scholarly journals Cardiovascular Characteristics of Patients with Genetic Variation in Desmoplakin (DSP)

2022 ◽  
Vol 12 (1) ◽  
pp. 24-36
Author(s):  
Nosheen Reza ◽  
Alejandro de Feria ◽  
Jessica L. Chowns ◽  
Lily Hoffman-Andrews ◽  
Laura Vann ◽  
...  
Keyword(s):  
Heart Failure ◽  
Genetic Variation ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
University Of Pennsylvania ◽  
Initial Assessment ◽  
Clinical Genetic ◽  
Pathogenic Variants ◽  
End Stage

Background: Variants in the desmoplakin (DSP) gene have been recognized in association with the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) for nearly 20 years. More recently, genetic variation in DSP has also been associated with left-dominant arrhythmogenic cardiomyopathy. Data regarding the cardiac phenotypes associated with genetic variation in DSP have been largely accumulated from phenotype-first studies of ARVC. Methods: We aimed to evaluate the clinical manifestations of cardiac disease associated with variants in DSP through a genotype-first approach employed in the University of Pennsylvania Center for Inherited Cardiovascular Disease registry. We performed a retrospective study of 19 individuals with “pathogenic” or “likely pathogenic” variants in DSP identified by clinical genetic testing. Demographics and clinical characteristics were collected. Results: Among individuals with disease-causing variants in DSP, nearly 40% had left ventricular enlargement at initial assessment. Malignant arrhythmias were prevalent in this cohort (42%) with a high proportion of individuals undergoing primary and secondary prevention implantable cardioverter defibrillator implantation (68%) and ablation of ventricular arrhythmias (16%). Probands also experienced end-stage heart failure requiring heart transplantation (11%). Conclusions: Our data suggest DSP cardiomyopathy may manifest with a high burden of heart failure and arrhythmic events, highlighting its importance in the pathogenesis of dilated and arrhythmogenic cardiomyopathies. Targeted strategies for diagnosis and risk stratification for DSP cardiomyopathy should be investigated.

scholarly journals Induction of Ankrd1 in Dilated Cardiomyopathy Correlates with the Heart Failure Progression

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Julius Bogomolovas ◽  
Kathrin Brohm ◽  
Jelena Čelutkienė ◽  
Giedrė Balčiūnaitė ◽  
Daiva Bironaitė ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Cardiac Remodeling ◽  
Expression Patterns ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Expression Levels ◽  
Potential Marker ◽  
End Stage

Progression of idiopathic dilated cardiomyopathy (IDCM) is marked with extensive left ventricular remodeling whose clinical manifestations and molecular basis are poorly understood. We aimed to evaluate the clinical potential of titin ligands in monitoring progression of cardiac remodeling associated with end-stage IDCM. Expression patterns of 8 mechanoptotic machinery-associated titin ligands (ANKRD1,ANKRD2,TRIM63,TRIM55,NBR1,MLP,FHL2, andTCAP) were quantitated in endomyocardial biopsies from 25 patients with advanced IDCM. When comparing NYHA disease stages, elevatedANKRD1expression levels marked transition from NYHA < IV to NYHA IV.ANKRD1expression levels closely correlated with systolic strain depression and short E wave deceleration time, as determined by echocardiography. On molecular level, myocardialANKRD1and serum adiponectin correlated with lowBAX/BCL-2ratios, indicative of antiapoptotic tissue propensity observed during the worsening of heart failure. ANKRD1 is a potential marker for cardiac remodeling and disease progression in IDCM.ANKRD1expression correlated with reduced cardiac contractility and compliance. The association ofANKRD1with antiapoptotic response suggests its role as myocyte survival factor during late stage heart disease, warranting further studies on ANKRD1 during end-stage heart failure.

scholarly journals Pathogenic variants in plakophilin-2 gene (PKP2) are associated with better survival in arrhythmogenic right ventricular cardiomyopathy

2021 ◽  
Author(s):  
Elżbieta K. Biernacka ◽  
Karolina Borowiec ◽  
Maria Franaszczyk ◽  
Małgorzata Szperl ◽  
Alessandra Rampazzo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Right Ventricular ◽  
Heart Transplant ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Cardiomyopathy ◽  
Ventricular Ejection Fraction ◽  
Pathogenic Variants ◽  
Plakophilin 2

AbstractArrhythmogenic right ventricular cardiomyopathy (ARVC) is mainly caused by mutations in genes encoding desmosomal proteins. Variants in plakophilin-2 gene (PKP2) are the most common cause of the disease, associated with conventional ARVC phenotype. The study aims to evaluate the prevalence of PKP2 variants and examine genotype–phenotype correlation in Polish ARVC cohort. All 56 ARVC patients fulfilling the current criteria were screened for genetic variants in PKP2 using denaturing high-performance liquid chromatography or next-generation sequencing. The clinical evaluation involved medical history, electrocardiogram, echocardiography, and follow-up. Ten variants (5 frameshift, 2 nonsense, 2 splicing, and 1 missense) in PKP2 were found in 28 (50%) cases. All truncating variants are classified as pathogenic/likely pathogenic, while the missense variant is classified as variant of uncertain significance. Patients carrying a PKP2 mutation were younger at diagnosis (p = 0.003), more often had negative T waves in V1–V3 (p = 0.01), had higher left ventricular ejection fraction (p = 0.04), and were less likely to present symptoms of heart failure (p = 0.01) and left ventricular damage progression (p = 0.04). Combined endpoint of death or heart transplant was more frequent in subgroup without PKP2 mutation (p = 0.03). Pathogenic variants in PKP2 are responsible for 50% of ARVC cases in the Polish population and are associated with a better prognosis. ARVC patients with PKP2 mutation are less likely to present left ventricular involvement and heart failure symptoms. Combined endpoint of death or heart transplant was less frequent in this group.

AIM2-driven inflammasome activation in chronic heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Ruppert ◽  
Z.S Onodi ◽  
P Leszek ◽  
V.E Toth ◽  
G Koncsos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Animal Models ◽  
Left Ventricular ◽  
Inflammasome Activation ◽  
Coronary Artery Ligation ◽  
Funding Source ◽  
Human Cardiomyocytes ◽  
Pannexin 1 ◽  
End Stage

Abstract Background Inflammation and cytokine release have been implicated in the pathogenesis of chronic heart failure (CHF). Of particular interest, Canakinumab, a monoclonal antibody against interleukin-1b (IL-1β), had provided benefit against cardiovascular events, suggesting that blockade of IL-1β secretion and signaling might be a promising new therapeutic target. Although, recent studies have provided evidence that inflammasome activation is the main contributor to IL-1β maturation, the role of inflammasome activation in CHF remains unknown. Objective Therefore, we aimed to assess inflammasome activation in myocardial samples from end-stage failing hearts. Methods Inflammasome activation was assessed by immunoblotting in left ventricular myocardial specimens harvested from patients with end-stage CHF. Furthermore, immunoblot measurements were also performed on translational animal models of CHF (e.g. rat models of permanent coronary artery ligation and transverse aortic constriction). Left ventricular monocyte and macrophage infiltration was detected by immunohistochemistry. To investigate the molecular background of inflammasome activation, a series of cell culture experiments were performed on AC16 human cardiomyocytes and THP-1 human monocytic cell lines. Results Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human CHF while the NLRP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change. A similar expression pattern in AIM2 and NLRC4 was also noted in CHF animal models. Furthermore, robust infiltration of Iba1+ monocytes/macrophages was observed in human failing hearts as well as in different animal models of CHF. In vitro AIM2 inflammasome activation, as induced by transfection with double-stranded DNA [poly(deoxyadenylic-deoxythymidylic)] was reduced significantly by the pharmacological blockade of pannexin-1 channels. Conclusions AIM2 and NLRC4 inflammasome activation might contribute to chronic inflammation in CHF. Our findings suggest that pannexin-1 channels might be a promising novel target to reduce inflammasome activation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

scholarly journals Left ventricular systolic function decreases in lamin a/c cardiomyopathy wihout concomitant ventricular dilatation

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
ES Eystein Skjolsvik ◽  
OL Oyvind Haugen Lie ◽  
MC Monica Chivulescu ◽  
MR Margareth Ribe ◽  
AIC Anna Isotta Castrini ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular ◽  
University Hospital ◽  
Lv Function ◽  
Lamin A ◽  
Age Related ◽  
End Stage Heart Failure ◽  
Lv Volumes ◽  
End Stage

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by the Norwegian Research Council [203489/030] onbehalf Department of Cardiology, Research group for genetic cardiac diseases and sudden cardiac death, Oslo University Hospital, Rikshospitalet, Oslo, Norwa Background Lamin A/C disease is an inheritable cardiomyopathy characterized by conduction abnormalities, ventricular arrhythmias and end stage heart failure with complete age-related penetrance. Purpose To assess left ventricular structural and functional progression in patients with lamin A/C cardiomyopathy. Methods We included and followed consecutive lamin A/C genotype positive patients with clinical examination and echocardiography at every visit. We evaluated progression of left- ventricular size and function by mixed model statistics. Results We included 101 consecutive lamin A/C genotype positive patients (age 44 [29-54] years, 39% probands, 51%female) with 576 echocardiographic exams during 4.9 (IQR 2.5-8.1) years of follow-up. LV ejection fraction (LVEF) declined from 50 ± 12% to 47 ± 13%, p &lt; 0.001 (rate -0.5%/year). LV end diastolic volumes (LVEDV) remained stationary with no significant dilatation in the total population (136 ± 45ml to 138 ± 43ml, p = 0.60), (Figure). In the subgroup of patients &gt;58 years, we observed a decline in LV volumes 148, SE 9 ml to 140, SE 9 ml p &lt; 0.001 (rate -2.7 ml/year) towards end stage heart failure. Conclusions LVEF deteriorated, while LV size remained unchanged during 4.9 years of follow-up in patients with lamin A/C cardiomyopathy. In patients &lt;58 years, we observed a reduction in LV volumes. These findings represent loss of LV function without the necessary compensatory dilation to preserve stroke volume indicating high risk of decompensated end stage heart failure in lamin A/C. Abstract Figure.

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