Impact of insulin treated and non-insulin-treated diabetes compared to patients without diabetes on 1-year outcomes following contemporary PCI.

OBJECTIVE: We compared 1-year outcomes in insulin-treated diabetes mellitus (ITDM) and non-ITDM patients compared to nondiabetic (DM) patients following contemporary percutaneous coronary intervention (PCI). BACKGROUND: ITDM is associated with extensive atherosclerotic disease and worse cardiovascular prognosis compared to non-ITDM patients. METHODS: We evaluated PCI patients at a large tertiary center from 2010 to 2016, grouped according to diabetes and treatment status at baseline. One-year major adverse cardiac events (MACE) were defined as a composite of death, myocardial infarction (MI), or target vessel revascularization. Outcomes were adjusted using multivariable Cox regression methods. RESULTS: During the study period, 16,889 patients underwent PCI including 13.7% ITDM, 34.0% non-ITDM, and 52.3% non-DM patients. Patients with DM were younger, including more females and non-white patients, with higher body mass index and greater prevalence of prior revascularization and chronic kidney disease. Compared to others, ITDM patients more often presented with acute coronary syndrome, in-stent restenosis, or severe lesion calcification. There were no differences in discharge rates of dual antiplatelet therapy and statins, whereas beta-blockers were more commonly prescribed in DM patients. At 1-year, both ITDM and non-ITDM patients had greater risk of MACE compared with non-DM patients, and ITDM conferred greater adjusted risk than non-ITDM (ITDM = HR: 2.11, 95% CI [1.79,2.50]; non-ITDM = HR: 1.27, 95%CI [1.09,1.47]). CONCLUSIONS: The negative prognostic effect of DM following contemporary PCI is heightened in the presence of insulin treatment, compared to non-DM patients. Focus on secondary prevention, prescription of and adherence to optimal medical therapy is necessary for post-PCI risk reduction.

Temporal trends, determinants, and impact of high-intensity statin prescriptions after percutaneous coronary intervention: Results from a large single-center prospective registry.

BACKGROUND: High-intensity statins (HIS) are recommended for secondary prevention following percutaneous coronary intervention (PCI). We aimed to describe temporal trends and determinants of HIS prescriptions after PCI in a usual-care setting. METHODS: All patients with age ≤75 years undergoing PCI between January 2011 and May 2016 at an urban, tertiary care center and discharged with available statin dosage data were included. HIS were defined as atorvastatin 40 or 80 mg, rosuvastatin 20 or 40 mg, and simvastatin 80 mg. RESULTS: A total of 10,495 consecutive patients were included. Prevalence of HIS prescriptions nearly doubled from 36.6% in 2011 to 60.9% in 2016 (P < .001), with a stepwise increase each year after 2013. Predictors of HIS prescriptions included ST-segment elevation myocardial infarction/non-ST-segment elevation myocardial infarction (odds ratio [OR] 4.60, 95% CI 3.98-5.32, P < .001) and unstable angina (OR 1.31, 95% CI 1.19-1.45, P < .001) as index event, prior myocardial infarction (OR 1.48, 95% CI 1.34-1.65, P < .001), and co-prescription of ß-blocker (OR 1.26, 95% CI 1.12-1.43, P < .001). Conversely, statin treatment at baseline (OR 0.86, 95% CI 0.77-0.96, P = .006), Asian races (OR 0.73, 95% CI 0.65-0.83, P < .001), and older age (OR 0.90, 95% CI 0.88-0.92, P < .001) were associated with reduced HIS prescriptions. There was no significant association between HIS prescriptions and 1-year rates of death, myocardial infarction, or target-vessel revascularization (adjusted hazard ratio 0.98, 95% CI 0.84-1.15, P = .84), although there was a trend toward reduced mortality (adjusted hazard ratio 0.71, 95% CI 0.50-1.00, P = .05). CONCLUSION: Although the rate of HIS prescriptions after PCI has increased in recent years, important heterogeneity remains and should be addressed to improve practices in patients undergoing PCI.

The prevalence, predictors and outcomes of guideline-directed medical therapy in patients with acute myocardial infarction undergoing PCI, an analysis from the PROMETHEUS registry.

OBJECTIVES: To investigate the prevalence, predictors and associations between guideline-directed medical therapy (GDMT) and clinical outcomes in acute myocardial infarction (AMI) patients undergoing percutaneous coronary intervention (PCI) from eight academic centers in the United States. BACKGROUND: Evidence for GDMT in patients with AMI comes from randomized controlled trials. The use of GDMT in clinical practice is unknown in this setting. METHODS: PROMETHEUS is a multicenter observational registry comprising 19,914 patients with acute coronary syndrome (ACS) undergoing PCI. Patients with AMI were divided into two groups based on the prescription of GDMT or not (non-GDMT) at discharge. GDMT was defined according to American College of Cardiology/American Heart Association (ACC/AHA) class I recommendations, specifically, dual antiplatelet therapy, statin and beta-blocker for all AMI patients, and additional ACEI/ARB in patients with left ventricular ejection fraction (LVEF) less than 40%, hypertension, diabetes mellitus (DM) or chronic kidney disease (CKD). The primary endpoint was major adverse cardiovascular events (MACE) defined as a composite of all-cause death, MI, stroke or unplanned target vessel revascularization (TVR) at 1 year. RESULTS: Out of 4,834 patients with AMI, 3,356 (69.4%) patients were discharged on GDMT. Patients receiving GDMT were more often younger and male. Compared with non-GDMT patients, GDMT patients had a significantly lower frequency of comorbidities. Predictors of greater GDMT prescription at discharge were ST-segment elevation myocardial infarction (STEMI), and increased body mass index (BMI), whereas hypertension, prior PCI, anemia and CKD were associated with less GDMT prescription. At 1 year, the use of GDMT was associated with a significantly lower incidence of MACE (13.7% vs. 22.5%; adjusted HR 0.68; 95%CI 0.58-0.80; P < 0.001), death (3.7% vs. 9.4%; adjusted HR 0.61; 95%CI 0.46-0.80; P < 0.001), and unplanned TVR (8.4% vs. 11.3%; adjusted HR 0.76; 95%CI 0.61-0.96; P = 0.020). However, there were no significant differences in the incidence of MI (4.3% vs. 7.0%; adjusted HR 0.75; 95%CI 0.56-1.01; P = 0.056), stroke (1.5% vs. 2.0%; adjusted HR 0.79; 95%CI 0.47-1.34; P = 0.384) between the two groups. CONCLUSION: In a contemporary practice setting in the United States, GDMT was utilized in just over two-thirds of AMI patients undergoing PCI. Predictors of GDMT prescription at discharge included STEMI, BMI and absence of hypertension, CKD, anemia or prior PCI. Use of GDMT was associated with significantly lower risk of 1-year MACE and mortality.

Use of prasugrel and clinical outcomes in African-American patients treated with percutaneous coronary intervention for acute coronary syndromes.

OBJECTIVE: To investigate the use of prasugrel after percutaneous coronary intervention (PCI) in African American (AA) patients presenting with acute coronary syndrome (ACS). BACKGROUND: AA patients are at higher risk for adverse cardiovascular outcomes after PCI and may derive greater benefit from the use of potent antiplatelet therapy. METHODS: Using the multicenter PROMETHEUS observational registry of ACS patients treated with PCI, we grouped patients by self-reported AA or other races. Clinical outcomes at 90-day and 1-year included non-fatal myocardial infarction (MI), major adverse cardiac events (composite of death, MI, stroke, or unplanned revascularization) and major bleeding. RESULTS: The study population included 2,125 (11%) AA and 17,707 (89%) non-AA patients. AA patients were younger, more often female (46% vs. 30%) with a higher prevalence of diabetes mellitus, chronic kidney disease, and prior coronary intervention than non-AA patients. Although AA patients more often presented with troponin (+) ACS, prasugrel use was much less common in AA vs. non-AA (11.9% vs. 21.4%, respectively, P = 0.001). In addition, the use of prasugrel increased with the severity of presentation in non-AA but not in AA patients. Multivariable logistic regression showed AA race was an independent predictor of reduced use of prasugrel (0.42 [0.37-0.49], P < 0.0001). AA race was independently associated with a significantly higher risk of MI at 90-days and 1 year after PCI. CONCLUSIONS: Despite higher risk clinical presentation and worse 1-year ischemic outcomes, AA race was an independent predictor of lower prasugrel prescription in a contemporary population of ACS patients undergoing PCI.

Sex-related differences in outcomes among men and women under 55 years of age with acute coronary syndrome undergoing percutaneous coronary intervention: Results from the PROMETHEUS study.

BACKGROUND: Young women undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) experience greater adverse events than men, potentially due to under-treatment. We sought to compare the 1-year outcomes by sex in patients ≤55 years of age from a contemporary PCI cohort. METHODS: PROMETHEUS was a retrospective multicenter observational US study comparing outcomes in clopidogrel and prasugrel treated patients following ACS PCI. MACE was defined as a composite of death, myocardial infarction, stroke or unplanned revascularization. Clinically significant bleeding was defined as bleeding requiring transfusion or hospitalization. Hazard ratios were generated using multivariable Cox proportional hazards regression. RESULTS: The study cohort included 4,851 patients of which 1,162 (24.0%) were women and 3,689 (76.0%) were men. In this cohort, the prevalence of diabetes (41.0 vs. 27.9%) and chronic kidney disease (12.7 vs. 7.2%) was higher among women compared with men. Irrespective of sex, prasugrel was used in less than one-third of patients (31.8% in men vs. 28.1% in women, P = 0.01). Unadjusted, 1-year MACE (21.1% vs. 16.2%, P < 0.001) and bleeding (3.6% vs. 2.2%, P = 0.01) was significantly higher in women compared with men, but these results were no longer significant after adjustment for risk (HR 1.13, 95% CI 0.94-1.36 for MACE and HR 1.31, 95% CI 0.85-2.04 for bleeding). CONCLUSION: Women ≤ 55 years of age undergoing ACS PCI have significantly greater comorbidities than young men. Despite a higher risk clinical phenotype in women, prasugrel use was significantly lower in women than men. Female sex was associated with a significantly higher risk of 1-year MACE and bleeding than male sex, findings that are attributable to baseline differences. © 2016 Wiley Periodicals, Inc.

Impact of proton pump inhibitors and dual antiplatelet therapy cessation on outcomes following percutaneous coronary intervention: Results From the PARIS Registry.

BACKGROUND: Proton pump inhibitors (PPI) may decrease the availability of clopidogrel by competitive antagonism, leading to a potential increase in ischemic events. METHODS: We evaluated patients from the all-comer PARIS registry treated with dual antiplatelet therapy (DAPT) with aspirin and clopidogrel following coronary stenting for outcomes stratified by PPI use. Two-year major adverse cardiovascular events (MACE), composite of cardiac death, myocardial infarction, definite or probable stent thrombosis or target lesion revascularization (TLR), and net adverse cardiac events (NACE), composite of MACE or Bleeding Academic Research consortium (BARC) type 3 or 5 bleeding were assessed. We also explored associations between PPI use and patterns of 2-year DAPT cessation. RESULTS: The cohort comprised 4635 patients (23% PPI users) with mean age 64.4 ±11.4 years. Two year adjusted risk of MACE (HR: 1.27, 95% CI: 1.04-1.55), NACE (HR: 1.21, 95% CI: 1.01-1.44) and TLR (HR: 1.33, 95% CI: 1.04-1.71) were significantly higher in PPI users vs. non-users, without a difference in bleeding. Although the incidence of 2-year DAPT discontinuation and interruption was similar, DAPT disruption was significantly lower among PPI users vs. non-users (10.0% vs. 14.7%, P <0.0001). Compared to non-PPI users on continued DAPT, disruption was associated with higher MACE in both PPI users (HR: 2.34, 95% CI: 1.38-3.97) and non-users (HR: 1.41, 95% CI: 1.02-1.94) but greater BARC 3,5 bleeding only in non-PPI users (HR: 2.06, 95% CI: 1.21-3.51). CONCLUSIONS: In clopidogrel treated PCI patients, the 2-year adjusted risk of MACE and NACE was significantly higher in PPI users driven by higher TLR compared to non-PPI users, without a difference in bleeding. PPI use was associated with lower incidence of DAPT disruption without an increase in disruption related bleeding compared to non-PPI users on DAPT. © 2016 Wiley Periodicals, Inc.

Target lesion failure with BRS? good old DES to the rescue.

Target lesion revascularization (TLR) for BRS failure is burdened with a high rate of adverse events. DES implantation appears to be the safest treatment option following BRS failure. A real world observational study with a minimum of 2-year follow-up would be required to investigate the long-term clinical outcomes in patients with a BRS failure and to assess the best treatment option in case of TLR.

Divergent regulation of ryanodine receptor 2 calcium release channels by arrhythmogenic human calmodulin missense mutants.

RATIONALE: Calmodulin (CaM) mutations are associated with an autosomal dominant syndrome of ventricular arrhythmia and sudden death that can present with divergent clinical features of catecholaminergic polymorphic ventricular tachycardia (CPVT) or long QT syndrome (LQTS). CaM binds to and inhibits ryanodine receptor (RyR2) Ca release channels in the heart, but whether arrhythmogenic CaM mutants alter RyR2 function is not known. OBJECTIVE: To gain mechanistic insight into how human CaM mutations affect RyR2 Ca channels. METHODS AND RESULTS: We studied recombinant CaM mutants associated with CPVT (N54I and N98S) or LQTS (D96V, D130G, and F142L). As a group, all LQTS-associated CaM mutants (LQTS-CaMs) exhibited reduced Ca affinity, whereas CPVT-associated CaM mutants (CPVT-CaMs) had either normal or modestly lower Ca affinity. In permeabilized ventricular myocytes, CPVT-CaMs at a physiological intracellular concentration (100 nmol/L) promoted significantly higher spontaneous Ca wave and spark activity, a typical cellular phenotype of CPVT. Compared with wild-type CaM, CPVT-CaMs caused greater RyR2 single-channel open probability and showed enhanced binding affinity to RyR2. Even a 1:8 mixture of CPVT-CaM:wild-type-CaM activated Ca waves, demonstrating functional dominance. In contrast, LQTS-CaMs did not promote Ca waves and exhibited either normal regulation of RyR2 single channels (D96V) or lower RyR2-binding affinity (D130G and F142L). None of the CaM mutants altered Ca/CaM binding to CaM-kinase II. CONCLUSIONS: A small proportion of CPVT-CaM is sufficient to evoke arrhythmogenic Ca disturbances, whereas LQTS-CaMs do not. Our findings explain the clinical presentation and autosomal dominant inheritance of CPVT-CaM mutations and suggest that RyR2 interactions are unlikely to explain arrhythmogenicity of LQTS-CaM mutations.

Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments.

RATIONALE: The Ca(2+) sensitivity of the myofilaments is increased in hypertrophic cardiomyopathy and other heart diseases and may contribute to a higher risk for sudden cardiac death. Ca(2+) sensitization increases susceptibility to reentrant ventricular tachycardia in animal models, but the underlying mechanism is unknown. OBJECTIVE: To investigate how myofilament Ca(2+) sensitization creates reentrant arrhythmia susceptibility. METHODS AND RESULTS: Using hypertrophic cardiomyopathy mouse models (troponinT-I79N) and a Ca(2+) sensitizing drug (EMD57033), here we identify focal energy deprivation as a direct consequence of myofilament Ca(2+) sensitization. To detect ATP depletion and thus energy deprivation, we measured accumulation of dephosphorylated Connexin 43 (Cx43) isoform P0 and AMP kinase activation by Western blotting and immunostaining. No differences were detected between groups at baseline, but regional accumulation of Connexin 43 isoform P0 occurred within minutes in all Ca(2+)-sensitized hearts, in vivo after isoproterenol challenge and in isolated hearts after rapid pacing. Lucifer yellow dye spread demonstrated reduced gap junctional coupling in areas with Connexin 43 isoform P0 accumulation. Optical mapping revealed that selectively the transverse conduction velocity was slowed and anisotropy increased. Myofilament Ca(2+) desensitization with blebbistatin prevented focal energy deprivation, transverse conduction velocity slowing, and the reentrant ventricular arrhythmias. CONCLUSIONS: Myofilament Ca(2+) sensitization rapidly leads to focal energy deprivation and reduced intercellular coupling during conditions that raise arrhythmia susceptibility. This is a novel proarrhythmic mechanism that can increase arrhythmia susceptibility in structurally normal hearts within minutes and may, therefore, contribute to sudden cardiac death in diseases with increased myofilament Ca(2+) sensitivity.

Accelerated sinus rhythm prevents catecholaminergic polymorphic ventricular tachycardia in mice and in patients.

RATIONALE: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) genes. Sinoatrial node dysfunction associated with CPVT may increase the risk for ventricular arrhythmia (VA). OBJECTIVE: To test the hypothesis that CPVT is suppressed by supraventricular overdrive stimulation. METHODS AND RESULTS: Using CPVT mouse models (Casq2(-/-) and RyR2(R4496C/+) mice), the effect of increasing sinus heart rate was tested by pretreatment with atropine and by atrial overdrive pacing. Increasing intrinsic sinus rate with atropine before catecholamine challenge suppressed ventricular tachycardia in 86% of Casq2(-/-) mice (6/7) and significantly reduced the VA score (atropine: 0.6±0.2 versus vehicle: 1.7±0.3; P<0.05). Atrial overdrive pacing completely prevented VA in 16 of 19 (84%) Casq2(-/-) and in 7 of 8 (88%) RyR2(R4496C/+) mice and significantly reduced ventricular premature beats in both CPVT models (P<0.05). Rapid pacing also prevented spontaneous calcium waves and triggered beats in isolated CPVT myocytes. In humans, heart rate dependence of CPVT was evaluated by screening a CPVT patient registry for antiarrhythmic drug-naïve individuals that reached >85% of their maximum-predicted heart rate during exercise testing. All 18 CPVT patients who fulfilled the inclusion criteria exhibited VA before reaching 87% of maximum heart rate. In 6 CPVT patients (33%), VA were paradoxically suppressed as sinus heart rates increased further with continued exercise. CONCLUSIONS: Accelerated supraventricular rates suppress VAs in 2 CPVT mouse models and in a subset of CPVT patients. Hypothetically, atrial overdrive pacing may be a therapy for preventing exercise-induced ventricular tachycardia in treatment-refractory CPVT patients.

Enrollment of Older Patients, Women, and Racial and Ethnic Minority Individuals in Valvular Heart Disease Clinical Trials: A Systematic Review.

Importance: Inadequate representation of older patients, women, and racial minority individuals in cardiovascular clinical trials limits both the generalizability of trial findings and inclusivity in access to novel therapies and therapeutic strategies. Objective: To report on temporal trends in the representation of older patients, women, and racial and ethnic minority individuals in clinical trials studying treatments for valvular heart disease. Evidence Review: All published clinical trials enrolling more than 100 adults with any valvular heart disease published between 2005 and 2020 were included after searches with PubMed and ClinicalTrials.gov. Data on age, sex, race, and ethnicity reported in the included studies were collected. Trials were assigned to 4 time periods based on the publication date, and temporal trends were analyzed in the representation of older patients, women, and racial and ethnic minority individuals. Findings: A total of 139 clinical trials with 51 527 participants were identified. Of these trials, 103 (74%) investigated aortic valve disease and the remainder mitral valve disease. Overall, 63 trials (45.3%) enrolled patients only in Europe, 24 (17.3%) only in North America, and 19 (13.7%) in multiple geographical regions. The weighted mean (SD) age of enrolled patients was 68.4 (11.4) years, increasing nonsignificantly from 61.9 (5.9) years in 2005-2008 to 72.8 (9.6) years in 2017-2020 (P = .09 for trend). The overall proportion of women enrolled in valvular heart disease trials was 41.1%, with no significant changes over time. Data on race and ethnicity of trial participants were reported in 13 trials (9.4%), in which trial-level representation of American Indian/Alaska Native, Asian, Black/African American, Hispanic, and Native Hawaiian/Pacific Islander patients ranged from 0.27% to 43.9%. There were no significant temporal trends noted in the enrollment of racial and ethnic minority populations. The representation of women in clinical trials was positively associated with enrollment rates of older patients and underrepresented racial and ethnic groups. Conclusions and Relevance: This review found that over the past 2 decades, women and racial and ethnic minority individuals have remained underrepresented in North American valvular heart disease clinical trials. Further work is needed to improve the reporting of race and ethnicity data and address barriers to trial enrollment for older patients, women, and racial and ethnic minority individuals.

First-in-Human Multicenter Experience of the Newest Generation Supra-Annular Self-Expanding Evolut FX TAVR System.

BACKGROUND: The latest-generation Evolut FX TAVR system (Medtronic) offers several potential design improvements over its predecessors, but early reported experience has been limited. OBJECTIVES: This study sought to report our multicenter, limited market release, first-in-human experience of transcatheter aortic valve replacement (TAVR) with the Evolut FX system and compare it with a single-center PRO+ (Medtronic) experience. METHODS: From June 27 to September 16, 2022, 226 consecutive patients from 9 US centers underwent transfemoral TAVR with the Evolut FX system for native aortic stenosis (89.4%) or prosthetic valve degeneration (10.6%). Commissural alignment was defined as 0° to 30° between native and FX commissures. Patient, anatomical, and procedural characteristics were retrospectively reviewed, and 30-day clinical and echocardiographic outcomes per Valve Academic Research Consortium-3 definitions were reported. RESULTS: Of 226 patients, 34.1% were low risk, 4% had a bicuspid valve, and 11.5% had a horizontal root (≥60°). Direct Inline sheath (Medtronic) was used in 67.6% and Lunderquist stiff wire (Cook Medical) in 35.4% of cases. Optimal hat marker orientation during deployment was achieved in 98.4%, with commissural alignment in 96.5%. At 30 days, 14.3% mild, 0.9% moderate, and no severe paravalvular leak were observed. Compared with the Evolut PRO+ experience from 1 center, FX had a more symmetrical implantation with shallower depth at the left coronary cusp (P < 0.001), fewer device recaptures (26.1% vs 39.5%; P = 0.004), and improved commissural alignment (96.5% vs 80.2%; P < 0.001). CONCLUSIONS: The Evolut FX system demonstrated favorable 30-day outcomes with a significant improvement over PRO+ in achieving commissural alignment, fewer device recaptures, and more symmetrical implantation. These features may benefit younger patients undergoing TAVR with the supra-annular, self-expanding valve, where lifetime management would be important.

Calsequestrin 2 and arrhythmias.

Calsequestrin is the most abundant Ca-binding protein of the specialized endoplasmic reticulum found in muscle, the sarcoplasmic reticulum (SR). Calsequestrin binds Ca with high capacity and low affinity and importantly contributes to the mobilization of Ca during each contraction both in skeletal and cardiac muscle. Surprisingly, mutations in the gene encoding the cardiac isoform of calsequestrin (Casq2) have been associated with an inherited form of ventricular arrhythmia triggered by emotional or physical stress termed catecholaminergic polymorphic ventricular tachycardia (CPVT). Despite normal cardiac contractility and normal resting ECG, CPVT patients present with a high risk of sudden death at a young age. Here, we review recent new insights regarding the role of calsequestrin in genetic and acquired arrhythmia disorders. Mouse models of CPVT have shed light on the pathophysiological mechanism underlying CPVT. Casq2 is not only a Ca-storing protein as initially hypothesized, but it has a far more complex function in Ca handling and regulating SR Ca release channels. The functional importance of Casq2 interactions with other SR proteins and the importance of alterations in Casq2 trafficking are also being investigated. Reports of altered Casq2 trafficking in animal models of acquired heart diseases such as heart failure suggest that Casq2 may contribute to arrhythmia risk beyond genetic forms of Casq2 dysfunction.

Calsequestrin mutations and catecholaminergic polymorphic ventricular tachycardia.

Cardiac calsequestrin (Casq2) is the major Ca2+ binding protein in the sarcoplasmic reticulum, which is the principle Ca2+ storage organelle of cardiac muscle. During the last decade, experimental studies have provided new concepts on the role of Casq2 in the regulation of cardiac muscle Ca2+ handling. Furthermore, mutations in the gene encoding for cardiac calsequestrin, CASQ2, cause a rare but severe form of catecholaminergic polymorphic ventricular tachycardia (CPVT). Here, we review the physiology of Casq2 in cardiac Ca2+ handling and discuss pathophysiological mechanisms that lead to CPVT caused by CASQ2 mutations. We also describe the clinical aspects of CPVT and provide an update of its contemporary clinical management.

The Purkinje-myocardial junction is the anatomic origin of ventricular arrhythmia in CPVT.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmia syndrome caused by gene mutations that render RYR2 Ca release channels hyperactive, provoking spontaneous Ca release and delayed afterdepolarizations (DADs). What remains unknown is the cellular source of ventricular arrhythmia triggered by DADs: Purkinje cells in the conduction system or ventricular cardiomyocytes in the working myocardium. To answer this question, we used a genetic approach in mice to knock out cardiac calsequestrin either in Purkinje cells or in ventricular cardiomyocytes. Total loss of calsequestrin in the heart causes a severe CPVT phenotype in mice and humans. We found that loss of calsequestrin only in ventricular myocytes produced a full-blown CPVT phenotype, whereas mice with loss of calsequestrin only in Purkinje cells were comparable to WT mice. Subendocardial chemical ablation or restoration of calsequestrin expression in subendocardial cardiomyocytes neighboring Purkinje cells was sufficient to protect against catecholamine-induced arrhythmias. In silico modeling demonstrated that DADs in ventricular myocardium can trigger full action potentials in the Purkinje fiber, but not vice versa. Hence, ectopic beats in CPVT are likely generated at the Purkinje-myocardial junction via a heretofore unrecognized tissue mechanism, whereby DADs in the ventricular myocardium trigger full action potentials in adjacent Purkinje cells.

Ferritin as a reporter gene for in vivo tracking of stem cells by 1.5-T cardiac MRI in a rat model of myocardial infarction.

The methods currently utilized to track stem cells by cardiac MRI are affected by important limitations, and new solutions are needed. We tested human ferritin heavy chain (hFTH) as a reporter gene for in vivo tracking of stem cells by cardiac MRI. Swine cardiac stem/progenitor cells were transduced with a lentiviral vector to overexpress hFTH and cultured to obtain cardiospheres (Cs). Myocardial infarction was induced in rats, and, after 45 min, the animals were subjected to intramyocardial injection of ∼200 hFTH-Cs or nontransduced Cs or saline solution in the border zone. By employing clinical standard 1.5-Tesla MRI scanner and a multiecho T2* gradient echo sequence, we localized iron-accumulating tissue only in hearts treated with hFTH-Cs. This signal was detectable at 1 wk after infarction, and its size did not change significantly after 4 wk (6.33 ± 3.05 vs. 4.41 ± 4.38 mm(2)). Cs transduction did not affect their cardioreparative potential, as indicated by the significantly better preserved left ventricular global and regional function and the 36% reduction in infarct size in both groups that received Cs compared with control infarcts. Prussian blue staining confirmed the presence of differentiated, iron-accumulating cells containing mitochondria of porcine origin. Cs-derived cells displayed CD31, α-smooth muscle, and α-sarcomeric actin antigens, indicating that the differentiation into endothelial, smooth muscle and cardiac muscle lineage was not affected by ferritin overexpression. In conclusion, hFTH can be used as a MRI reporter gene to track dividing/differentiating stem cells in the beating heart, while simultaneously monitoring cardiac morpho-functional changes.

Long-term Outcome of Pulmonary Vein Isolation Versus Amiodarone Therapy in Patients with Coexistent Persistent AF and Congestive Heart Failure.

Although pharmacological rhythm control of AF in patients with heart failure with reduced ejection fraction (HFrEF) does not seem to provide any benefit over rate control, catheter ablation of AF has been shown to improve clinical outcomes. These results can be explained with higher success rates of catheter ablation in restoring and maintaining sinus rhythm compared with antiarrhythmic drugs. In addition, pharmacotherapy is not void of side-effects, which are thought to offset its potential antiarrhythmic benefits. Therefore, efforts should be made towards optimisation of ablation techniques for AF in patients with HFrEF.

Comparison of Age (<75 Years Vs ≥75 Years) and Platelet Reactivity to the Risk of Thrombotic and Bleeding Events After Successful Percutaneous Coronary Intervention With Drug-Eluting Stents (from the ADAPT-DES Study).

Elderly patients may have increased platelet reactivity and adverse events after percutaneous coronary intervention. Whether age is an independent predictor of worse outcomes after accounting for platelet reactivity is unknown. We sought to determine the relation between age and platelet reactivity on 2-year outcomes after percutaneous coronary intervention with drug-eluting stents (DES). ADAPT-DES was a prospective observational registry comprising 8,582 DES-treated patients. Patients were categorized with an age cutoff of 75 years. On-clopidogrel platelet reactivity was evaluated with VerifyNow P2Y12 testing. Multivariable Cox proportional hazards regression models were used to describe the relation between increasing age and 2-year clinical outcomes. Patients ≥75 old were more likely to be women and had more cardiovascular risk factors and more extensive coronary artery disease than younger patients. Residual platelet reactivity on-clopidogrel increased slightly with age (adjusted r = 0.05, p <0.0001). Age ≥75 years was associated with greater all-cause mortality (adjusted HR 1.64, 95% CI 1.25 to 2.15, p <0.001), myocardial infarction (adjusted HR 1.33, 95% CI 1.01 to 1.74, p = 0.04) and clinically relevant bleeding (adjusted HR 1.33, 95% CI 1.10 to 1.61 p = 0.003). In contrast, the risk of stent thrombosis was independent of age (adjusted HR 0.83, 95% CI 0.46 to 1.52, and p = 0.55). Considered as a continuous variable, age was directly related to clinically relevant bleeding, cardiac and all-cause mortality, was inversely related to stent thrombosis, and was not related to myocardial infarction. There was no significant interaction between age and on-treatment platelet reactivity for the risk of 2-year clinical outcomes. In conclusion, increasing age had a stronger association with the risk of death and bleeding than of thrombotic events. Despite being associated with older age, higher residual platelet reactivity did not modify the adjusted relative risks of ischemic and bleeding events associated with age.