Journal Of Clinical & Experimental Cardiology[JOURNAL]
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200 papers
Targeting Brain Aminopeptidase A: A New Strategy for the Treatment of Hypertension and Heart Failure.
Marc Y, Boitard SE, Balavoine F … +2 more , Azizi M, Llorens-Cortes C
Can J Cardiol · 2020 May · PMID 32389345 · Publisher ↗
The pathophysiology of heart failure (HF) and hypertension are thought to involve brain renin-angiotensin system (RAS) hyperactivity. Angiotensin III, a key effector peptide in the brain RAS, provides tonic stimulatory c...
The pathophysiology of heart failure (HF) and hypertension are thought to involve brain renin-angiotensin system (RAS) hyperactivity. Angiotensin III, a key effector peptide in the brain RAS, provides tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme responsible for generating brain angiotensin III, constitutes a potential therapeutic target for hypertension treatment. We focus here on studies of RB150/firibastat, the first prodrug of the specific and selective APA inhibitor EC33 able to cross the blood-brain barrier. We consider its development from therapeutic target discovery to clinical trials of the prodrug. After oral administration, firibastat crosses the gastrointestinal and blood-brain barriers. On arrival in the brain, it is cleaved to generate EC33, which inhibits brain APA activity, lowering BP in various experimental models of hypertension. Firibastat was clinically and biologically well tolerated, even at high doses, in phase I trials conducted in healthy human subjects. It was then shown to decrease BP effectively in patients of various ethnic origins with hypertension in phase II trials. Brain RAS hyperactivity leads to excessive sympathetic activity, which can contribute to HF after myocardial infarction (MI). Chronic treatment with oral firibastat (4 or 8 weeks after MI) has been shown to normalize brain APA activity in mice. This effect is accompanied by a normalization of brain RAS and sympathetic activities, reducing cardiac fibrosis and hypertrophy and preventing cardiac dysfunction. Firibastat may therefore represent a novel therapeutic advance in the clinical management of patients with hypertension and potentially with HF after MI.
Role of Hyperinsulinemia and Insulin Resistance in Hypertension: Metabolic Syndrome Revisited.
da Silva AA, do Carmo JM, Li X … +3 more , Wang Z, Mouton AJ, Hall JE
Can J Cardiol · 2020 May · PMID 32389340 · Full text
Hyperinsulinemia and insulin resistance were proposed more than 30 years ago to be important contributors to elevated blood pressure (BP) associated with obesity and the metabolic syndrome, also called syndrome X. Suppor...
Hyperinsulinemia and insulin resistance were proposed more than 30 years ago to be important contributors to elevated blood pressure (BP) associated with obesity and the metabolic syndrome, also called syndrome X. Support for this concept initially came from clinical and population studies showing correlations among hyperinsulinemia, insulin resistance, and elevated BP in individuals with metabolic syndrome. Short-term studies in experimental animals and in humans provided additional evidence that hyperinsulinemia may evoke increases in sympathetic nervous system (SNS) activity and renal sodium retention that, if sustained, could increase BP. Although insulin infusions may increase SNS activity and modestly raise BP in rodents, chronic insulin administration does not significantly increase BP in lean or obese insulin-resistant rabbits, dogs, horses, or humans. Multiple studies in humans and experimental animals have also shown that severe insulin resistance and hyperinsulinemia may occur in the absence of elevated BP. These observations question whether insulin resistance and hyperinsulinemia are major factors linking obesity/metabolic syndrome with hypertension. Other mechanisms, such as physical compression of the kidneys, activation of the renin-angiotensin-aldosterone system, hyperleptinemia, stimulation of the brain melanocortin system, and SNS activation, appear to play a more critical role in initiating hypertension in obese subjects with metabolic syndrome. However, the metabolic effects of insulin resistance, including hyperglycemia and dyslipidemia, appear to interact synergistically with increased BP to cause vascular and kidney injury that can exacerbate the hypertension and associated injury to the kidneys and cardiovascular system.
Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection.
Turley TN, O'Byrne MM, Kosel ML … +5 more , de Andrade M, Gulati R, Hayes SN, Tweet MS, Olson TM
JAMA Cardiol · 2020 Aug · PMID 32374345 · Full text
IMPORTANCE: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction...
IMPORTANCE: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death. OBJECTIVE: To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility. DESIGN, SETTING, AND PARTICIPANTS: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019. MAIN OUTCOMES AND MEASURES: Genetic loci and positional candidate genes associated with SCAD. RESULTS: This study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1). CONCLUSIONS AND RELEVANCE: This study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.
T cell subsets and functions in atherosclerosis.
Saigusa R, Winkels H, Ley K
Nat Rev Cardiol · 2020 Jul · PMID 32203286 · Full text
Atherosclerosis is a chronic inflammatory disease of the arterial wall and the primary underlying cause of cardiovascular disease. Data from in vivo imaging, cell-lineage tracing and knockout studies in mice, as well as...
Atherosclerosis is a chronic inflammatory disease of the arterial wall and the primary underlying cause of cardiovascular disease. Data from in vivo imaging, cell-lineage tracing and knockout studies in mice, as well as clinical interventional studies and advanced mRNA sequencing techniques, have drawn attention to the role of T cells as critical drivers and modifiers of the pathogenesis of atherosclerosis. CD4 T cells are commonly found in atherosclerotic plaques. A large body of evidence indicates that T helper 1 (T1) cells have pro-atherogenic roles and regulatory T (T) cells have anti-atherogenic roles. However, T cells can become pro-atherogenic. The roles in atherosclerosis of other T cell subsets such as T2, T9, T17, T22, follicular helper T cells and CD28 T cells, as well as other T cell subsets including CD8 T cells and γδ T cells, are less well understood. Moreover, some T cells seem to have both pro-atherogenic and anti-atherogenic functions. In this Review, we summarize the knowledge on T cell subsets, their functions in atherosclerosis and the process of T cell homing to atherosclerotic plaques. Much of our understanding of the roles of T cells in atherosclerosis is based on findings from experimental models. Translating these findings into human disease is challenging but much needed. T cells and their specific cytokines are attractive targets for developing new preventive and therapeutic approaches including potential T cell-related therapies for atherosclerosis.
Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis.
Chen HY, Cairns BJ, Small AM … +43 more , Burr HA, Ambikkumar A, Martinsson A, Thériault S, Munter HM, Steffen B, Zhang R, Levinson RT, Shaffer CM, Rong J, Sonestedt E, Dufresne L, Ljungberg J, Näslund U, Johansson B, Ranatunga DK, Whitmer RA, Budoff MJ, Nguyen A, Vasan RS, Larson MG, Harris WS, Damrauer SM, Stark KD, Boekholdt SM, Wareham NJ, Pibarot P, Arsenault BJ, Mathieu P, Gudnason V, O'Donnell CJ, Rotter JI, Tsai MY, Post WS, Clarke R, Söderberg S, Bossé Y, Wells QS, Smith JG, Rader DJ, Lathrop M, Engert JC, Thanassoulis G
JAMA Cardiol · 2020 Jun · PMID 32186652 · Full text
IMPORTANCE: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. OBJECTIVE: To identify novel genetic loci and pathways associated with A...
IMPORTANCE: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. OBJECTIVE: To identify novel genetic loci and pathways associated with AS. DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. EXPOSURES: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. MAIN OUTCOMES AND MEASURES: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. RESULTS: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). CONCLUSIONS AND RELEVANCE: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.
CRISPLD1: a novel conserved target in the transition to human heart failure.
Khadjeh S, Hindmarsh V, Weber F … +10 more , Cyganek L, Vidal RO, Torkieh S, Streckfuss-Bömeke K, Lbik D, Tiburcy M, Mohamed BA, Bonn S, Toischer K, Hasenfuss G
Basic Res Cardiol · 2020 Mar · PMID 32146539 · Full text
Heart failure is a major health problem worldwide with a significant morbidity and mortality rate. Although studied extensively in animal models, data from patients at the compensated disease stage are lacking. We sample...
Heart failure is a major health problem worldwide with a significant morbidity and mortality rate. Although studied extensively in animal models, data from patients at the compensated disease stage are lacking. We sampled myocardium biopsies from aortic stenosis patients with compensated hypertrophy and moderate heart failure and used transcriptomics to study the transition to failure. Sequencing and comparative analysis of analogous samples of mice with transverse aortic constriction identified 25 candidate genes with similar regulation in response to pressure overload, reflecting highly conserved molecular processes. The gene cysteine-rich secretory protein LCCL domain containing 1 (CRISPLD1) is upregulated in the transition to failure in human and mouse and its function is unknown. Homology to ion channel regulatory toxins suggests a role in Ca cycling. CRISPR/Cas9-mediated loss-of-function leads to dysregulated Ca handling in human-induced pluripotent stem cell-derived cardiomyocytes. The downregulation of prohypertrophic, proapoptotic and Ca-signaling pathways upon CRISPLD1-KO and its upregulation in the transition to failure implicates a contribution to adverse remodeling. These findings provide new pathophysiological data on Ca regulation in the transition to failure and novel candidate genes with promising potential for therapeutic interventions.
Improved Myocardial Function With Coronary Sinus Reducer in a Patient With Refractory Angina and Heart Failure With Reduced Ejection Fraction.
Gallone G, Palmisano A, Baldetti L … +6 more , Monti CB, Ponticelli F, Tzanis G, Colombo A, Esposito A, Giannini F
Can J Cardiol · 2020 Apr · PMID 32144039 · Publisher ↗
The coronary sinus Reducer represents a novel therapeutic option with established safety and clinical benefit in the treatment of patients with refractory angina, possibly achieved by enhancing perfusion of myocardial is...
The coronary sinus Reducer represents a novel therapeutic option with established safety and clinical benefit in the treatment of patients with refractory angina, possibly achieved by enhancing perfusion of myocardial ischemic territories. We report the first case providing insight on how improved perfusion might translate into improved myocardial function as assessed by cardiac magnetic resonance strain imaging, thus suggesting a physiological rationale to test coronary sinus Reducer in the setting of ischemic cardiomyopathy with reduced ejection fraction and adverse remodelling.
Association of Pulse Pressure With Clinical Outcomes in Patients Under Different Antiplatelet Strategies After Percutaneous Coronary Intervention: Analysis of GLOBAL LEADERS.
de Faria AP, Modolo R, Chichareon P … +19 more , Chang CC, Kogame N, Tomaniak M, Takahashi K, Rademaker-Havinga T, Wykrzykowska J, de Winter RJ, Ferreira RC, Sousa A, Lemos PA, Garg S, Hamm C, Juni P, Vranckx P, Valgimigli M, Windecker S, Onuma Y, Steg PG, Serruys PW
Can J Cardiol · 2020 May · PMID 32139280 · Publisher ↗
BACKGROUND: We evaluated the association of pulse pressure (PP) and different antiplatelet regimes with clinical and safety outcomes in an all-comers percutaneous coronary intervention (PCI) population. METHODS: In this...
BACKGROUND: We evaluated the association of pulse pressure (PP) and different antiplatelet regimes with clinical and safety outcomes in an all-comers percutaneous coronary intervention (PCI) population. METHODS: In this analysis of GLOBAL LEADERS (n = 15,936) we compared the experimental therapy of 23 months of ticagrelor after 1 month of dual-antiplatelet therapy (DAPT) vs standard DAPT for 12 months followed by aspirin monotherapy in subjects who underwent PCI and were divided into 2 groups according to the median PP (60 mm Hg). The primary end point (all-cause death or new Q-wave myocardial infarction) and the composite end points: patient-oriented composite end points (POCE), Bleeding Academic Research Consortium (BARC) 3 or 5, and net adverse clinical events (NACE) were evaluated. RESULTS: At 2 years, subjects in the high-PP group (n = 7971) had similar rates of the primary end point (4.3% vs 3.9%; P = 0.058), POCE (14.9% vs 12.7%; P = 0.051), and BARC 3 or 5 (2.5% vs 1.7%; P = 0.355) and higher rates of NACE (16.4% vs 13.7%; P = 0.037) compared with the low-PP group (n = 7965). Among patients with PP < 60 mm Hg, the primary end point (3.4% vs 4.4%, adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.61-0.96), POCE (11.8% vs 13.5%, aHR 0.86, 95% CI 0.76-0.98), NACE (12.8% vs 14.7%, aHR 0.85, 95% CI 0.76-0.96), and BARC 3 or 5 (1.4% vs 2.1%, aHR 0.69, 95% CI 0.49-0.97) were lower with ticagrelor monotherapy compared with DAPT. The only significant interaction was for BARC 3 or 5 (P = 0.008). CONCLUSIONS: After contemporary PCI, subjects with high PP levels experienced high rates of NACE at 2 years. In those with low PP, ticagrelor monotherapy led to a lower risk of bleeding events compared with standard DAPT.
[Pleiotropic effects of ezetimibe].
Shaposhnik II, Genkel VV
Kardiologiia · 2019 Dec · PMID 31995721 · Publisher ↗
The article discusses in detail the question of the additional positive effects of ezetimibe in addition to direct hypolipidemic action. The data of experimental and clinical studies in which the effect of ezetimibe on c...
The article discusses in detail the question of the additional positive effects of ezetimibe in addition to direct hypolipidemic action. The data of experimental and clinical studies in which the effect of ezetimibe on carbohydrate metabolism, inflammation, endothelial dysfunction, and liver is studied. The article also discusses the results of clinical studies that examined the effect of ezetimibe on atherosclerotic plaque.
Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload.
Mohammadzadeh N, Melleby AO, Palmero S … +6 more , Sjaastad I, Chakravarti S, Engebretsen KVT, Christensen G, Lunde IG, Tønnessen T
Cardiology · 2020 · PMID 31968347 · Full text
INTRODUCTION: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fib...
INTRODUCTION: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so-lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). METHODS AND RESULTS: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/-) hearts compared to wild-type (WT) controls. LUM+/- mice were subjected to AB. There was no difference in survival between LUM+/- and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/- and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/- mice. LUM+/- hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/- compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/- and WT mice post-AB, as assessed by histology and qPCR. CONCLUSIONS: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.
Selective intrarenal delivery of mesenchymal stem cell-derived extracellular vesicles attenuates myocardial injury in experimental metabolic renovascular disease.
Zhang L, Zhu XY, Zhao Y … +6 more , Eirin A, Liu L, Ferguson CM, Tang H, Lerman A, Lerman LO
Basic Res Cardiol · 2020 Jan · PMID 31938859 · Full text
Extracellular vesicles (EVs) deliver genes and proteins to recipient cells, and mediate paracrine actions of their parent cells. Intrarenal delivery of mesenchymal stem cell (MSC)-derived EVs preserves stenotic-kidney fu...
Extracellular vesicles (EVs) deliver genes and proteins to recipient cells, and mediate paracrine actions of their parent cells. Intrarenal delivery of mesenchymal stem cell (MSC)-derived EVs preserves stenotic-kidney function and reduces release of pro-inflammatory cytokines in a swine model of coexisting metabolic syndrome (MetS) and renal artery stenosis (RAS). We hypothesized that this approach is also capable of blunting cardiac injury and dysfunction. Five groups of pigs were studied after 16 weeks of diet-induced MetS and RAS (MetS + RAS), MetS and MetS + RAS treated 4 weeks earlier with a single intrarenal delivery of EVs-rich fraction harvested from autologous adipose tissue-derived MSCs, and lean and MetS Shams. Cardiac structure, function, and myocardial oxygenation were assessed in vivo using imaging, and cardiac inflammation, senescence, and fibrosis ex vivo. Inflammatory cytokine levels were measured in circulating and renal vein blood. Intrarenal EV delivery improved stenotic-kidney glomerular filtration rate and renal blood flow, and decreased renal release of monocyte-chemoattractant protein-1 and interleukin-6. Furthermore, despite unchanged systemic hemodynamics, intrarenal EV delivery in MetS + RAS normalized cardiac diastolic function, attenuated left ventricular remodeling, cellular senescence and inflammation, and improved myocardial oxygenation and capillary density in MetS + RAS. Intrarenal delivery of MSC-derived EVs blunts myocardial injury in experimental MetS + RAS, possibly related to improvement in renal function and systemic inflammatory profile. These observations underscore the central role of inflammation in the crosstalk between the kidney and heart, and the important contribution of renal function to cardiac structural and functional integrity in coexisting MetS and RAS.
Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community.
Tester DJ, Bombei HM, Fitzgerald KK … +13 more , Giudicessi JR, Pitel BA, Thorland EC, Russell BG, Hamrick SK, Kim CSJ, Haglund-Turnquist CM, Johnsrude CL, Atkins DL, Ochoa Nunez LA, Law I, Temple J, Ackerman MJ
JAMA Cardiol · 2020 Mar · PMID 31913406 · Full text
IMPORTANCE: The exome molecular autopsy may elucidate a pathogenic substrate for sudden unexplained death. OBJECTIVE: To investigate the underlying cause of multiple sudden deaths in young individuals and sudden cardiac...
IMPORTANCE: The exome molecular autopsy may elucidate a pathogenic substrate for sudden unexplained death. OBJECTIVE: To investigate the underlying cause of multiple sudden deaths in young individuals and sudden cardiac arrests that occurred in 2 large Amish families. DESIGN, SETTING, AND PARTICIPANTS: Two large extended Amish families with multiple sudden deaths in young individuals and sudden cardiac arrests were included in the study. A recessive inheritance pattern was suggested based on an extended family history of sudden deaths in young individuals and sudden cardiac arrests, despite unaffected parents. A family with exercise-associated sudden deaths in young individuals occurring in 4 siblings was referred for postmortem genetic testing using an exome molecular autopsy. Copy number variant (CNV) analysis was performed on exome data using PatternCNV. Chromosomal microarray validated the CNV identified. The nucleotide break points of the CNV were determined by mate-pair sequencing. Samples were collected for this study between November 2004 and June 2019. MAIN OUTCOMES AND MEASURES: The identification of an underlying genetic cause for sudden deaths in young individuals and sudden cardiac arrests consistent with the recessive inheritance pattern observed in the families. RESULTS: A homozygous duplication, involving approximately 26 000 base pairs of intergenic sequence, RYR2's 5'UTR/promoter region, and exons 1 through 4 of RYR2, was identified in all 4 siblings of a family. Multiple distantly related relatives experiencing exertion-related sudden cardiac arrest also had the identical RYR2 homozygous duplication. A second, unrelated family with multiple exertion-related sudden deaths and sudden cardiac arrests in young individuals, with the same homozygous duplication, was identified. Several living, homozygous duplication-positive symptomatic patients from both families had nondiagnostic cardiologic testing, with only occasional ventricular ectopy occurring during exercise stress tests. CONCLUSIONS AND RELEVANCE: In this analysis, we identified a novel, highly penetrant, homozygous multiexon duplication in RYR2 among Amish youths with exertion-related sudden death and sudden cardiac arrest but without an overt phenotype that is distinct from RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. Considering that no cardiac tests reliably identify at-risk individuals and given the high rate of consanguinity in Amish families, identification of unaffected heterozygous carriers may provide potentially lifesaving premarital counseling and reproductive planning.
Heart non-specific effector CD4 T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis.
Zarak-Crnkovic M, Kania G, Jaźwa-Kusior A … +15 more , Czepiel M, Wijnen WJ, Czyż J, Müller-Edenborn B, Vdovenko D, Lindner D, Gil-Cruz C, Bachmann M, Westermann D, Ludewig B, Distler O, Lüscher TF, Klingel K, Eriksson U, Błyszczuk P
Basic Res Cardiol · 2019 Dec · PMID 31863205 · Full text
Heart-specific CD4 T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart...
Heart-specific CD4 T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4 T cells in the progression of the disease. Heart non-specific CD4 T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4 T cells expressed exclusively effector (T) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific T infiltrated the heart shortly after injection, heart non-specific T effectively accumulated during myocarditis and became the major heart-infiltrating CD4 T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4 T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific T and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific T. Adoptive transfer of heart non-specific T in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human T stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific T cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.
Importance of infarct size versus other variables for clinical outcomes after PPCI in STEMI patients.
Bochaton T, Claeys MJ, Garcia-Dorado D … +7 more , Mewton N, Bergerot C, Jossan C, Amaz C, Boussaha I, Thibault H, Ovize M
Basic Res Cardiol · 2019 Dec · PMID 31832789 · Publisher ↗
Despite promising experimental studies and encouraging proof-of-concept clinical trials, interventions aimed at limiting infarct size have failed to improve clinical outcomes in patients with ST-elevation myocardial infa...
Despite promising experimental studies and encouraging proof-of-concept clinical trials, interventions aimed at limiting infarct size have failed to improve clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). Our objective was to examine whether variables (cardiovascular risk factors, comorbidities, post-procedural variables, cotreatments) might be associated with clinical outcomes in STEMI patients independently from infarct size reduction. The present study was based on a post hoc analysis of the CIRCUS trial database (Clinicaltrials.gov NCT01502774) that assessed the clinical benefit of a single intravenous bolus of cyclosporine in 969 patients with anterior STEMI. Since cyclosporine had no detectable effect on clinical outcomes as well as on any measured variable, we here considered the whole study population as one group. Multivariate analysis was performed to address the respective weight of infarct size and variables in clinical outcomes. Multivariate analysis revealed that several variables (including gender, hypertension, renal dysfunction, TIMI flow grade post-PCI < 3, and treatment administered after PCI with betablockers and angiotensin-converting enzyme inhibitors) had per se a significant influence on the occurrence of [death or hospitalization for heart failure] at 1 year. The relative weight of infarct size and variables on the composite endpoint of [death or hospitalization for heart failure] at 1 year was 18% and 82%, respectively. Several variables contribute strongly to the clinical outcomes of STEMI patients suggesting that cardioprotective strategy might not only focus on infarct size reduction.
Association of Sex With Outcomes in Patients Undergoing Percutaneous Coronary Intervention: A Subgroup Analysis of the GLOBAL LEADERS Randomized Clinical Trial.
Chichareon P, Modolo R, Kerkmeijer L … +21 more , Tomaniak M, Kogame N, Takahashi K, Chang CC, Komiyama H, Moccetti T, Talwar S, Colombo A, Maillard L, Barlis P, Wykrzykowska J, Piek JJ, Garg S, Hamm C, Steg PG, Jüni P, Valgimigli M, Windecker S, Onuma Y, Mehran R, Serruys PW
JAMA Cardiol · 2020 Jan · PMID 31693078 · Full text
IMPORTANCE: Women experience worse ischemic and bleeding outcomes after percutaneous coronary intervention (PCI). OBJECTIVES: To assess the association of sex with patient outcomes at 2 years after contemporary PCI and w...
IMPORTANCE: Women experience worse ischemic and bleeding outcomes after percutaneous coronary intervention (PCI). OBJECTIVES: To assess the association of sex with patient outcomes at 2 years after contemporary PCI and with the efficacy and safety of 2 antiplatelet strategies. DESIGN, SETTING, AND PARTICIPANTS: This study is a prespecified subgroup analysis of the investigator-initiated, prospective, randomized GLOBAL LEADERS study evaluating 2 strategies of antiplatelet therapy after PCI in an unselected population including 130 secondary/tertiary care hospitals in different countries. The main study enrolled 15 991 unselected patients undergoing PCI between July 2013 and November 2015. Patients had an outpatient clinic visit at 30 days and 3, 6, 12, 18, and 24 months after the index procedure. Data were analyzed between January 1, 2019, and March 31, 2019. INTERVENTIONS: Eligible patients were randomized to either the experimental or reference antiplatelet strategy. Experimental strategy consisted of 1 month of dual antiplatelet therapy (DAPT) followed by 23 months of ticagrelor monotherapy, while the reference strategy comprised of 12 months of DAPT followed by 12 months of aspirin monotherapy. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the composite of all-cause mortality and new Q-wave myocardial infarction at 2 years. The secondary safety end point was Bleeding Academic Research Consortium type 3 or 5 bleeding. RESULTS: Of the 15 968 patients included in this study, 3714 (23.3%) were women. The risk of the primary end point at 2 years was similar between women and men (adjusted hazard ratio [HR], 1.00; 95% CI, 0.83-1.20). Compared with men, women had higher risk of Bleeding Academic Research Consortium type 3 or 5 bleeding (adjusted HR, 1.32; 95% CI, 1.04-1.67) and hemorrhagic stroke at 2 years (adjusted HR, 4.76; 95% CI, 1.92-11.81). At 2 years, there was no between-sex difference in the efficacy and safety of the 2 antiplatelet strategies. At 1 year, compared with DAPT, ticagrelor monotherapy was associated with a lower risk of bleeding in men (HR, 0.72; 95% CI, 0.53-0.98) but not in women (HR, 1.23; 95% CI, 0.80-1.89; P for interaction = .045). CONCLUSIONS AND RELEVANCE: Compared with men, women experienced a higher risk of bleeding and hemorrhagic stroke after PCI. The effect of 2 antiplatelet strategies on death and Q-wave myocardial infarction following PCI did not differ between the sexes at 2 years. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01813435.
A Man in His 80s With Hypertension, Left Ventricular Hypertrophy, and Enlarged Biceps.
Martone R, Perfetto F, Cappelli F
JAMA Cardiol · 2019 Dec · PMID 31617859 · Publisher ↗
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[The Role of microRNA in the Development of Ischemic Heart Disease].
Kukava NG, Shkhnovich RM, Osmak GZ … +3 more , Baulina NM, Matveeva NA, Favorova OO
Kardiologiia · 2019 Oct · PMID 31615390 · Publisher ↗
Coronary artery disease is the most clinically significant manifestation of atherosclerosis and the main cause of morbidity and mortality around the world. Atherogenesis is a complex process, involving various types of c...
Coronary artery disease is the most clinically significant manifestation of atherosclerosis and the main cause of morbidity and mortality around the world. Atherogenesis is a complex process, involving various types of cells and regulatory molecules. MicroRNA molecules were discovered at the end of the 20th century, and nowadays are the important regulators of several pathophysiological processes of atherogenesis. The review examines data on the participation of various microRNAs in the development of atherosclerosis and its main clinical manifestations and discusses the possibility of using microRNAs as diagnostic markers for these diseases.
[The Relationship of the Concentration of Lipoprotein(a) and Markers of Inflammation with Multifocal Atherosclerosis in Women].
Afanasieva OI, Tmoyan NA, Klesareva EA … +4 more , Razova OA, Ezhov MV, Afanasieva MI, Pokrovsky SN
Kardiologiia · 2019 Oct · PMID 31615387 · Publisher ↗
PURPOSE: to study relationship of lipoprotein(a) [Lp(a)], indicators of systemic inflammation and humoral immunity with severity of atherosclerotic involvement of various vascular beds in women. MATERIALS AND METHODS: We...
PURPOSE: to study relationship of lipoprotein(a) [Lp(a)], indicators of systemic inflammation and humoral immunity with severity of atherosclerotic involvement of various vascular beds in women. MATERIALS AND METHODS: We included in this study 148 women aged 69±11 years with results of instrumental investigation of coronary, carotid arteries, and arteries of lower extremities. According to results of coronary angiography and ultrasound study patients were distributed into two groups: with stenosing atherosclerosis (those with hemodynamically significant [>50%] atherosclerotic lesions in any of these vascular beds, n=108), and control (those without hemodynamically significant stenoses, n=40). In dependence of extent of atherosclerotic involvement patients with stenosing atherosclerosis were divided into subgroups: with lesions in one vascular bed (subgroup 1, n=44) and with lesions in two and more vascular beds (subgroup 2, n=64). All patients with stenosing atherosclerosis and 78% of control patients took statins. In all patients we measured lipid spectrum, Lp(a) concentration, C-reactive protein (CRP). Preparations of oxidized lipoproteins [oxLp(a)] were obtained by Cu2+-induced free radical oxidation at 37 °С for 3 hours. Titer of autoantibodies to Lp(a), LDL and their oxidized modifications was determined by enzyme-linked immunosorbent assay (ELISA). Concentration of low-density lipoprotein cholesterol corrected on cholesterol in Lp(a) (LDLCh corr) was calculated by Dahlen modification of Friedewald formula. RESULTS: Stenosing atherosclerosis was diagnosed in 60 of 74 women (80%) with Lp(a) concentration above median - 33 mg/dl (in 38 multifical). Increase of blood serum Lp(a) concentration was associated with presence of isolated as well as multifocal atherosclerosis according to unifactorial, multifactorial, and logistic analysis, irrespective of other factors of risk and indicators of inflammation. According to results of logistic regression analysis increase of Lp(a) concentration by 1 mg/dl was associated with 1 % elevation of probability of appearance and development of multifocal atherosclerosis in women. Low level of class IgM autoantibodies to Lp(a) was linked with detection of stenosing atherosclerosis in any of 3 vascular beds (1st vs. 4th quartile of IgM autoantibodies concentration - OR 7.6., 95%CI 1.9-29.4; р=0.004) and had diagnostic significance. Indicators of systemic inflammation such as CRP and circulating immune complexes were high and had diagnostic significance for detection of multifocal atherosclerosis in studied women. However none of indicators was predictor of appearance of stenosing atherosclerosis according to data of logistic regression analysis. CONCLUSION: Elevated concentration of Lp(a) is an independent predictor of risk of development stenosing atherosclerosis in various vascular beds and appearance of multifocal irrespective of other risk factors, indicators of systemic inflammation, and factors of humoral immunity in women. Markers of inflammation, as well as IgM autoantibodies against Lp(a) have diagnostic value for detection of patients stenosing lesions ib one or several vascular beds.
Genetics of dilated cardiomyopathy: practical implications for heart failure management.
Rosenbaum AN, Agre KE, Pereira NL
Nat Rev Cardiol · 2020 May · PMID 31605094 · Publisher ↗
Given the global burden of heart failure, strategies to understand the underlying cause or to provide prognostic information are critical to reducing the morbidity and mortality associated with this highly prevalent dise...
Given the global burden of heart failure, strategies to understand the underlying cause or to provide prognostic information are critical to reducing the morbidity and mortality associated with this highly prevalent disease. Cardiomyopathies often have a genetic cause, and the field of heart failure genetics is progressing rapidly. Through a deliberate investigation, evaluation for a familial component of cardiomyopathy can lead to increased identification of pathogenic genetic variants. Much research has also been focused on identifying markers of risk in patients with cardiomyopathy with the use of genetic testing. Advances in our understanding of genetic variants have been slightly offset by an increased recognition of the heterogeneity of disease expression. Greater breadth of genetic testing can increase the likelihood of identifying a variant of uncertain significance, which is resolved only rarely by cellular functional validation and segregation analysis. To increase the use of genetics in heart failure clinics, increased availability of genetic counsellors and other providers with experience in genetics is necessary. Ultimately, through ongoing research and increased clinical experience in cardiomyopathy genetics, an improved understanding of the disease processes will facilitate better clinical decision-making about the therapies offered, exemplifying the implementation of precision medicine.
Epidemiology of inherited arrhythmias.
Offerhaus JA, Bezzina CR, Wilde AAM
Nat Rev Cardiol · 2020 Apr · PMID 31582838 · Publisher ↗
The primary electrical disorders are a group of inherited cardiac ventricular arrhythmias that are a major cause of sudden cardiac death in young individuals. Inherited ventricular arrhythmias result from mutations in ge...
The primary electrical disorders are a group of inherited cardiac ventricular arrhythmias that are a major cause of sudden cardiac death in young individuals. Inherited ventricular arrhythmias result from mutations in genes encoding cardiac ion channels or their modulatory subunits. Advances in genetic screening in the past three decades have led to the assembly of large patient cohorts with these disorders. Studies in these patients, as well as in the general population, have striven to define the prevalence of these inherited arrhythmias and the characteristics of patients with different genetic subtypes of the disease. In this Review, we provide a comprehensive update on the epidemiology of inherited ventricular arrhythmias, focusing on natural history, prevalence and patient demographics. In addition, we summarize the various founder populations (groups of individuals with a disease that is caused by a genetic defect inherited from a common ancestor) that have been identified for some of these disorders and which lead to increased prevalence in some geographical regions. To date, although numerous studies have markedly increased our understanding of the epidemiology of these disorders, demographic data, especially from non-Western countries, remain scarce. Furthermore, defining the true prevalence of these disorders remains challenging. International collaboration will undoubtedly accelerate the collection of demographic information and improve the accuracy of prevalence data.
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