Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy

Mutations in the cardiac ryanodine receptor 2 (RyR2) have been associated with catecholaminergic polymorphic ventricular tachycardia and a form of arrhythmogenic right ventricular dysplasia. To study the relationship between RyR2 function and these phenotypes, we developed knockin mice with the human disease-associated RyR2 mutation R176Q. Histologic analysis of hearts from RyR2(R176Q/+) mice revealed no evidence of fibrofatty infiltration or structural abnormalities characteristic of arrhythmogenic right ventricular dysplasia, but right ventricular end-diastolic volume was decreased in RyR2(R176Q/+) mice compared with controls, indicating subtle functional impairment due to the presence of a single mutant allele. Ventricular tachycardia (VT) was observed after caffeine and epinephrine injection in RyR2(R176Q/+), but not in WT, mice. Intracardiac electrophysiology studies with programmed stimulation also elicited VT in RyR2(R176Q/+) mice. Isoproterenol administration during programmed stimulation increased both the number and duration of VT episodes in RyR2(R176Q/+) mice, but not in controls. Isolated cardiomyocytes from RyR2(R176Q/+) mice exhibited a higher incidence of spontaneous Ca(2+) oscillations in the absence and presence of isoproterenol compared with controls. Our results suggest that the R176Q mutation in RyR2 predisposes the heart to catecholamine-induced oscillatory calcium-release events that trigger a calcium-dependent ventricular arrhythmia.     

Cardiac rupture complicating myocardial infarction

Rupture of the ventricular free wall is a leading cause of death in patients with acute myocardial infarction (MI). There are a number of risk indicators that are associated with cardiac rupture, such as female gender, old age, hypertension, and first MI. Typical symptoms of cardiac rupture are recurrent or persistent chest pain, syncope, and distension of jugular veins. Electrocardiographic signs may include sinus tachycardia, new Q-waves in 2 or more leads, persistent or recurrent ST segment elevation, deviation of expected evolutionary T-wave pattern, and electromechanical dissociation in end-stage cases. Once patients at risk have been identified using clinical symptoms and electrocardiographic signs, a fast and sensitive diagnostic test to confirm cardiac rupture is transthoracic echocardiography (TTE). New insights in the etiology of subacute myocardial rupture suggests that defective cardiac remodeling may predispose the heart for rupture. The matrix metalloproteinase (MMP) system has been shown to play an important role in cardiac extracellular matrix (ECM) remodeling and cardiac rupture. Current therapy of cardiac rupture consists mainly of surgery, and conservative management with hemodynamic monitoring, prolonged bed rest, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors in selected cases.     

Mutation-specific effects of lidocaine in Brugada syndrome

Brugada syndrome (BrS) is a hereditary cardiac disease characterized by right bundle-branch block, an elevation of the ST-segment in leads V1 through V3 on the electrocardiogram, and ventricular fibrillation that can lead to sudden cardiac death. Mutations in the cardiac sodium channel gene SCN5A, which encodes the alpha-subunit of the human cardiac voltage-dependent Na+ channel (Na(v)1.5), are identified in 15-30% of patients with BrS. Most SCN5A mutations lead to a 'loss-of-function' phenotype, reducing the Na+ current during the early phases of the action potential. Anti-arrhythmic drugs that affect Na+ channels typically block these Na+ channels, thereby exaggerating the ECG abnormalities and arrhythmogenicity in the BrS. However, the N406S mutation in SCN5A causes distinct gating defects and enhanced intermediate inactivation of Na+ channels, which led to unexpected pharmacological effects of lidocaine in a patient carrying this mutation. In the presence of the N406S mutation, use-dependent block by lidocaine is reduced and recovery from intermediate inactivation is hastened by lidocaine. These findings suggest that lidocaine may improve the Brugada phenotype in patients with N406S by increasing the availability of Na+ channels.     

Worsening renal function is not associated with response to treatment in acute heart failure

Background

About a fourth of acute decompensated heart failure (ADHF) patients develop renal dysfunction during their admission. To date, the association of ADHF treatment with the development of worsening renal function (WRF) remains contentious. Thus, we examined the association of WRF with changes in BNP levels and with mortality.

Methods

We performed retrospective chart review of patients admitted with ADHF who had BNP, eGFR, creatinine and blood urea nitrogen (BUN) values measured both on admission and discharge. Survival analysis was conducted using Cox proportional hazards model and correlation was measured using Spearman's rank correlation test.

Results

358 patients admitted for ADHF were evaluated. WRF was defined as > 20% reduction in eGFR from admission to discharge and response to treatment was assessed by ΔBNP. There was a statistically significant reduction in BNP and increase in BUN during the admission. ΔBNP did not correlate with either ΔGFR or ΔBUN. Patients who developed WRF and those who did not, had a similar reduction in BNP. On univariate survival analysis, ΔBUN, but not ΔeGFR, was associated with 1-year mortality. In multivariate Cox proportional hazards model, BUN at discharge was associated with 1-year mortality (HR: 1.02, p < 0.001), but ΔeGFR and ΔBUN were not associated with the primary endpoint.

Conclusion

During ADHF treatment, ΔBNP was not associated with changes in renal function. Development of WRF during ADHF treatment was not associated with mortality. Our study suggests that development of WRF should not preclude diuresis in ADHF patients in the absence of volume depletion.     

Health programs struggling with complexity: a case study of the Dutch 'PreCare' project

This article aims to understand the effects of rationalized health programs (the basic components of which are efficiency, calculability, predictability and control) on local practices. We discuss how a successful U.S. intervention in preventive youth health care (the Nurse Family Partnership) has been translated and adapted within a Dutch setting. The Dutch version of the program is called 'PreCare'. The empirical analysis highlights the effects of rationalized health programs on local practices, in terms of the amount of work required, how local practices are disciplined, how these programs (re)draw boundaries, the 'travel expenditures' involved (and developed 'coping strategies'), and how local practices (try to) reshape the program. Our empirical analysis builds on a combination of qualitative methods. We conducted 16 semi-structured interviews with 19 people involved in the PreCare program. The majority of the interviews were conducted between July and November 2008. We also conducted an analysis of relevant documents related to the PreCare intervention and protocol. Furthermore, we observed at several meetings, including case conferences and management intervision meetings. The article makes a theoretical and practical contribution to the field. Theoretically, we show how the rationalization process is linked to a broader development of quantification and how both developments are based on a particularly modern ontology and epistemology in which what is considered 'real' and 'knowledgeable' becomes closely tied to what is measurable. The article offers a different conceptualization of rationalized health programs, one that acknowledges the need to standardize some elements, but also recognizes the need to be open and flexible toward local practices. We specifically focus on the tools that are able to deal with both the need to standardize and the need to be open toward local practices. We suggest that '(re)writing devices' are a fruitful category of tools for this purpose.     

Angiogenesis-independent cardioprotection in FGF-1 transgenic mice

OBJECTIVE: This study was performed to evaluate the cardioprotective role of acidic fibroblast growth factor-1 (FGF-1) in transgenic mice with cardiac-specific overexpression of human FGF-1. METHODS: Mice were subjected to coronary artery occlusion for 15-75 min with a continuously recorded 3-lead electrocardiogram (ECG). Infarct size was measured and ERK-1 and -2 activity was assessed by Western blot analysis. Creatine kinase and lactate dehydrogenase activity as marker for cell viability were measured in isolated ventricular myocytes subjected to simulated ischemia. RESULTS: Infarct development was markedly delayed in transgenics with first signs of myocardial infarction visible at 45 min after coronary artery occlusion compared to 15 min in wildtype. Maximal infarct size (60% of risk area) did not differ, but transgenics reached maximal infarction after 75 min compared to 45 min in wildtype animals. ECG revealed delayed Q-wave development and delayed ST-segment elevation in transgenics. Creatine kinase and lactate dehydrogenase release was significantly attenuated from isolated transgenic myocytes at 4 and 8 h after simulated ischemia. The delay in infarct development is partially due to a constitutive higher expression of the extracellular signal-regulated kinases ERK-1 and -2 in the myocardium of transgenics. Additionally, injection of the ERK-1/2 inhibitor UO126 decreased the cardioprotective effect of FGF-1. CONCLUSION: Cardiac specific overexpression of FGF-1 provides cardioprotection at the level of the cardiac myocyte, independent from angiogenesis, and at least partially mediated via activation of the mitogen activated protein kinase (MAP) ERK-1 and -2.     

Targeting ryanodine receptors for anti-arrhythmic therapy

Antiarrhythmic drugs are a group of pharmaceuticals that suppress or prevent abnormal heart rhythms, which are often associated with substantial morbidity and mortality. Current antiarrhythmic drugs that typically target plasma membrane ion channels have limited clinical success and in some cases have been described as being pro-arrhythmic. However, recent studies suggest that pathological release of calcium (Ca(2+)) from the sarcoplasmic reticulum via cardiac ryanodine receptors (RyR2) could represent a promising target for antiarrhythmic therapy. Diastolic SR Ca(2+) release has been linked to arrhythmogenesis in both the inherited arrhythmia syndrome 'catecholaminergic polymorphic ventricular tachycardia' and acquired forms of heart disease (eg, atrial fibrillation, heart failure). Several classes of pharmaceuticals have been shown to reduce abnormal RyR2 activity and may confer protection against triggered arrhythmias through reduction of SR Ca(2+) leak. In this review, we will evaluate the current pharmacological methods for stabilizing RyR2 and suggest treatment modalities based on current evidence of molecular mechanisms.