Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis.

Clonal hematopoiesis, a condition in which individual hematopoietic stem cell clones generate a disproportionate fraction of blood leukocytes, correlates with higher risk for cardiovascular disease. The mechanisms behind this association are incompletely understood. Here, we show that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis. Mathematical analysis demonstrates that increased stem cell proliferation expedites somatic evolution and expansion of clones with driver mutations. The experimentally determined division rate elevation in atherosclerosis patients is sufficient to produce a 3.5-fold increased risk of clonal hematopoiesis by age 70. We confirm the accuracy of our theoretical framework in mouse models of atherosclerosis and sleep fragmentation by showing that expansion of competitively transplanted Tet2-/- cells is accelerated under conditions of chronically elevated hematopoietic activity. Hence, increased hematopoietic stem cell proliferation is an important factor contributing to the association between cardiovascular disease and clonal hematopoiesis.

Sex and Gender-related Disparities in Clinical Characteristics and Outcomes in Heart Transplantation.

PURPOSE OF REVIEW: Limited research has been conducted on sex disparities in heart transplant (HT). The aim of this review is to analyse the available evidence on the influence of sex and gender-related determinants in the entire HT process, as well as to identify areas for further investigation. RECENT FINDINGS: Although women make up half of the population affected by heart failure and related mortality, they account for less than a third of HT recipients. Reasons for this inequality include differences in disease course, psychosocial factors, concerns about allosensitisation, and selection or referral bias in female patients. Women are more often listed for HT due to non-ischaemic cardiomyopathy and have a lower burden of cardiovascular risk factors. Although long-term prognosis appears to be similar for both sexes, there are significant disparities in post-HT morbidity and causes of mortality (noting a higher incidence of rejection in women and of malignancy and cardiac allograft vasculopathy in men). Additional research is required to gain a better understanding of the reasons behind gender disparities in eligibility and outcomes following HT. This would enable the fair allocation of resources and enhance patient care.

Mapping genetic changes in the cAMP-signaling cascade in human atria.

AIM: To obtain a quantitative expression profile of the main genes involved in the cAMP-signaling cascade in human control atria and in different cardiac pathologies. METHODS AND RESULTS: Expression of 48 target genes playing a relevant role in the cAMP-signaling cascade was assessed by RT-qPCR. 113 samples were obtained from right atrial appendages (RAA) of patients in sinus rhythm (SR) with or without atrium dilation, paroxysmal atrial fibrillation (AF), persistent AF or heart failure (HF); and left atrial appendages (LAA) from patients in SR or with AF. Our results show that right and left atrial appendages in donor hearts or from SR patients have similar expression values except for AC7 and PDE2A. Despite the enormous chamber-dependent variability in the gene-expression changes between pathologies, several distinguishable patterns could be identified. PDE8A, PI3Kγ and EPAC2 were upregulated in AF. Different phosphodiesterase (PDE) families showed specific pathology-dependent changes. CONCLUSION: By comparing mRNA-expression patterns of the cAMP-signaling cascade related genes in right and left atrial appendages of human hearts and across different pathologies, we show that 1) gene expression is not significantly affected by cardioplegic solution content, 2) it is appropriate to use SR atrial samples as controls, and 3) many genes in the cAMP-signaling cascade are affected in AF and HF but only few of them appear to be chamber (right or left) specific. TOPIC: Genetic changes in human diseased atria. TRANSLATIONAL PERSPECTIVE: The cyclic AMP signaling pathway is important for atrial function. However, expression patterns of the genes involved in the atria of healthy and diseased hearts are still unclear. We give here a general overview of how different pathologies affect the expression of key genes in the cAMP signaling pathway in human right and left atria appendages. Our study may help identifying new genes of interest as potential therapeutic targets or clinical biomarkers for these pathologies and could serve as a guide in future gene therapy studies.

The impact of frailty in aortic valve surgery.

BACKGROUND: Frailty is a geriatric syndrome that diminishes potential functional recovery after any surgical procedure. Preoperative surgical risk assessment is crucial to calibrate the risk and benefit of cardiac surgery. The aim of this study was to test usefulness of FRAIL Scale and other surgical-risk-scales and individual features of frailty in cardiac aortic valve surgery. METHODS: Prospective study. From May-2014 to February-2016, we collected 200 patients who underwent aortic valve replacement, either surgically or transcatheter. At 1-year follow-up, quality of life measurements were recorded using the EQ-5D (EuroQol). Univariate and multivariate analyses correlated preoperative condition, features of frailty and predicted risk scores with mortality, morbidity and quality of life at 1 year of follow-up. RESULTS: Mean age 78.2y, 56%male. Mean-preoperative-scores: FRAIL scale 1.5(SD 1.02), STS 2.9(SD 1.13), BI 93.8(SD 7.3), ESlog I 12.8(SD 8.5) and GS 7.3 s (SD 1.9). Morbidity at discharge, 6 m and 1 year was 51, 14 and 28%. Mortality 4%. Survival at 6 m/ 1-y was 97% / 88%. Complication-rate was higher in TAVI group due to-vascular complications. Renal dysfunction, anemia, social dependence and GS slower than 7 s were associated with morbidity. On multivariate analysis adjusted STS, BI and GS speed were statistically significant. Quality of life at 1-year follow-up adjusted for age and prosthesis type showed a significant association with STS and FRAIL scale scores. CONCLUSIONS: Frailty increases surgical risk and is associated with higher morbidity. Preoperative GS slower 7 s, and STS and FRAIL scale scores seem to be reliable predictors of quality of life at 1-year follow-up.

Tricuspid valve replacement with mechanical prostheses: Short and long-term outcomes.

BACKGROUND AND AIM: Tricuspid valve replacement has been associated with high mortality and poor long-term outcomes. We report the preoperative risk factors associated with short and long-term outcomes following tricuspid valve replacement with mechanical prostheses. METHODS: In 62 patients who underwent mechanical tricuspid valve replacement, clinical, laboratory, and echocardiographic findings were analyzed using both univariate and multivariate analyses to describe operative and long-term mortality. RESULTS: In our population (mean age 59 ± 9.7 years, 82.3% female), most common causes of tricuspid valve disease were rheumatic fever (69.4%) and functional regurgitation (19.4%). Operative and long-term mortality were 17.7 and 33.9%, respectively. Age, diabetes mellitus, and coronary artery disease were independently associated with increased long-term mortality. New York Heart Association (NYHA) class and right heart failure symptoms significantly improved during follow-up. CONCLUSIONS: In this series of mechanical tricuspid valve replacements in patients with predominately rheumatic heart disease, operative and long-term mortality were increased; however, survivors had significant improvement in their NYHA class and freedom from right heart failure symptoms. Three preoperative factors (age, diabetes mellitus, and coronary artery disease) were independently associated with long-term mortality.

Implantation of a double allogeneic human engineered tissue graft on damaged heart: insights from the PERISCOPE phase I clinical trial.

BACKGROUND: In preclinical studies, the use of double allogeneic grafts has shown promising results in promoting tissue revascularization, reducing infarct size, preventing adverse remodelling and fibrosis, and ultimately enhancing cardiac function. Building upon these findings, the safety of PeriCord, an engineered tissue graft consisting of a decellularised pericardial matrix and umbilical cord Wharton's jelly mesenchymal stromal cells, was evaluated in the PERISCOPE Phase I clinical trial (NCT03798353), marking its first application in human subjects. METHODS: This was a double-blind, single-centre trial that enrolled patients with non-acute myocardial infarction eligible for surgical revascularization. Seven patients were implanted with PeriCord while five served as controls. FINDINGS: Patients who received PeriCord showed no adverse effects during post-operative phase and one-year follow-up. No significant changes in secondary outcomes, such as quality of life or cardiac function, were found in patients who received PeriCord. However, PeriCord did modulate the kinetics of circulating monocytes involved in post-infarction myocardial repair towards non-classical inflammation-resolving macrophages, as well as levels of monocyte chemoattractants and the prognostic marker Meteorin-like in plasma following treatment. INTERPRETATION: In summary, the PeriCord graft has exhibited a safe profile and notable immunomodulatory properties. Nevertheless, further research is required to fully unlock its potential as a platform for managing inflammatory-related pathologies. FUNDING: This work was supported in part by grants from MICINN (SAF2017-84324-C2-1-R); Instituto de Salud Carlos III (ICI19/00039 and Red RICORS-TERAV RD21/0017/0022, and CIBER Cardiovascular CB16/11/00403) as a part of the Plan Nacional de I + D + I, and co-funded by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER) and AGAUR (2021-SGR-01437).

Postpartum acute coronary syndrome due to intramural hematoma and coronary artery dissection.

A 38-year-old woman presented with acute coronary syndrome 9 days postpartum. Coronary catheterization showed an intramural hematoma of the left main artery (LM) and the left anterior descending artery (LAD). During angiography, dissection of the LM, with involvement of the LAD and circumflex artery occurred. The patient presented unstable hemodynamic status. After resuscitation, intra-aortic balloon pump was inserted. The patient underwent two-vessel off-pump surgical revascularization. She was discharged 10 days later.

Mechanical complications in STEMI: prevalence and mortality trends in the primary PCI era. The Ruti-STEMI registry.

INTRODUCTION AND OBJECTIVES: Mechanical complications confer a dreadful prognosis in ST-elevation myocardial infarction (STEMI). Their prevalence and prognosis are not well-defined in the current era of primary percutaneous coronary intervention (pPCI) reperfusion networks. We aimed to analyze prevalence and mortality trends of post-STEMI mechanical complications over 2 decades, before and after the establishment of pPCI networks. METHODS: Prospective, consecutive registry of STEMI patients within a region of 850 000 inhabitants over 2 decades: a pre-pPCI period (1990-2000) and a pPCI period (2007-2017). We analyzed the prevalence of mechanical complications, including ventricular septal rupture, papillary muscle rupture, and free wall rupture (FWR). Twenty eight-day and 1-year mortality trends were compared between the 2 studied decades. RESULTS: A total of 6033 STEMI patients were included (pre-pPCI period, n=2250; pPCI period, n=3783). Reperfusion was supported by thrombolysis in the pre-pPCI period (99.1%) and by pPCI in in the pPCI period (95.7%). Mechanical complications developed in 135 patients (2.2%): ventricular septal rupture in 38 patients, papillary muscle rupture in 24, and FWR in 73 patients. FWR showed a relative reduction of 60% in the pPCI period (0.8% vs 2.0%, P<.001), without significant interperiod changes in the other mechanical complications. After multivariate adjustment, FWR remained higher in the pre-pPCI period (OR, 1.93; 95%CI, 1.10-3.41; P=.023). At 28 days and 1 year, mortality showed no significant changes in all the mechanical complications studied. CONCLUSIONS: The establishment of regional pPCI networks has modified the landscape of mechanical complications in STEMI. FWR is less frequent in the pPCI era, likely due to reduced transmural infarcts.

Bone marrow adipocytes fuel emergency hematopoiesis after myocardial infarction.

After myocardial infarction (MI), emergency hematopoiesis produces inflammatory myeloid cells that accelerate atherosclerosis and promote heart failure. Since the balance between glycolysis and mitochondrial metabolism regulates hematopoietic stem cell homeostasis, metabolic cues may influence emergency myelopoiesis. Here, we show in humans and female mice that hematopoietic progenitor cells increase fatty acid metabolism after MI. Blockade of fatty acid oxidation by deleting carnitine palmitoyltransferase (Cpt1A) in hematopoietic cells of Vav1Cre/+Cpt1Afl/fl mice limited hematopoietic progenitor proliferation and myeloid cell expansion after MI. We also observed reduced bone marrow adiposity in humans, pigs and mice following MI. Inhibiting lipolysis in adipocytes using AdipoqCreERT2Atglfl/fl mice or local depletion of bone marrow adipocytes in AdipoqCreERT2iDTR mice also curbed emergency hematopoiesis. Furthermore, systemic and regional sympathectomy prevented bone marrow adipocyte shrinkage after MI. These data establish a critical role for fatty acid metabolism in post-MI emergency hematopoiesis.

Impact of Tricuspid Regurgitation Severity and Repair on Aortic Valve Replacement.

BACKGROUND: Aortic stenosis is one of the most prevalent valve diseases but is rarely accompanied by tricuspid regurgitation. Our objective was to analyze the impact of tricuspid regurgitation severity and its surgical treatment on prognosis of patients undergoing aortic valve replacement. METHODS: This was a retrospective cohort study including all patients presenting with aortic stenosis with some degree of tricuspid regurgitation between 2001 and 2018. Patients were grouped according to the degree of tricuspid regurgitation. RESULTS: From a sample of 8080 patients with aortic stenosis, 143 (1.8%) presented with more than trace tricuspid regurgitation. Among patients with mild, moderate, or severe tricuspid regurgitation, we observed no differences in 30-day (15.1% vs 14.8% vs 8.7%; P = .727), 12-month (51.2% vs 56% vs 55%; P = .892), or 5-year (64% vs 73.3% vs 66.7%; P = .798) survival. Aortic valve replacement plus tricuspid annuloplasty, when compared with aortic valve replacement only was associated with longer intensive care unit stay (9 vs 3 days; P = .043) but not higher 30-day (0% vs 15.5%; P = .112), 12-month (38.5% vs 54.3%; P = .278), or 5-year mortality (57.1% vs 67.1%; P = .594). Only history of liver disease and postoperative major morbidity were independent predictors of survival 30 days, 12 months and 5 years after surgery. CONCLUSIONS: Severity of tricuspid regurgitation in patients with aortic stenosis was not associated with increased mortality. Tricuspid annuloplasty did not improve survival in this subset of patients but was associated with increased postoperative morbidity.

Long-term outcomes with the On-X bileaflet mitral valve: clinical events up to 17 years in 661 patients.

OBJECTIVES: This study reports long-term clinical outcomes-up to 17 years-among patients undergoing mitral valve replacement with the On-X bileaflet mechanical valve. Prior data regarding long-term outcomes with the On-X mitral valve have been limited. METHODS: This retrospective observational study included all patients who underwent mitral valve replacement with the On-X (Standard or Conform-X) valve at 2 major Spanish cardiac surgery centres between 2001 and 2018. The primary study end point was freedom from death. The secondary study end points included surgical mortality and freedom from any valve-related events. Data were obtained from an institutional database, medical records review, direct telephone interviews or the Spanish population registry. Statistical and Kaplan-Meier analyses were performed. RESULTS: A total of 661 patients (mean age 63.1 ± 10.9 years, 63% female) were followed for a mean of 5.6 years (range, 0-17.4 years). Survival at 5, 10 and 15 years was 85%, 71% and 63%, respectively. Surgical mortality was 7.3% (48/661). The linearized rate of global mortality was 1.3% patient-year. Freedom from reoperation was 97%, 95% and 92% at 5, 10 and 15 years, respectively; freedom from anticoagulation-related events was 94%, 89% and 89%, respectively. Multivariable analysis showed that mortality increased with total length of stay, age, smoking history, severe pulmonary hypertension and a permanent pacemaker. Patients who received the On-X 25 -mm valve had decreased long-term survival relative to patients who received other On-X valve sizes, possibly due to underlying risk factors. CONCLUSIONS: Patients in this study showed good long-term survival and freedom from valve-related events.

Bone marrow endothelial dysfunction promotes myeloid cell expansion in cardiovascular disease.

Abnormal hematopoiesis advances cardiovascular disease by generating excess inflammatory leukocytes that attack the arteries and the heart. The bone marrow niche regulates hematopoietic stem cell proliferation and hence the systemic leukocyte pool, but whether cardiovascular disease affects the hematopoietic organ's microvasculature is unknown. Here we show that hypertension, atherosclerosis and myocardial infarction (MI) instigate endothelial dysfunction, leakage, vascular fibrosis and angiogenesis in the bone marrow, altogether leading to overproduction of inflammatory myeloid cells and systemic leukocytosis. Limiting angiogenesis with endothelial deletion of Vegfr2 (encoding vascular endothelial growth factor (VEGF) receptor 2) curbed emergency hematopoiesis after MI. We noted that bone marrow endothelial cells assumed inflammatory transcriptional phenotypes in all examined stages of cardiovascular disease. Endothelial deletion of Il6 or Vcan (encoding versican), genes shown to be highly expressed in mice with atherosclerosis or MI, reduced hematopoiesis and systemic myeloid cell numbers in these conditions. Our findings establish that cardiovascular disease remodels the vascular bone marrow niche, stimulating hematopoiesis and production of inflammatory leukocytes.

Mitochondrial genetic effect on atrial fibrillation: A case-control study.

Atrial fibrillation (AF) is a common arrhythmia in the general population and following cardiac surgery. The influence of mitochondrial genomics on AF pathogenesis is not fully understood. We analyzed mitochondrial variables from 78 human atrial samples collected from cardiac surgeries in the following groups: 1) permanent preoperative AF; 2) preoperative sinus rhythm (SR) with postoperative AF; and 3) pre-/postoperative SR. Haplogroup H appeared offer protection against, and haplogroup U predispose to permanent AF. mtDNA content was higher in group 2 than in 3. These findings contribute to a better understanding of the influence of mitochondria on AF pathogenesis.

Long-term antibiotic therapy in patients with surgery-indicated not undergoing surgery infective endocarditis.

BACKGROUND: To date, there is little information regarding management of patients with infective endocarditis (IE) that did not undergo an indicated surgery. Therefore, we aimed to evaluate prognosis of these patients treated with a long-term antibiotic treatment strategy, including oral long term suppressive antibiotic treatment in five referral centres with a multidisciplinary endocarditis team. METHODS: This retrospective, multicenter study retrieved individual patient-level data from five referral centres in Spain. Among a total of 1797, 32 consecutive patients with IE were examined (median age 72 years; 78% males) who had not undergone an indicated surgery, but received long-term antibiotic treatment (LTAT) and were followed by a multidisciplinary endocarditis team, between 2011 and 2019. Primary outcomes were infection relapse and mortality during follow-up. RESULTS: Among 32 patients, 21 had IE associated with prostheses. Of the latter, 8 had an ascending aorta prosthetic graft. In 24 patients, a switch to long-term oral suppressive antibiotic treatment (LOSAT) was considered. The median duration of LOSAT was 277 days. Four patients experienced a relapse during follow-up. One patient died within 60 days, and 12 patients died between 60 days and 3 years. However, only 4 deaths were related to IE. CONCLUSIONS: The present study results suggest that a LTAT strategy, including LOSAT, might be considered for patients with IE that cannot undergo an indicated surgery. After hospitalization, they should be followed by a multidisciplinary endocarditis team.

Destination Therapy with Left Ventricular Assist Devices in Non-transplant Centres: The Time is Right.

For almost half a century, cardiac transplant has been the only long-term treatment for patients with end-stage heart failure. Implantable left ventricular assist devices (LVADs) have emerged as a new treatment option for advanced heart failure as destination therapy for patients either too old or not suitable for transplant. A meta-analysis presenting head-to-head comparisons of cardiac transplant versus LVAD as destination therapy (LVAD-DT) found no difference in 1-year mortality rates between LVAD-DT and cardiac transplant (OR 1.49; 95% CI [0.48-4.66]; I2=82.8%). Moreover, a recent subanalysis from the Interagency Registry for Mechanically Assisted Circulatory Support found similar outcomes after LVAD-DT implantation in both transplant and non-transplant centres. The time is right for LVAD-DT in non-transplant centres, provided multidisciplinary heart failure teams and expertise are in place.

Mini-extracorporeal circulation surgery produces less inflammation than off-pump coronary surgery.

OBJECTIVES: Both off-pump coronary artery bypass grafting surgery (OPCABG) and mini-extracorporeal circulation (MECC) have been associated with lower morbidity and mortality and less inflammation than conventional cardiopulmonary bypass. However, studies comparing the 2 techniques are scarce and the results are controversial. We compared the clinical outcomes and inflammatory response of low-risk patients undergoing coronary bypass grafting with MECC versus OPCABG. METHODS: We conducted a prospective, randomized study in patients undergoing coronary heart surgery. Two hundred and thirty consecutive low-risk patients were randomly assigned to either receive OPCABG (n = 117) or MECC (n = 113). Clinical outcomes and postoperative biochemical results were analysed in both groups. We also analysed 19 circulating inflammatory markers in a subgroup of 40 patients at 4 perioperative time points. The area under the curve for each marker was calculated to monitor differences in the inflammatory response. RESULTS: No significant differences were found between groups regarding perioperative clinical complications and no deaths occurred during the trial. Plasma levels in 9 of the 19 inflammatory markers were undetectable or showed no temporal variation, 3 were higher in the MECC group [interleukin (IL)-10, macrophage inflammatory protein-1ß and epidermal growth factor] and 7 were higher in the OPCABG group (growth regulator oncogene, IL-6, IL-8, soluble CD40 ligand, monocyte chemoattractant protein-1, monocyte chemoattractant protein-3 and tumour necrosis factor-α). Differences in 2 proinflammatory cytokines, IL-6 and monocyte chemoattractant protein 1, between the 2 surgical procedures were statistically significant. CONCLUSIONS: No clinical differences were observed between in low-risk patients undergoing MECC or OPCABG surgery, but OPCABG was associated with an increased release of proinflammatory cytokines compared with MECC. Studies in larger cohorts and in patients at higher risk are needed to confirm these findings. CLINICAL TRIAL REGISTRATION NUMBER: NCT02118025.

First-in-human PeriCord cardiac bioimplant: Scalability and GMP manufacturing of an allogeneic engineered tissue graft.

BACKGROUND: Small cardiac tissue engineering constructs show promise for limiting post-infarct sequelae in animal models. This study sought to scale-up a 2-cm2 preclinical construct into a human-size advanced therapy medicinal product (ATMP; PeriCord), and to test it in a first-in-human implantation. METHODS: The PeriCord is a clinical-size (12-16 cm2) decellularised pericardial matrix colonised with human viable Wharton's jelly-derived mesenchymal stromal cells (WJ-MSCs). WJ-MSCs expanded following good manufacturing practices (GMP) met safety and quality standards regarding the number of cumulative population doublings, genomic stability, and sterility. Human decellularised pericardial scaffolds were tested for DNA content, matrix stiffness, pore size, and absence of microbiological growth. FINDINGS: PeriCord implantation was surgically performed on a large non-revascularisable scar in the inferior wall of a 63-year-old male patient. Coronary artery bypass grafting was concomitantly performed in the non-infarcted area. At implantation, the 16-cm2 pericardial scaffold contained 12·5 × 106 viable WJ-MSCs (85·4% cell viability; <0·51 endotoxin units (EU)/mL). Intraoperative PeriCord delivery was expeditious, and secured with surgical glue. The post-operative course showed non-adverse reaction to the PeriCord, without requiring host immunosuppression. The three-month clinical follow-up was uneventful, and three-month cardiac magnetic resonance imaging showed ~9% reduction in scar mass in the treated area. INTERPRETATION: This preliminary report describes the development of a scalable clinical-size allogeneic PeriCord cardiac bioimplant, and its first-in-human implantation. FUNDING: La Marató de TV3 Foundation, Government of Catalonia, Catalan Society of Cardiology, "La Caixa" Banking Foundation, Spanish Ministry of Science, Innovation and Universities, Institute of Health Carlos III, and the European Regional Development Fund.

Short- and long-term mortality in patients with left-sided infective endocarditis not undergoing surgery despite indication.

INTRODUCTION AND OBJECTIVES: In infective endocarditis (IE), decisions on surgical interventions are challenging and a high percentage of patients with surgical indication do not undergo these procedures. This study aimed to evaluate the short- and long-term prognosis of patients with surgical indication, comparing those who underwent surgery with those who did not. METHODS: We included 271 patients with left-sided IE treated at our institution from 2003 to 2018 and with an indication for surgery. There were 83 (31%) surgery-indicated not undergoing surgery patients with left-sided infective endocarditis (SINUS-LSIE). The primary outcome was all-cause death by day 60 and the secondary outcome was all-cause death from day 61 to 3 years of follow-up. Multivariable Cox regression and propensity score matching were used for the analysis. RESULTS: At the 60-day follow-up, 40 (21.3%) surgically-treated patients and 53 (63.9%) SINUS-LSIE patients died (P <.001). Risk of 60-day mortality was higher in SINUS-LSIE patients (HR, 3.59; 95%CI, 2.16-5.96; P <.001). Other independent predictors of the primary endpoint were unknown etiology, heart failure, atrioventricular block, and shock. From day 61 to the 3-year follow-up, there were no significant differences in the risk of death between surgically-treated and SINUS-LSIE patients (HR, 1.89; 95%CI, 0.68-5.19; P=.220). Results were consistent after propensity score matching. Independent variables associated with the secondary endpoint were previous IE, diabetes mellitus, and Charlson index. CONCLUSIONS: Two-thirds of SINUS-LSIE patients died within 60 days. Among survivors, the long-term mortality depends more on host conditions than on the treatment received during admission.

The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis.

AIMS: Single nucleotide polymorphisms on chromosome 4q25 have been associated with risk of atrial fibrillation (AF) but the exiguous knowledge of the mechanistic links between these risk variants and underlying electrophysiological alterations hampers their clinical utility. Here, we tested the hypothesis that 4q25 risk variants cause alterations in the intracellular calcium homoeostasis that predispose to spontaneous electrical activity. METHODS AND RESULTS: Western blotting, confocal calcium imaging, and patch-clamp techniques were used to identify mechanisms linking the 4q25 risk variants rs2200733T and rs13143308T to defects in the calcium homoeostasis in human atrial myocytes. Our findings revealed that the rs13143308T variant was more frequent in patients with AF and that myocytes from carriers of this variant had a significantly higher density of calcium sparks (14.1 ± 4.5 vs. 3.1 ± 1.3 events/min, P = 0.02), frequency of transient inward currents (ITI) (1.33 ± 0.24 vs. 0.26 ± 0.09 events/min, P < 0.001) and incidence of spontaneous membrane depolarizations (1.22 ± 0.26 vs. 0.56 ± 0.17 events/min, P = 0.001) than myocytes from patients with the normal rs13143308G variant. These alterations were linked to higher sarcoplasmic reticulum calcium loading (10.2 ± 1.4 vs. 7.3 ± 0.5 amol/pF, P = 0.01), SERCA2 expression (1.37 ± 0.13 fold, P = 0.03), and RyR2 phosphorylation at ser2808 (0.67 ± 0.08 vs. 0.47 ± 0.03, P = 0.01) but not at ser2814 (0.28 ± 0.14 vs. 0.31 ± 0.14, P = 0.61) in patients carrying the rs13143308T risk variant. Furthermore, the presence of a risk variant or AF independently increased the ITI frequency and the increase in the ITI frequency observed in carriers of the risk variants was exacerbated in those with AF. By contrast, the presence of a risk variant did not affect the amplitude or properties of the L-type calcium current in patients with or without AF. CONCLUSIONS: Here, we identify the 4q25 variant rs13143308T as a genetic risk marker for AF, specifically associated with excessive calcium release and spontaneous electrical activity linked to increased SERCA2 expression and RyR2 phosphorylation.