Sex‐Dependent Phenotypic Variability of an
            <i>SCN5A</i>
            Mutation: Brugada Syndrome and Sick Sinus Syndrome

Aizawa, Yoshifusa; Fujisawa, Taishi; Katsumata, Yoshinori; Kohsaka, Shun; Kunitomi, Akira; Ohno, Seiko; Sonoda, Koji; Hayashi, Hidemori; Hojo, Rintaro; Fukamizu, Seiji; Nagase, Satoshi; Ito, Shogo; Nakajima, Kiyokazu; Nishiyama, Takahiko; Kimura, Tokuhiro; Kurita, Yasuo; Furukawa, Yoshiko; Takatsuki, Seiji; Ogawa, Satoshi; Nakazato, Yuji; Sumiyoshi, Masataka; Kosaki, Kenjiro; Horie, Minoru; Fukuda, Keiichi

doi:10.1161/jaha.118.009387

Cited by 18 publications

(12 citation statements)

References 18 publications

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“…Although IFN-γ is implicated in immune and inflammatory responses as a component of the Th1 response, its increased expression has been shown to exert contrasting effects; promote cardiovascular dysfunction or mediate cardioprotective effects [ 61 – 66 ]. However, unlike in other studies [ 62 – 66 ], changes in IFN-γ levels did not correlate with suppression of cardiac hypertrophy in the sac/val-treated ZO rats.…”

Section: Discussioncontrasting

confidence: 99%

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

Aroor

Mummidi

López-Alvarenga

et al. 2021

Cardiovasc Diabetol

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Objective Cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy. Methods Sixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg−1•day−1; ZOSV); Group 3: valsartan (31 mg•kg−1•day−1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg−1•day−1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. Results Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD. Conclusions These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.

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Section: Discussioncontrasting

confidence: 99%

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

Aroor

Mummidi

López-Alvarenga

et al. 2021

Cardiovasc Diabetol

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“…The presence of modifier genes in Asians but not in Whites 19 could play a role. These modifier genes in Asians affect the phenotype and could have sex specific effects 20 . Another possible explanation might come from female susceptibility to triggers and/or the prevalence of triggers that might differ between genders of Asian or White origin 21 .…”

Section: Differences Between Whites and Asiansmentioning

confidence: 99%

Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome

et al. 2019

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Background There is limited information on ethnic differences between patients with Brugada syndrome (BrS) with arrhythmic events (AEs). Objectives To compare clinical, electrocardiographic (ECG), electrophysiologic (EP) and genetic characteristics between White and Asian BrS-patients with AE. Methods SABRUS is a multicenter survey from Western and Asian countries, gathering 678 BrSpatients with first documented AE. After excluding patients with other (n=14; 2.1%) or unknown (n=30; 4.4%) ethnicity, 364 (53.7%) Whites and 270 (39.8%) Asians comprised the study group. Results There was no difference in AE age onset (41.3±16.1 years in Whites vs. 43.3±12.3 years in Asians, P=0.285). Higher proportions of Whites were observed in pediatric and elderly populations. Asians were predominantly males (98.1% vs. 85.7% in Whites, P<0.001) and frequently presented with aborted cardiac arrest (ACA) (71.1% vs. 56%, P<0.001). Asians tended to display more spontaneous type 1 BrS-ECG (71.5% vs. 64.3%, P=0.068). Family history of sudden cardiac death (FHSCD) was noted more in Whites (29.1% vs. 11.5%, P<0.001), with higher rate of SCN5A mutation carriers (40.1% vs. 13.2% in Asians, P<0.001), as well as more fever-related AEs (8.5% vs. 2.9%, 0.011). No difference was observed between the two groups regarding prior history of syncope and ventricular arrhythmia inducibility. Conclusions There are important differences between Asian and White BrS-patients. Asian patients present almost exclusively as male adults, more often with ACA and spontaneous type 1 BrS-ECG. However, they have less FHSCD and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.

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“…The SCN5A (sodium voltage-gated channel alpha subunit 5) gene codes the pore-forming alfa subunit of the primary cardiac channel. Genetic variants of SCN5A play role in Brugada syndrome, progressive familial heart block, Romano-Ward syndrome, sick sinus syndrome, familial atrial fibrillation, and familial dilated cardiomyopathy ( 51 – 53 ). In our study, a mother (III:5) without any cardiac condition had a heterozygous (VUS) variant, c.4171G>A (p.Gly1391Arg) in the SCN5A gene and it wasn't transmitted to a currently living offspring.…”

Section: Resultsmentioning

confidence: 99%

Sudden Cardiac Death—A New Insight Into Potentially Fatal Genetic Markers

Primorac

Odak

Perić³

et al. 2021

Front. Med.

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Sudden cardiac death (SCD) is an unexpected and dramatic event. It draws special attention especially in young, seemingly healthy athletes. Our scientific paper is based on the death of a young, 23-year-old professional footballer, who died on the football field after a two-year history of cardiac symptoms. In this study we analyzed clinical, ECG and laboratory data, as well as results of genetic testing analysis in family members. To elucidate potential genetic etiology of SCD in this family, our analysis included 294 genes related to various cardiac conditions.

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Sex‐Dependent Phenotypic Variability of an SCN5A Mutation: Brugada Syndrome and Sick Sinus Syndrome

Cited by 18 publications

References 18 publications

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome

Sudden Cardiac Death—A New Insight Into Potentially Fatal Genetic Markers

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