Gabriel Vorobiof

Variation in left atrial transmural wall thickness at sites commonly targeted for ablation of atrial fibrillation

BackgroundThe number of catheter ablations performed for atrial fibrillation (AF) has increased dramatically over the past several years. Regional variation in left atrial (LA) wall thickness is known to exist but have not been described in detail. AF ablation success and complication rates may be related to regional differences in LA wall thickness.ObjectiveTo evaluate differences in transmural wall thickness in five pre-defined anatomic areas within the LA which are commonly targeted for AF ablation.Materials and methodsWe measured LA wall transmural thickness in 34 human heart specimens using calipers in five anatomic areas frequently targeted during AF ablation (anterior wall, septum, mitral isthmus, posterior wall and roof).ResultsThe autopsied individuals were 53% female, 67.7% had CAD, 14.7% had atrial fibrillation, 61.8% had hypertension, and 21.6% had congestive heart failure. The roof was the thinnest region with mean thickness measuring significantly less than each other area (p 0.005 for the posterior wall and <0.001 for all other areas). The septum was the thickest region with mean thickness measuring significantly greater than each other area (p = 0.05, 0.001, <0.001, <0.001 measured against the anterior wall, isthmus, posterior wall and roof, respectively).ConclusionsSignificant regional differences exist for mean left atrial wall thickness among the different anatomic areas within the left atrium which are often targeted during catheter ablation of AF. These differences may have significant implications in determining the ideal intensity and total duration of radiofrequency energy required to achieve a safe and successful ablation.

The common apolipoprotein A-1 polymorphism -75A>G is associated with ethnic differences in recurrent coronary events after recovery from an acute myocardial infarction.

Since data regarding the relationship between a common polymorphism (SNP) of the apoA1 gene with apoA1 levels and risk of coronary artery disease are inconsistent, we hypothesized that its association with recurrent coronary events differs for White and Black individuals with diagnosed coronary heart disease. The apoA1 −75G>A SNP was genotyped in a cohort of 834 Black (n=129) and White (n=705) post-myocardial infarction patients. Recurrent coronary events (coronary-related death, non-fatal myocardial infarction, or unstable angina) were documented during an average follow-up of 28 months. Thirty percent of White and 21% of Black patients carried the SNP. Cox proportional-hazards regression analysis, adjusting for clinical and laboratory covariates, demonstrated that the SNP was not associated with recurrent events in the total cohort (HR=1.37, 95% CI 0.95–1.97; p= 0.09) but was the only variable associated with an increased risk of recurrent cardiac events in Blacks (HR=2.40, 95% CI 1.07–5.40; p= 0.034). Conversely in Whites, the SNP was not associated with recurrent events (HR=1.12, 95% CI 0.75–1.67; p= 0.59) whereas apoB (HR=1.78, 95% CI 1.20 −2.65; p= 0.0042) and calcium channel blocker use (HR=2.53, 95% CI 1.72–3.72; p<0.001) were associated; p= 0.0024 for interaction between ethnicity and the SNP. A common apoA1 SNP is associated with a significantly increased risk of recurrent cardiac events among Black, but not White, postmyocardial infarction patients. Relationships with lipoproteins may help explain this finding.

Changes in myocardial deformation after transcatheter and surgical aortic valve replacement

Speckle tracking echocardiography (STE) has emerged as a novel angle‐independent modality in assessing myocardial velocity, deformation, and strain. Its role in assessing change before and after aortic valve replacement in patients with aortic stenosis (AS) has recently generated interest. This review summarizes the practical utility and clinical implications of myocardial deformation by STE after surgical or transcatheter aortic valve replacement (TAVR). Overall, atrial strain and ventricular strain as measured by STE improve after surgical and transcatheter aortic intervention in short‐ and long‐term follow‐up with evidence of a more pronounced acute improvement in patients who undergo TAVR. STE assessment of strain, particularly global longitudinal strain, can detect subtle changes in myocardial systolic function prior to conventional variables such as left ventricular ejection fraction and is clinically useful in predicting mortality and symptom development in patients with AS. This underscores the emerging role of STE in monitoring post‐procedural improvements in cardiac function as well as the potential value in guiding optimal timing of AS intervention.

Small Molecule Disruption of Gβγ Signaling Inhibits the Progression of Heart FailureNovelty and Significance

Rationale: Excess signaling through cardiac G&bgr;&ggr; subunits is an important component of heart failure (HF) pathophysiology. They recruit elevated levels of cytosolic G protein–coupled receptor kinase (GRK)2 to agonist-stimulated &bgr;-adrenergic receptors (&bgr;-ARs) in HF, leading to chronic &bgr;-AR desensitization and downregulation; these events are all hallmarks of HF. Previous data suggested that inhibiting G&bgr;&ggr; signaling and its interaction with GRK2 could be of therapeutic value in HF. Objective: We sought to investigate small molecule G&bgr;&ggr; inhibition in HF. Methods and Results: We recently described novel small molecule G&bgr;&ggr; inhibitors that selectively block G&bgr;&ggr;-binding interactions, including M119 and its highly related analog, gallein. These compounds blocked interaction of G&bgr;&ggr; and GRK2 in vitro and in HL60 cells. Here, we show they reduced &bgr;-AR–mediated membrane recruitment of GRK2 in isolated adult mouse cardiomyocytes. Furthermore, M119 enhanced both adenylyl cyclase activity and cardiomyocyte contractility in response to &bgr;-AR agonist. To evaluate their cardiac-specific effects in vivo, we initially used an acute pharmacological HF model (30 mg/kg per day isoproterenol, 7 days). Concurrent daily injections prevented HF and partially normalized cardiac morphology and GRK2 expression in this acute HF model. To investigate possible efficacy in halting progression of preexisting HF, calsequestrin cardiac transgenic mice (CSQ) with extant HF received daily injections for 28 days. The compound alone halted HF progression and partially normalized heart size, morphology, and cardiac expression of HF marker genes (GRK2, atrial natriuretic factor, and &bgr;-myosin heavy chain). Conclusions: These data suggest a promising therapeutic role for small molecule inhibition of pathological G&bgr;&ggr; signaling in the treatment of HF.Rationale: Excess signaling through cardiac Gβγ subunits is an important component of heart failure (HF) pathophysiology. They recruit elevated levels of cytosolic G protein–coupled receptor kinase (GRK)2 to agonist-stimulated β-adrenergic receptors (β-ARs) in HF, leading to chronic β-AR desensitization and downregulation; these events are all hallmarks of HF. Previous data suggested that inhibiting Gβγ signaling and its interaction with GRK2 could be of therapeutic value in HF. Objective: We sought to investigate small molecule Gβγ inhibition in HF. Methods and Results: We recently described novel small molecule Gβγ inhibitors that selectively block Gβγ-binding interactions, including M119 and its highly related analog, gallein. These compounds blocked interaction of Gβγ and GRK2 in vitro and in HL60 cells. Here, we show they reduced β-AR–mediated membrane recruitment of GRK2 in isolated adult mouse cardiomyocytes. Furthermore, M119 enhanced both adenylyl cyclase activity and cardiomyocyte contractility in response to β-AR agonist. To evaluate their cardiac-specific effects in vivo, we initially used an acute pharmacological HF model (30 mg/kg per day isoproterenol, 7 days). Concurrent daily injections prevented HF and partially normalized cardiac morphology and GRK2 expression in this acute HF model. To investigate possible efficacy in halting progression of preexisting HF, calsequestrin cardiac transgenic mice (CSQ) with extant HF received daily injections for 28 days. The compound alone halted HF progression and partially normalized heart size, morphology, and cardiac expression of HF marker genes (GRK2, atrial natriuretic factor, and β-myosin heavy chain). Conclusions: These data suggest a promising therapeutic role for small molecule inhibition of pathological Gβγ signaling in the treatment of HF.