Ryanodine Receptor Glycation Favors Mitochondrial Damage in the Senescent Heart.

BACKGROUND: Senescent cardiomyocytes exhibit a mismatch between energy demand and supply that facilitates their transition toward failing cells. Altered calcium transfer from sarcoplasmic reticulum (SR) to mitochondria has been causally linked to the pathophysiology of aging and heart failure. METHODS: Because advanced glycation-end products accumulate throughout life, we investigated whether intracellular glycation occurs in aged cardiomyocytes and its impact on SR and mitochondria. RESULTS: Quantitative proteomics, Western blot and immunofluorescence demonstrated a significant increase in advanced glycation-end product-modified proteins in the myocardium of old mice (≥20months) compared with young ones (4-6months). Glyoxalase-1 activity (responsible for detoxification of dicarbonyl intermediates) and its cofactor glutathione were decreased in aged hearts. Immunolabeling and proximity ligation assay identified the ryanodine receptor (RyR2) in the SR as prominent target of glycation in aged mice, and the sites of glycation were characterized by quantitative mass spectrometry. RyR2 glycation was associated with more pronounced calcium leak, determined by confocal microscopy in cardiomyocytes and SR vesicles. Interfibrillar mitochondria-directly exposed to SR calcium release-from aged mice had increased calcium content compared with those from young ones. Higher levels of advanced glycation-end products and reduced glyoxalase-1 activity and glutathione were also present in atrial appendages from surgical patients ≥75 years as compared with the younger ones. Elderly patients also exhibited RyR2 hyperglycation and increased mitochondrial calcium content that was associated with reduced myocardial aerobic capacity (mitochondrial O2 consumption/g) attributable to less respiring mitochondria. In contracting HL-1 cardiomyocytes, pharmacological glyoxalase-1 inhibition recapitulated RyR2 glycation and defective SR-mitochondria calcium exchange of aging. CONCLUSIONS: Mitochondria from aging hearts develop calcium overload secondary to SR calcium leak. Glycative damage of RyR2, favored by deficient dicarbonyl detoxification capacity, contributes to calcium leak and mitochondrial damage in the senescent myocardium.

Rationale, design, and methods for the early surgery in infective endocarditis study (ENDOVAL 1): a multicenter, prospective, randomized trial comparing the state-of-the-art therapeutic strategy versus early surgery strategy in infective endocarditis.

BACKGROUND: The prognosis of infective endocarditis is poor and has remained steady over the last 4 decades. Several nonrandomized studies suggest that early surgery could improve prognosis. METHODS: ENDOVAL 1 is a multicenter, prospective, randomized study designed to compare the state-of-the-art therapeutic strategy (advised by the international societies in their guidelines) with the early-surgery strategy in high-risk patients with infective endocarditis. Patients with infective endocarditis without indication for surgery will be included if they meet at least one of the following: (1) early-onset prosthetic endocarditis; (2) Staphylococcus aureus endocarditis; (3) periannular complications; (4) new-onset conduction abnormalities; (5) new-onset severe valvular dysfunction. A total of 216 patients will be randomized to either of the 2 strategies. Stratification will be done within 3 days of admission. In the early surgery arm, the surgical procedure will be performed within 48 hours of randomization. The only event to be considered will be death within 30 days. The study will be extended to 1 year. In the follow-up substudy, death and a new episode of endocarditis will be regarded as events. CONCLUSION: ENDOVAL 1, the first randomized study on endocarditis, will provide crucial information regarding the putative benefit of early surgery over the state-of-the-art therapeutic approach in high-risk patients with infective endocarditis.

Ischemic postconditioning of the isolated human myocardium: Role of the applied protocol.

BACKGROUND: Ischemic postconditioning (IPostC), has been proposed as a useful approach to reduce infarct size in all species, but its clinical utility remains unclear. OBJECTIVE: To investigate the role played by the protocol used on the efficacy of IPostC in protecting the diseased human myocardium. METHODS: Myocardial atrial samples from patients were subjected to a 90 min ischemia/120 min reoxygenation followed by different IPostC protocols to investigate the role of the time of ischemia (30, 60, 90 and 120 s) and the number of cycles (1, 2, 3 and 4) with 60 and 120 s of total ischemic time. Muscles were also subjected to ischemic preconditioning (IPreC). The release of lactate dehydrogenase (LDH) and the measurement of tetrazolium bromide (MTT) were determined. RESULTS: IPostC increased the LDH and decreased the MTT values from those of control, independently of the duration of the conditioning ischemia. LDH and MTT values also worsened by augmenting the number of IPostC cycles whereas they were significantly improved by IPreC. However, analysis of individual results indicated that in approximately 1/3 of the cases IPostC exhibited some degree of protection especially in the presence of increased ischemic injury. CONCLUSIONS: The present findings show that IPostC of the human myocardium may be influenced by the protocol used and also by the degree of the preceding ischemic injury. IPostC was beneficial in approximately 1/3 of the cases; however in the remaining cases it increased ischemic damage and, therefore, these results raise a word of caution on its broad clinical use.

[Cardiac surgery in elderly patients]. / Cirugía cardíaca en el anciano.

OBJECTIVE: The morbimortality of elderly patients, (age 70 years or older), who underwent surgery for valvular and coronary artery disease in the last 17 years was analyzed. PATIENTS AND METHOD: A total of 1,305 patients (654 valvular, 531 coronary and 120 combined) operated from January 1985 to December 2000 were retrospectively studied. Mean age was 73.7 years. We analyzed the progression of the pathology, comorbidity, and results. A second retrospective analysis was made of patients who underwent surgery in the last three years (436 patients) to determine the relation between preoperative comorbidity and postoperative evolution. RESULTS: The mean hospital mortality was 16% (18% valvular, 11% coronary artery, and 23% combined). In the last three years this mortality was reduced to 11% (15.17, 6.26, and 16.18%, respectively) despite an increase in comorbidity. Comorbidity and complications increased with age (p < 0.05). Mean hospital stay was 15.5 days and the stay in intensive/semi-intensive care was 5 days. Independent risk factors of postoperative complications were creatinine levels > 2 mg/dl, combined surgery, and prior surgery. Predictors of death were prior surgery, valvular surgery, and combined surgery, with a clear tendency in the case of obesity. The presence of any complication in the postoperative period (renal or respiratory failure, infections, or myocardial infarction) was an independent predictor of mortality. Off-pump coronary surgery reduced mortality. In recent years, the mortality of patients operated without extracorporeal circulation has decreased from 5.71% to 4% for those who underwent extracorporeal circulation. CONCLUSIONS: Nowadays, cardiac surgery in older patients accounts for more than 30% of our surgical activity. Mortality is being controlled although comorbidity is increasing. The difference with respect to younger people is due to comorbidity (creatinine > 2 mg/dl, combined surgery, and previous surgery) and the higher probability of complications (infections, renal, and respiratory complications), which worsens prognosis. We believe that off-pump coronary surgery helps to improve results.

Subxyphoid approach for closed-chest atrial fibrillation surgery: the one hand operation.

Although the classical Cox maze operation has been shown to be effective for curing atrial fibrillation, it is not popular due to its complexity and associated morbidity. This has led to the development of alternative methods for the creation of the Cox maze pattern. These methods are based on the creation of lines of tissue necrosis on the atrial tissue. These new methods have been shown to be equally as effective as the Cox maze operation. We describe a new technique for epicardial microwave atrial ablation for pulmonary vein isolation. This technique is performed on patients without sternotomy, through the subxyphoid process to reduce pulmonary complications.