Secretogranin II; a Protein Increased in the Myocardium and Circulation in Heart Failure with Cardioprotective Properties

Background: Several beneficial effects have been demonstrated for secretogranin II (SgII) in non-cardiac tissue. As cardiac production of chromogranin A and B, two related proteins, is increased in heart failure (HF), we hypothesized that SgII could play a role in cardiovascular pathophysiology. Methodology/Principal Findings: SgII production was characterized in a post-myocardial infarction heart failure (HF) mouse model, functional properties explored in experimental models, and circulating levels measured in mice and patients with stable HF of moderate severity. SgII mRNA levels were 10.5 fold upregulated in the left ventricle (LV) of animals with myocardial infarction and HF (p<0.001 vs. sham-operated animals). SgII protein levels were also increased in the LV, but not in other organs investigated. SgII was produced in several cell types in the myocardium and cardiomyocyte synthesis of SgII was potently induced by transforming growth factor-beta and norepinephrine stimulation in vitro. Processing of SgII to shorter peptides was enhanced in the failing myocardium due to increased levels of the proteases PC1/3 and PC2 and circulating SgII levels were increased in mice with HF. Examining a pathophysiological role of SgII in the initial phase of post-infarction HF, the SgII fragment secretoneurin reduced myocardial ischemia-reperfusion injury and cardiomyocyte apoptosis by 30% and rapidly increased cardiomyocyte Erk1/2 and Stat3 phosphorylation. SgII levels were also higher in patients with stable, chronic HF compared to age-and gender-matched control subjects: median 0.16 (Q1-3 0.14-0.18) vs. 0.12 (0.10-0.14) nmol/L, p<0.001. Conclusions: We demonstrate increased myocardial SgII production and processing in the LV in animals with myocardial infarction and HF, which could be beneficial as the SgII fragment secretoneurin protects from ischemia-reperfusion injury and cardiomyocyte apoptosis. Circulating SgII levels are also increased in patients with chronic, stable HF and may represent a new cardiac biomarker

Genes Involved in Systemic and Arterial Bed Dependent Atherosclerosis - Tampere Vascular Study

BACKGROUND: Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the genes generally involved in human advanced atherosclerotic (AHA type V-VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25). CONCLUSIONS: This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds

Systemic arterial properties during normal pregnancies in healthy women

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Impact of pregnancy and risk factors for ventricular arrhythmias in women operated for tetralogy of Fallot

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): South-Eastern Norway Regional Health Authority Background Patients with tetralogy of Fallot (TOF) have a high survival rate 30 years after surgical repair, and generally enjoy a satisfactory quality of life. Many female patients experience pregnancy during adulthood, however the effects of pregnancy on the long-term cardiovascular outcome in this group of patients are not well known. Purpose We aimed to investigate the association of pregnancy and cardiac function with occurrence of ventricular arrhythmia (VA) in women operated for TOF. Methods We included 80 patients recruited from the national database for patients diagnosed for TOF. All were examined with echocardiography, including strain echocardiography. We assessed mechanical dispersion of right ventricle (RV) as measure of heterogeneous contraction. Holter monitoring or implanted devices detected ventricular arrhythmias (VA), defined as non-sustained or sustained ventricular tachycardia or aborted cardiac arrest. Blood tests included N-terminal pro-brain natriuretic peptide (NT-proBNP). Results In all, 55 (69%) women had experienced pregnancy (age 40 ± 9 years, parity median 1, range 1-4), while 25 (31%) women were nulliparous. The mean age was lower in nulliparous compared to those with children (30 ± 9 vs 40 ± 9, p &amp;lt; 0.01). VA was more prevalent in women who had experienced pregnancy (n = 16, 94%) compared to nulliparous (n = 1, 6%) (p = 0.02), and importantly also when adjusted for age [adjusted OR 9.8 (95% CI 1.2-79.1), p = 0.02]. RV mechanical dispersion was more pronounced in patients with VA [39.2 ± 14 ms vs. 49.6 ± 8 ms, p = 0.009, adjusted OR 2.1 (95% CI 1.3 - 7.5), p = 0.01 adjusted for age]. Higher NT-proBNP was also a marker of VA [211 ng/L (127-836) vs. 139 ng/L (30-465), p = 0.007, adjusted OR 1.4 (95% CI 1.1 - 1.8) p = 0.017 adjusted for age]. NT-proBNP &amp;gt;182 ng/L (normal values &amp;lt; 170 ng/L) optimally detected women with VA (p = 0.019), also independent of age [OR 7.2 (95% CI 1.7-30.1), p = 0.007]. Conclusion History of pregnancy was associated with higher prevalence of VA among women with surgically corrected TOF. Right ventricular mechanical dispersion and NT-proBNP were age independent markers of VA. These findings may have importance for risk stratification and preconception counselling of these patients. </jats:sec

Mitral annulus disjunction is associated with adverse outcome in patients with Marfan syndrome and Loeys-Dietz syndrome

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority Background Mitral valve prolapse is a common finding in patients with Marfan (MFS) and Loeys-Dietz syndromes (LDS). Mitral annulus disjunction (MAD) is an atrial displacement of the hinge point of the mitral valve that frequently coexists with mitral valve prolapse, but its clinical relevance in connective tissue disorders is unknown. Purpose To explore the association between MAD and severity of mitral valve and aortic disease in patients with MFS and LDS. Methods We included consecutive MFS patients and LDS patients fulfilling established diagnostic criteria. MAD was identified by echocardiography and defined as the distance from the ventricular myocardium to the hinge point of the posterior mitral leaflet (Figure, panel A). Aortic surgery was defined as emergency surgery for aortic dissection or prophylactic aortic surgery for aortic aneurysm. We recorded the need of mitral valve surgery including mitral valve repair or replacement. Results We included 168 patients of whom 103 (61%) had MFS and 65 (39%) had LDS. We identified MAD in 69 (41%) patients. Aortic surgery was performed in 112 (67%) patients (27 dissections and 85 prophylactic interventions). Patients with MAD were younger at the time of aortic surgery than those without MAD (p log rank = 0.02) (Figure, panel B). Patients needing aortic surgery had greater MAD distance (8 [7-10] mm vs. 7 [6-8] mm, p = 0.04). Mitral valve surgery was performed in 12 (7%) patients, more frequently in patients with MAD than in those without (16% vs. 1%, p &amp;lt; 0.001, p log rank &amp;lt; 0.001) (Figure, panel C). Conclusion MAD was frequent and detected in 41% of patients with MFS and LDS. MAD was associated with a more severe disease phenotype including aortic surgery at younger age and frequent need for mitral valve surgery. Screening patients with MFS and LDS for MAD may provide prognostic information and may be relevant in planning surgical interventions. Abstract Figure </jats:sec