Felix M. Heidrich

Calcium, Calpains, and Cardiac Hypertrophy: A New Link

To The Editor: In the March 28, 2008 issue of Circulation Research , Letavernier et al assessed the effects of calpain inhibition on angiotensin (Ang) II–induced cardiovascular remodeling.1 These authors used transgenic mice expressing high levels of calpastatin to inhibit Ang II–dependent calpain activation. They show that prevention of Ang II–induced calpain activation is associated with impaired nuclear factor (NF)-κB activation in heart tissue, which eventually leads to decreased Ang II–induced cardiac hypertrophy. This finding adds substantial novel information to our understanding of how calpains might be involved in the complex regulation of cardiac hypertrophy. However, compelling evidence as to how calpains are activated by Ang II in the myocardium and how the calpain/calpastatin system is linked to NF-κB activation is not provided. In the May 23, 2008 issue of Circulation Research , we show that Ang II induces calcium release via the inositol 1,4,5-trisphosphate receptor …

From Bench to Bedside: Chromogranin B—A Promising Novel Biomarker in Heart Failure

C hromogranin B belongs to a family of proteins that are co-stored and co-secreted with other hormones. Chromogranins have a widespread distribution in the endocrine system and have been attributed to diverse cellular functions such as regulating intracellular calcium homeostasis and signaling, serving as precursors for biologically active peptides and inducing secretory granule biogenesis. To date, the best characterized members of the chromogranin family are the chromogranins A and B (CGA and CGB). CGA already is clinically used routinely as a biomarker in patients with neuroendocrine tumors, and evidence is now accumulating that CGA might as well aid in diagnosis, risk assessment, and treatment of cardiovascular disease including heart failure (HF). However, two major drawbacks significantly reduce the level of diagnostic certainty of CGA as a reliable biomarker: decreased renal function and treatment with proton pump inhibitors (PPIs) that both increase CGA plasma concentrations. Remarkably, CGB plasma levels instead do not seem to be affected by limited renal functionality or PPI medication. Because the elderly HF patient population has diminished renal function and ⁄or is taking PPI medication, CGB would clinically be clearly superior to CGA as a biomarker. To date, only little is known about CGB in cardiovascular (patho-) physiology. In 2008, we were the first to identify CGB as a novel regulator of cardiomyocyte signaling pathways that mediate hypertrophy and HF. We demonstrated that CGB regulates inositol 1,4,5-trisphosphate ⁄calcium-dependent cardiomyocyte signaling, nuclear factor-jB activity, and basal and angiotensin II (Ang II)–stimulated production and secretion of brain natriuretic peptide (BNP). Finally, we showed increased ventricular CGB protein levels in mice chronically treated with Ang II. Based on this evidence, we proposed a crucial role for CGB in cardiac hypertrophy and HF. We hoped our study would pave the road for future experimental studies and clinical trials that would continue to investigate the role of CGB in cardiovascular disease. Hence, it was with great interest that we read the article by Røsjø and colleagues on CGB in HF that was recently published in Circulation Heart Failure. In a post-myocardial infarction HF mouse model, the authors showed increased left ventricular CGB gene expression and protein levels that were confined to cardiomyocytes. Signaling molecules known to be regulated in HF, such as norepinephrine and Ang II, are shown to induce cardiomyocyte CGB. In HF mice, the authors showed increased circulating CGB plasma levels. Building the bridge from bench to bedside, the authors go on to demonstrate that CGB plasma levels are also increased in HF patients and correlate with HF disease severity assessed by New York Heart Association (NYHA) functional class. The clinical data from this study provide the first promising evidence for CGB to become a novel biomarker in HF whilst the experimental data obtained in HF mice confirm our earlier results. Notably, the authors investigated and discussed the potential sources of plasma CGB in HF development. We agree with the authors in that the ventricular myocardium is evidently an important source of circulating CGB. However, we believe that—different from the authors’ postulation—CGB production and secretion in HF is not entirely restricted to the ventricles. Instead, the authors’ results and statistics suggest that significant CGB production and secretion in HF in parallel occurs by another organ, which we believe are the adrenals. This is because the adrenal glands play a central role in the neurohumoral HF signaling axis, because the adrenal medulla is a major (if not the largest) store of CGB that is co-stored and cosecreted with catecholamines, and because production and secretion of NE by the adrenals is induced in HF in proportion to patient NYHA functional class. Although this is suggestive evidence, the authors did not consider the adrenomedullary CGB content when they investigated CGB protein levels in nonmyocardial tissues in the development of HF. That substantial CGB production and secretion in HF in parallel occurs by Felix M. Heidrich, MD; Kun Zhang, MD; Ruth H. Strasser, MD, PhD, FESC From the Department of Cardiology and Internal Medicine, Dresden University of Technology, Heart Center, Dresden; and the Department of Cardiology and Angiology, Charité—Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany

Association of platelet activation markers with recurrence of atrial fibrillation after pulmonary vein isolation

Abstract Atrial fibrillation (AF) is known to cause platelet activation. AF and its degree of thrombogenesis could be associated with monocyte-platelet aggregates (MPAs). We investigated on whether the content of MPAs or other platelet activation markers is associated with the recurrence of AF after pulmonary vein isolation (PVI). A total of 73 patients with symptomatic AF underwent PVI. After 6 months, all patients were evaluated for episodes of AF recurrence. At the same time, flow-cytometric quantification analyses were performed to determine the content of MPAs. Further platelet activation parameters were detected by using either cytometric bead arrays or quantitative immunological determination. Patients with recurrent AF (n = 20) compared to individuals without AF relapse (n = 53) were associated with an increased content of MPAs (43 ± 3% vs. 33 ± 2%, p = 0.004), as well as an increased CD41 expression on monocytes (191 ± 20 vs. 113 ± 6, p = 0.001). The level of the soluble platelet activation markers such as D-dimer, sCD40L, and sP-selectin did not differ between these groups. The content of MPAs correlated weakly with the level of sCD40L (r = 0.26, p = 0.03), but not with sP-selectin and D-dimer, whereas sP-selectin and sCD40L correlated with each other (r = 0.38, p = 0.001). Only the cellular marker of platelet activation, the content of MPAs, was increased in patients with recurrent AF after PVI. In contrast, soluble markers remained unaltered. These data indicate a distinct mechanism and level of platelet activation in AF. The clinical relevance of MPAs in identifying AF recurrence or in guiding the therapy with anticoagulants remains to be elucidated.

Reduction of atrial fibrillation burden by pulmonary vein isolation leads to a decrease of CD11b expression on inflammatory cells

Aims It is hypothesized that inflammation could promote structural and electrical remodelling processes in atrial fibrillation (AF). Atrial infiltration of monocytes and granulocytes has been shown to be dependent on CD11b expression. The aim of this study was to investigate whether treatment of AF by pulmonary vein isolation (PVI) may lead to reduced inflammation, as indicated by a decrease of CD11b expression on monocytes and granulocytes. Methods and results Flow-cytometric quantification analysis and determination of systemic inflammatory markers of peripheral blood were performed in 75 patients undergoing PVI 1 day before and 6 months after PVI. The extent of activation of monocytes and granulocytes was measured by quantifying the cell adhesion molecule CD11b. The mean expression of CD11b on monocytes (20.9 ± 2.5 vs. 10.2 ± 1.4; P < 0.001) and granulocytes (13.9 ± 1.6 vs. 6.8 ± 0.5; P < 0.001), as well as the relative count of CD11b-positive monocytes (P < 0.05) and CD11b-positive granulocytes (P < 0.01) were significantly reduced when comparing the identical patients before and 6 months after PVI. Systemic inflammatory parameters showed only a declining tendency after 6 months. Patients with unsuccessful PVI and ongoing AF on the day of follow-up showed no decrease in CD11b expression. Conclusions A significant reduction of CD11b expression on monocytes and granulocytes, as a sign of reduced cellular inflammation, was achieved by treatment of AF using PVI. These data strongly support that AF is not only a consequence of but also a cause for inflammatory processes, which, in turn, may contribute to atrial remodelling.

Three-dimensional transoesophageal echocardiography is crucial for valid assessment of mitral valve leaflet morphology in severe mitral regurgitation prior to interventional repair

Abstract Background: Interventional mitral valve (MV) repair of severe symptomatic mitral regurgitation (MR) is a therapeutic option in high-risk surgical or inoperable patients. Assessment of the MV remains a crucial part of pre-interventional screening. Three-dimensional transoesophageal echocardiography (3D-TOE) may compensate for well-known pitfalls that occur in 2D-TOE. Purpose: We investigated whether the functional length of the central segments of the posterior and anterior MV leaflets (PML-P2 and AML-A2) is more reliably determined by 3D-TOE full volume datasets (3D-MPR) or orthogonal biplane-imaging (Xplane) when compared to 2D-TOE. Methods and results: Between February 2014 and August 2015, 265 consecutive patients with moderate to severe symptomatic MR were screened. Seventy patients were judged suitable for interventional MV repair by the in-house Heart-Team. Eventually, 59 patients remained for data analysis. Inter-observer variability was lowest in 3D-MPR followed by Xplane (r = 0.92 and 0.90, p < .001 for both) and highest in Mplane (r = 0.82, p < .001). Mean functional PML-P2 lengths were similar in Xplane (12.6 ± 1.7 mm) and 3D-MPR (12.1 ± 2.0 mm), however, significantly different in 2D-TOE (10.0 ± 2.1 mm, p < .001). 2D-TOE underestimated PML-P2 length with a bias of –2.5 mm compared to Xplane and –1.95 mm compared to 3D-MPR. In contrast, functional AML-A2 length was determined similar across all methods. Conclusions: Our results demonstrate the superiority of 3D-TOE over 2D-TOE for accurate MV assessment in MR, especially for the determination of the functional PML length. Erroneous MV leaflet assessment may result in inadequate therapy restriction if the MV is deemed not suitable for interventional repair.

Comparison of diverse platelet activation markers as indicators for left atrial thrombus in atrial fibrillation

Abstract Atrial fibrillation (AF) is well known for being a major risk factor of thromboembolic stroke. We could recently demonstrate an association of monocyte–platelet aggregates (MPAs) with the degree of thrombogenicity in patients with AF. This study investigated platelet activation markers, as potential biomarkers for the presence of left atrial (LA) thrombus in patients with AF. One hundred and eight patients with symptomatic AF underwent transesophageal echocardiography (TEE) before scheduled cardioversion or pulmonary vein isolation. In order to determine the content of MPAs by flow-cytometric quantification analyses, blood was drawn on the day of TEE. The soluble CD40 Ligand (sCD40L) and soluble P-selectin (sP-selectin) were obtained by Cytometric Bead Arrays (CBA). D-dimer levels were detected by quantitative immunological determination of fibrin degradation products. Clinical, laboratory, and echocardiographic standard parameters were obtained from all patients, including the determination of the flow in the left atrial appendage (LAA). Patients with detected LA thrombus (n = 28) compared with patients without thrombus (n = 80) showed an increased number of common risk factors, such as age, diabetes, heart failure, and coronary artery disease (CAD). The presence of LA thrombus was associated with significantly increased levels of MPAs (147 ± 12 vs. 304 ± 29 per µl; p < 0.00), sCD40L (106.3 ± 31.0 vs. 33.5 ± 2.1 pg/ml, p = 0.027), and D-dimer (0.13 ± 0.02 vs. 0.69 ± 0.21 mg FEU/l, p = 0.015). In contrast, sP-selectin showed no association with LA thrombus. A multivariate regression analysis showed that MPAs, sCD40L as well as D-dimers were independent indicators for the existence of LA thrombus. MPAs above 170 cells/µl indicated LA thrombus with a high sensitivity of 93% and a specificity of 73% (OR 62, 95% CI. 6.9–557.2, p < 0.001) in patients with AF, whereas the D-dimer lost their quality as independent indicator by using the conventional cut-off of 0.5 mg/l within the regression analysis. MPAs, as well as the D-dimer, correlated significantly negatively with the flow in the LAA measured during TEE. The content of MPAs, sCD40L, and D-dimer, but not sP-selectin showed an increased dependence on LA thrombus in patients with AF. In our study group, MPAs showed the best diagnostic test accuracy of the compared platelet markers. The different results of the examined platelet activation markers could be an indication of diverse mechanisms of LA thrombus in AF. Further studies should evaluate whether determination of MPAs in clinical routine may suffice to indicate the presence of LA thrombus in patients with AF.

Regulation of circulating chromogranin B levels in heart failure

Abstract Background: Chromogranin B (CGB) regulates B-type natriuretic peptide (BNP) production. Circulating CGB levels are elevated in heart failure (HF) animal models and HF patients, but also increase in healthy individuals in response to physical activity. Therefore, CGB seems to integrate information from myocardial stress and systemic neuro-endocrine activation. Substantial gaps remain in our understanding of CGB regulation in HF. Methods and results: We conducted a retrospective registry study including 372 patients. CGB and N-terminal pro-BNP (NT-proBNP) plasma levels were assessed in acute HF and chronic valvular HF patients and controls. CGB levels were significantly increased in acute HF and chronic valvular HF, but significantly higher in the latter. Patients in chronic valvular HF with severe mitral regurgitation (cHF-MR) showed significantly higher CGB levels than patients in chronic valvular HF with severe aortic stenosis. CGB levels progressively increased with worsening NYHA functional status and were moderately correlated to NT-proBNP, but independent of left ventricular (LV) ejection fraction (LVEF), LV mass, age and body weight. Finally, cHF-MR patients showed significant reductions of CGB levels after interventional mitral valve repair. Conclusion: CGB is a promising emerging biomarker in HF patients with unique potential to integrate information from myocardial stress and neuro-endocrine activation.

Letter by Heidrich et al Regarding Article, “A Word of Caution: Risk of Device Erosion After Percutaneous Treatment of Atrial Septal Defect in Patients With Dilated Aortic Root”

In this interesting report, Dardas et al1 describe another case of a rare yet potentially life-threatening complication of interventional atrial septal defect closure with a 20-mm Amplatzer septal occluder device. Transesophageal echocardiography revealed a 15-mm atrial septal defect complicated by a deficient aortic rim and a bicuspid aortic valve, along with aortic root dilation (42 mm). At the routine 6-month follow-up, transesophageal echocardiography showed device perforation into the aortic root. We previously described a series of 2 patients who underwent primarily uncomplicated interventional patent foramen ovale closure by a Cardia Star …

Percutaneous Transjugular Removal of an Intracardial Bone Cement Fragment After Dorsal Stabilization

A 79-year-old woman was admitted to our center for atypical angina pectoris with chest pains worse at coughing. Her medical history revealed a dorsal stabilization of 3 lumbar vertebral bodies, 5 months ago. Laboratories showed moderate elevation of high-sensitive troponin T. Therefore, a coronary angiography was performed and ruled out significant coronary artery stenoses. However, fluoroscopy showed a toothpick-shaped structure of ≈9 cm reaching from the superior vena cava down to the diaphragmal base of the right ventricle (RV; Figure [A] and [B]). Chest x-ray and 3-dimensional echocardiography confirmed the presence of a toothpick-like structure within the RV, along with a small pericardial effusion (Figure [C–E]; see Movie IA and IB in the Data Supplement). In-depth investigation of the patient’s medical record revealed usage of bone cement (polymethylmethacrylate [PMMA]) during the orthopedic procedure 5 months ago. A computed tomographic scan was performed, and 3-dimensional reconstruction showed multiple pulmonary emboli of identical Hounsfield units in addition to the structure in the RV (Figure [F] and [G]). Considering the patient’s medical history, we hypothesized the visualized structures being PMMA fragments accidentally penetrating into the paravertebral venous system causing consecutive cardiopulmonary embolism after the orthopedic procedure. For retrieval, open heart surgery was declined by the patient. …

Letter by Heidrich et al Regarding Article, “Inositol 1,4,5-Trisphosphate Receptors and Human Left Ventricular Myocytes”

It was with great interest that we read the comprehensive study by Signore et al1 addressing the impact of inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3Rs) on the electromechanical behavior of mouse cardiomyocytes and human ventricular myocardium. Published in the September 17, 2013, issue of Circulation , this article provides compelling evidence that the Gαq-protein–coupled receptor (GPCR)/InsP3R axis plays a critical role in the regulation of cardiomyocyte calcium homeostasis, electric stability, and contractile performance. The authors demonstrate that GPCR agonists generate InsP3, which activates InsP3Rs to liberate calcium from internal stores, resulting in decreased resting membrane potential, prolongation of myocyte action potential, and the …