Crosstalk between PKC and MAPK pathway activation in cardiac fibroblasts in a rat model of atrial fibrillation.

OBJECTIVE: Atrial fibrillation (AF) is the most frequent form of cardiac arrhythmia and major cause of cardiac ischemia. Defective calcium homeostasis due to anomalous expression of ryanodine receptor type 2 (RyR2) or its hyperactivation by phosphorylation by serine threonine kinases has been implicated as a central mechanism of AF pathogenesis. Given the role of protein kinase C (PKC) isoforms in cardiac function we investigated role of PKC in AF using a rat model. RESULTS: PMA induced global increase in protein synthesis in cardiac fibroblasts isolated from AF rats, but not healthy controls, and the increase was inhibited by PKC inhibition. PMA mediated activation of both PKC and ERK and either inhibition of PKC by Go6983 or ERK by the MEK inhibitor Trametinib attenuated both P-ERK and P-PKC in both cardiac fibroblasts isolated from AF rats or from healthy rats but transduced with PKC-delta. The PKC and ERK mediated induction of global protein synthesis was found to be mediated by increased phosphorylation of the ribosomal protein S6. CONCLUSION: Our findings provide a foundation for future testing of PKC and MEK inhibitors to treat AF in pre-clinical models. It also needs to be determined if PKC and MAPK pathway activation is functioning via RyR2 or some yet undefined substrates.

Long-term outcome of patients with atrial myxoma after surgical intervention: analysis of 403 cases.

OBJECTIVE: To assess long-term survival and late cardiovascular events in patients with atrial myxoma after surgical intervention. METHODS: Retrospective analysis of 403 patients undergoing resection of atrial myxoma from January 2002 to December 2016 was conducted with a median follow-up period of 4.5 (range: 0.5-15) years. RESULTS: The cross-clamp time and cardiopulmonary bypass times were 41.1 ± 21.4 and 65.2 ± 27.3 min, respectively. A diagnosis of myxoma was histopathologically confirmed in all cases. The early in-hospital mortality rate was 0.7% (n = 3). During the follow-up period, tumor recurrence occurred in six patients and cerebral infarction in nine. There were 48 (11.9%) patients with late onset atrial fibrillation (AF). By multivariate analysis, age (HR = 1.05, 95% CI: 1.02-1.09, P < 0.001), left atrial diameter (HR = 1.23, 95% CI: 1.08-1.36, P = 0.012), and mitral valve surgery (HR = 1.17, 95% CI: 1.05-1.29, P = 0.027) were independent predictors of late onset AF. Twenty-one (5.2%) patients died during the follow-up period. Advanced age (HR = 1.07, 95% CI: 1.04-1.10, P = 0.003) and multiple surgical procedures (HR = 1.18, 95% CI: 1.06-1.29, P = 0.012) were significantly associated with overall mortality. CONCLUSIONS: Atrial myxoma can be resected with good long-term survival. Late onset AF is common after surgery in patients with atrial myxoma. Advanced age, left atrial diameter, and mitral valve surgery were independent predictors of outcomes.

Elevated homocysteine increases the risk of left atrial/left atrial appendage thrombus in non-valvular atrial fibrillation with low CHA2DS2-VASc score.

Aims: To assess the association and the predictive value of plasma homocysteine (Hcy) levels with LA/LAA thrombus in non-valvular Atrial fibrillation (AF) patients with low CHA2DS2-VASc score. Methods and results: Eight hundred and eighty-eight consecutive patients in non-valvular AF with CHA2DS2-VASc score of 0 and 1 were enrolled. All patients routinely underwent transthoracic echocardiography and transoesophageal echocardiography. A total of thirty-two patients had LA/LAA thrombus. Compared with patients without LA/LAA thrombus, plasma Hcy levels were significantly higher in patients with LA/LAA thrombus (16.5 ± 4.8 mmol/L vs. 13.4 ± 4.1 mmol/L, P = 0.009). In multivariate analysis, Hcy was independently associated with LA/LAA thrombus (OR 1.048, 95% CI 1.007-1.090, P = 0.022). Hcy demonstrated a significant predictive value with area under the curve of 0.722 (95% CI 0.662-0.781, P < 0.001). The optimal cut-off point for Hcy predicting LA/LAA thrombus was 13.5 mmol/L (sensitivity 67%, specificity 65%). Patients with Hcy ≥13.5 mmol/L had higher prevalence of LA/LAA thrombus compared with those with Hcy <13.5 mmol/L (6.1% vs. 2.1%, P < 0.001). Elevated Hcy significantly increased the risk of LA/LAA thrombus in patients with CHA2DS2-VASc score of 0 and 1 (OR 11.789, 95% CI 1.437-96.746, P = 0.022; OR 2.256, 95% CI 1.007-5.155, P = 0.048, respectively). Conclusion: Elevated plasma Hcy increases the risk of LA/LAA thrombus in non-valvular AF patients with low CHA2DS2-VASc score, thus it should be taken into account in prediction of thromboembolism.

Homocysteine in non-valvular atrial fibrillation: Role and clinical implications.

Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with a series of adverse complications that cause so-called AF socioeconomic burden. Apart from the classical risk factors, it seems to be novel factors that increase the risk of AF and AF-related stroke. Recently, more and more evidence has well documented the close relationships between homocysteine (Hcy) and AF. As a well-known marker for pro-oxidation and pro-inflammation, Hcy plays an important role in a number of vascular diseases having strong association with AF. This review will discuss the expression of Hcy and its association with ischemic stroke in AF patients especially for elderly patients, and the role and clinical implications of Hcy in the thromboembolic events and rhythm outcome in AF patients. The possible mechanisms linking elevated Hcy and cardiovascular events in AF patients will also be addressed, including oxidative stress, inflammatory response, atrial remodeling, etc.

Effect of advanced age on plasma homocysteine levels and its association with ischemic stroke in non-valvular atrial fibrillation.

BACKGROUND: Elevated homocysteine (Hcy) has been reported to be associated with cardiovascular events in atrial fibrillation (AF) patients, while the age-related expression pattern of plasma Hcy in AF remains unknown. The study was aimed to investigate the effect of advanced age on plasma Hcy levels and its association with ischemic stroke in non-valvular AF patients. METHODS: A total of 2562 consecutive patients with non-valvular AF and 535 controls were enrolled and divided into six age groups. Plasma Hcy levels were analyzed among different age groups, and the effect of advanced age on Hcy was investigated. RESULTS: Plasma Hcy levels did not show any difference among groups aged below 65 years, while it increased sharply in patients aged 65-74 years and aged over 75 years (15.7 ± 4.6 µmol/L, 17.1 ± 4.9 µmol/L, both P < 0.01 compared with the first four age groups). Hcy was much higher in AF patients than in controls at the same age group (all P < 0.05). The proportion of patients with hyperhomocysteinemia increased gradually with age from 32.3%, 29.2%, 31.2%, 32.4%, 45.9%, to 51.4% in six age groups. The concentration of Hcy in AF patients with ischemic stroke increased progressively with age, and was higher than those without stroke at the same age. Logistic regression analysis demonstrated that age 65-74 years [odds ratios (OR): 1.742, 95% confidence interval (CI): 1.223-2.482, P = 0.002] and age ≥ 75 years (OR: 2.637, 95% CI: 1.605-4.335, P < 0.001) were significantly independent predictors of elevated plasma Hcy levels. CONCLUSIONS: Advanced age was significantly associated with elevated Hcy levels, which may provide a possible explanation for the progressive increase in ischemic stroke especially in elderly AF patients.