart failure-related protein expression. A calcineurin activity assay demonstrated decreased calcineurin activity in the KI mice, accompanied by the decreased ability of CnB1 to bind CnA. CONCLUSIONS: CnB1 p.D102A is a disease-associated variant that confers susceptibility to cardiac dilatation. This variant is associated with impaired calcineurin activity and a subsequent decrease in the ability of CnB1 to bind CnA.

Preconditioning enhances myocardial protection in patients undergoing open heart surgery.

To date, ischemic preconditioning is regarded as the most powerful form of endogenous myocardial protection. For the purpose of surgical myocardial protection, a few clinical studies have investigated the effects of ischemic preconditioning in conjunction with hypothermia or blood cardioplegia during open heart surgery, but the results were controversial. We now tested the hypothesis that preconditioning improves myocardial protection in patients undergoing cold crystalloid cardioplegic arrest. 36 patients needing mitral prosthetic valve replacement for rheumatic heart disease were studied. Patients were evenly divided into two groups at random. Preconditioning was elicited by two cycles of 3 minutes ischemia by occlusion of vena cava and aortic cross-clamping followed by 2 minutes reperfusion under cardiopulmonary bypass. All hearts were arrested using 4 degrees C St. Thomas' Hospital solution before the intracardiac operative program. Myocardial protective effects were mainly assessed by electrocardiac activities, leakage of myocardial enzymes, myocardial contractility, and early postoperative recovery. The results indicated that there was a significant reduction of ST-segment shifting (ST-segment elevation, 0.07 +/- 0.02 vs 0.22 +/- 0.07 mV, p < 0.05, at 4 hours post reperfusion) and smaller release of creatine kinase-MB (87 +/- 11.5 vs 143 +/- 17.2 IU/L, p < 0.05, at 12 hours post reperfusion) in the preconditioning group. Preconditioning also enhanced myocardial contractility (dp/dtmax = 1490 +/- 75 vs 1280 +/- 88 mmHg/sec, at 30 minutes post reperfusion, p < 0.05) and promoted early postoperative recovery. The present study suggests that ischemic preconditioning reduces ischemia-reperfusion injury in human hearts even when combined with cold crystalloid cardioplegia.

Preconditioning improves myocardial preservation in patients undergoing open heart operations.

BACKGROUND: Our previous work has shown that preconditioning can promote the recovery of cardiac function in patients having an open heart procedure. Because preconditioning is regarded as the most powerful form of endogenous myocardial protection, we tested the hypothesis that preconditioning protects against myocardial ischemia-reperfusion injury in patients undergoing prolonged cold crystalloid cardioplegic arrest. METHODS: Thirty patients who had rheumatic heart disease and required both aortic and mitral valve replacement were studied. Patients were randomly divided into two equal groups. Preconditioning was accomplished using two cycles of 2-minute occlusion of the vena cava and aorta followed by 3 minutes of reperfusion under cardiopulmonary bypass. All hearts were arrested with 4 degrees C St. Thomas' Hospital cardioplegic solution. Myocardial protective effects were assessed by changes in myocardial levels of adenosine triphosphate, electrocardiographic activity, leakage of myocardial enzymes, and myocardial contractility. RESULTS: The adenosine triphosphate content in ischemic myocardium was higher in the preconditioning group than in the control group (p < 0.05 90 minutes after ischemia), and there was a significant reduction in release of the myocardial-specific isoenzyme of creatine kinase in the preconditioning group. Preconditioning improved the recovery of myocardial contractility (first derivative of left ventricular developed pressure, 1,490 +/- 102 mm Hg/s versus 1,250 +/- 97 mm Hg/s 30 minutes after reperfusion; p < 0.05), and there was also a protective effect on electrocardiographic activity. CONCLUSIONS: Our results suggest that ischemic preconditioning protects the myocardium in humans from the severe ischemia-reperfusion injury produced after prolonged arrest with cold crystalloid cardioplegia.

Surgical treatment of solitary peripheral pulmonary artery aneurysm associated with ventricular septal defect.

In the case presented a solitary peripheral pulmonary artery aneurysm occurred in a woman with ventricular septal defect (VSD). During the operation of repairing the VSD under cardiopulmonary bypass, the pulmonary artery aneurysm (PAA) suddenly ruptured into the bronchus and a large amount of air entered the pulmonary artery and right ventricle when the anesthetist inflated the lungs. The air in the right ventricle could not be evacuated completely, so we had to remove the lobe where the aneurysm was located. The operation was successful and the postoperative course was uncomplicated.