Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease最新文献_第3页

Sex‐Based Differences in Outcomes Following Peripheral Artery Revascularization: Insights From VOYAGER PAD 外周动脉血运重建术后结果的性别差异:来自VOYAGER PAD的见解

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Pub Date : 2022-06-14 DOI: 10.1161/JAHA.121.024655

Connie N. Hess, I. Baumgartner, Sonia S Anand, M. Nehler, M. Patel, E. S. Debus, M. Szarek, W. Capell, E. Muehlhofer, S. Berkowitz, L. Haskell, R. Bauersachs, M. Bonaca, Judith Hsia

Background Despite high female prevalence of peripheral artery disease (PAD), little is known about sex‐based outcomes after lower extremity revascularization (LER) for symptomatic PAD. The effects of rivaroxaban according to sex following LER have not been fully reported. Methods and Results In VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease), low‐dose rivaroxaban versus placebo on a background of aspirin reduced the composite primary efficacy outcome of cardiovascular and limb events in patients with PAD undergoing LER. Unplanned index limb revascularization was prespecified and prospectively ascertained. The primary safety outcome was Thrombolysis in Myocardial Infarction major bleeding. Analyses of outcomes and treatment effects by sex were performed using Cox proportional hazards models. Among 6564 randomly assigned patients followed for a median of 28 months, 1704 (26.0%) were women. Among patients administered placebo, women were at similar risk for the primary efficacy outcome (hazard ratio [HR], 0.90; [95% CI, 0.74–1.09]; P=0.29) as men, while female sex was associated with a trend toward higher risk of unplanned index limb revascularization (HR, 1.18; [95% CI, 1.00–1.40]; P=0.0499). Irrespective of sex, effects of rivaroxaban were consistent for the primary efficacy outcome (P‐interaction=0.22), unplanned index limb revascularization (P‐interaction=0.64), and bleeding (P‐interaction=0.61). Women were more likely than men to discontinue study treatment (HR, 1.13; [95% CI, 1.03–1.25]; P=0.0099). Conclusions Among >1700 women with PAD undergoing LER, women and men were at similar risk for the primary outcome, but a trend for greater risk of unplanned index limb revascularization among women was observed. Effects of rivaroxaban were consistent by sex, though women more often discontinued treatment. Better understanding of sex‐based outcomes and treatment adherence following LER is needed. Registration URL: http://clinicaltrials.gov; Unique identifier: NCT02504216.

背景:尽管女性外周动脉疾病(PAD)的患病率很高，但对有症状的PAD患者下肢血运重建术(LER)后基于性别的结局知之甚少。利伐沙班对LER后性别的影响尚未得到充分报道。方法和结果在VOYAGER PAD(血管结局研究ASA[乙酰水杨酸]联合利伐沙班进行外周动脉疾病的血管内或手术肢体血运重建术)中，低剂量利伐沙班与阿司匹林背景下的安慰剂相比，降低了接受LER治疗的PAD患者心血管和肢体事件的复合主要疗效。计划外的下肢血运重建术是预先确定和前瞻性确定的。主要的安全终点是心肌梗死大出血时的溶栓。采用Cox比例风险模型对结果和治疗效果进行性别分析。在6564名随机分配的患者中，随访时间中位数为28个月，其中1704名(26.0%)为女性。在服用安慰剂的患者中，女性在主要疗效结局方面的风险相似(风险比[HR]， 0.90;[95% ci, 0.74-1.09];P=0.29)，而女性与计划外下肢血运重建术的高风险趋势相关(HR, 1.18;[95% ci, 1.00-1.40];P = 0.0499)。不论性别，利伐沙班对主要疗效结局(P -相互作用=0.22)、计划外下肢血管重建(P -相互作用=0.64)和出血(P -相互作用=0.61)的影响是一致的。女性比男性更有可能停止研究治疗(HR, 1.13;[95% ci, 1.03-1.25];P = 0.0099)。结论:在bb17000名接受LER治疗的女性PAD患者中，女性和男性在主要结局方面的风险相似，但观察到女性发生计划外下肢血运重建术的风险更高。利伐沙班的效果在性别上是一致的，尽管女性更经常停止治疗。需要更好地了解LER后基于性别的结局和治疗依从性。注册网址:http://clinicaltrials.gov;唯一标识符:NCT02504216。

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引用次数: 6

Prognostic Value of Exercise Capacity in Kidney Transplant Candidates 运动能力对肾移植候选人的预后价值

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Pub Date : 2022-06-14 DOI: 10.1161/JAHA.121.025862

Sean Tan, Y. Thang, W. Mulley, K. Polkinghorne, S. Ramkumar, K. Cheng, J. Chan, J. Galligan, M. Nolan, A. Brown, S. Moir, J. Cameron, Stephen J. Nicholls, P. Mottram, N. Nerlekar

Background Exercise stress testing for cardiovascular assessment in kidney transplant candidates has been shown to be a feasible alternative to pharmacologic methods. Exercise stress testing allows the additional assessment of exercise capacity, which may have prognostic value for long‐term cardiovascular outcomes in pre‐transplant recipients. This study aimed to evaluate the prognostic value of exercise capacity on long‐term cardiovascular outcomes in kidney transplant candidates. Methods and Results We retrospectively evaluated exercise capacity in 898 consecutive kidney transplant candidates between 2013 and 2020 who underwent symptom‐limited exercise stress echocardiography for pre‐transplant cardiovascular assessment. Exercise capacity was measured by age‐ and sex‐predicted metabolic equivalents (METs). The primary outcome was incident major adverse cardiovascular events, defined as cardiac death, non‐fatal myocardial infarction, and stroke. Cox proportional hazard multivariable modeling was performed to define major adverse cardiovascular events predictors with transplantation treated as a time‐varying covariate. A total of 429 patients (48%) achieved predicted METs. During follow‐up, 93 (10%) developed major adverse cardiovascular events and 525 (58%) underwent transplantation. Achievement of predicted METs was independently associated with reduced major adverse cardiovascular events (hazard ratio [HR] 0.49; [95% CI 0.29–0.82], P=0.007), as was transplantation (HR, 0.52; [95% CI 0.30–0.91], P=0.02). Patients achieving predicted METs on pre‐transplant exercise stress echocardiography had favorable outcomes that were independent (HR, 0.78; [95% CI 0.32–1.92], P=0.59) and of similar magnitude to subsequent transplantation (HR, 0.97; [95% CI 0.42–2.25], P=0.95). Conclusions Achievement of predicted METs on pre‐transplant exercise stress echocardiography confers excellent prognosis independent of and of similar magnitude to subsequent kidney transplantation. Future studies should assess the benefit on exercise training in this population.

研究背景:运动应激测试已被证明是替代药理学方法的可行方法。运动压力测试允许对运动能力进行额外的评估，这可能对移植前受者的长期心血管结果具有预后价值。本研究旨在评估运动能力对肾移植候选人长期心血管结局的预后价值。方法和结果我们回顾性评估了2013年至2020年间898例连续肾移植候选人的运动能力，这些患者在移植前接受了症状限制运动应激超声心动图检查，用于心血管评估。通过年龄和性别预测的代谢当量(METs)来测量运动能力。主要终点是主要不良心血管事件的发生率，定义为心源性死亡、非致死性心肌梗死和中风。采用Cox比例风险多变量模型来确定主要心血管不良事件的预测因素，并将移植作为时变协变量。共有429名患者(48%)达到了预期的METs。在随访期间，93例(10%)发生了严重的心血管不良事件，525例(58%)接受了移植。达到预期的METs与主要不良心血管事件的减少独立相关(危险比[HR] 0.49;[95% CI 0.29-0.82]， P=0.007)，移植也是如此(HR, 0.52;[95% ci 0.30-0.91]， p =0.02)。在移植前运动应激超声心动图上达到预期METs的患者具有良好的独立预后(HR, 0.78;[95% CI 0.32-1.92]， P=0.59)，且与随后的移植相似(HR, 0.97;[95% ci 0.42-2.25]， p =0.95)。结论:移植前运动应激超声心动图预测的METs具有良好的预后，与后续肾移植无关，且程度相似。未来的研究应该评估运动训练对这一人群的益处。

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引用次数: 0

Association of Familial History of Diabetes, Hypertension, Dyslipidemia, Stroke, or Myocardial Infarction With Risk of Kawasaki Disease 糖尿病、高血压、血脂异常、中风或心肌梗死家族史与川崎病风险的关系

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Pub Date : 2022-06-14 DOI: 10.1161/JAHA.121.023840

J. Kwak, E. K. Ha, J. Kim, Hye Ryung Cha, Seung Won Lee, M. Han

Background There are few studies on the association with Kawasaki disease in children and the family’s history of cardiovascular disease (CVD). The aim of this study was to identify the association of increased risks for Kawasaki disease in children with a family history of CVD. Methods and Results Clinical data of children born in 2008 and 2009 (n=917 707) were obtained from the National Health Insurance Service and the National Health Screening Program for Infants and Children for this study. The cohort consisted of 495 215 participants (53.8%) who completed the family history questionnaire for children 54 to 60 months old. Family history of CVD included 5 medical conditions: hypertension, dyslipidemia, myocardial infarction, stroke, and diabetes. Kawasaki disease was defined using the disease code, intravenous immunoglobulin prescription, and use of antipyretics for more than 25 days. Severe Kawasaki disease was defined as diagnosis of accompanied cardiac/coronary artery complications or intravenous immunoglobulin use ≥2 times. The incidence rate of Kawasaki disease was 124/100 000 person‐years (95% CI, 117.5–131.5) for children <2 years old, 95/100 000 person‐years (95% CI, 90.5–100.4) in children 2 to 5 years old, and 14/100 000 person‐years (95% CI, 12.6–15.6) in children >5 years old. After propensity‐score matching, 829 participants with a family history of CVD were diagnosed as having Kawasaki disease (0.68% [95% CI, 0.63–0.72]), and 690 patients with Kawasaki disease (0.56% [95% CI, 0.52–0.61]) had no family history of CVD. The family history of CVD was associated with increased risk for Kawasaki disease (risk ratio, 1.20 [95% CI, 1.08–1.32]) but not for severe Kawasaki disease (risk ratio, 1.23 [95% CI, 0.92–1.65]). Conclusions In this nationwide propensity‐score matched study, those with a family history of CVD had a significantly greater risk of Kawasaki disease compared with those who had no family history of CVD.

背景目前关于儿童川崎病与心血管疾病家族史之间关系的研究很少。本研究的目的是确定有心血管疾病家族史的儿童患川崎病风险增加的相关性。方法与结果本研究从国家健康保险服务中心和国家婴幼儿健康筛查计划中获取2008年和2009年出生的儿童临床资料(n= 917707)。该队列包括495215名参与者(53.8%)，他们完成了54至60个月大儿童的家族史问卷。心血管疾病家族史包括5种疾病:高血压、血脂异常、心肌梗死、中风和糖尿病。川崎病的定义采用疾病代码、静脉注射免疫球蛋白处方和使用退烧药超过25天。重度川崎病定义为诊断伴有心脏/冠状动脉并发症或静脉注射免疫球蛋白≥2次。5岁儿童的川崎病发病率为124/10万人-年(95% CI, 117.5-131.5)。倾向评分匹配后，829名有心血管疾病家族史的参与者被诊断为川崎病(0.68% [95% CI, 0.63-0.72])， 690名川崎病患者(0.56% [95% CI, 0.52-0.61])没有心血管疾病家族史。心血管疾病家族史与川崎病风险增加相关(风险比1.20 [95% CI, 1.08-1.32])，但与严重川崎病无关(风险比1.23 [95% CI, 0.92-1.65])。结论:在这项全国性的倾向评分匹配研究中，有心血管疾病家族史的人患川崎病的风险明显高于没有心血管疾病家族史的人。

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引用次数: 2

Genetic Determinants of Body Mass Index and Fasting Glucose Are Mediators of Grade 1 Diastolic Dysfunction. 体重指数和空腹血糖的遗传决定因素是1级舒张功能障碍的介质。

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Pub Date : 2022-06-07 Epub Date: 2022-06-03 DOI: 10.1161/JAHA.122.025578

Nataraja Sarma Vaitinadin, Mingjian Shi, Christian M Shaffer, Eric Farber-Eger, Brandon D Lowery, Vineet Agrawal, Deepak K Gupta, Dan M Roden, Quinn S Wells, Jonathan D Mosley

Background Early (grade 1) cardiac left ventricular diastolic dysfunction (G1DD) increases the risk for heart failure with preserved ejection fraction and may improve with aggressive risk factor modification. Type 2 diabetes, obesity, hypertension, and coronary heart disease are associated with increased incidence of diastolic dysfunction. The genetic drivers of G1DD are not defined. Methods and Results We curated genotyped European ancestry G1DD cases (n=668) and controls with normal diastolic function (n=1772) from Vanderbilt's biobank. G1DD status was explored through (1) an additive model genome-wide association study, (2) shared polygenic risk through logistic regression, and (3) instrumental variable analysis using 2-sample Mendelian randomization (the inverse-variance weighted method, Mendelian randomization-Egger, and median) to determine potential modifiable risk factors. There were no common single nucleotide polymorphisms significantly associated with G1DD status. A polygenic risk score for BMI was significantly associated with increased G1DD risk (odds ratio [OR], 1.20 for 1-SD increase in BMI [95% CI, 1.08-1.32]; P=0.0003). The association was confirmed by the inverse-variance weighted method (OR, 1.89 [95% CI, 1.37-2.61]). Among the candidate mediators for BMI, only fasting glucose was significantly associated with G1DD status by the inverse-variance weighted method (OR, 4.14 for 1-SD increase in fasting glucose [95% CI, 1.55-11.02]; P=0.005). Multivariable Mendelian randomization showed a modest attenuation of the BMI association (OR, 1.84 [95% CI, 1.35-2.52]) when adjusting for fasting glucose. Conclusions These data suggest that a genetic predisposition to elevated BMI increases the risk for G1DD. Part of this effect may be mediated through altered glucose homeostasis.

背景：早期（1级）心脏左室舒张功能障碍（G1DD）增加了保留射血分数的心力衰竭的风险，并可能随着积极的危险因素改变而改善。2型糖尿病、肥胖、高血压和冠心病与舒张功能障碍的发生率增加有关。G1DD的遗传驱动因素尚未确定。方法与结果我们从Vanderbilt’s生物库中筛选了欧洲血统G1DD患者（n=668）和舒张功能正常的对照组（n=1772）。通过(1)加性模型全基因组关联研究，(2)通过逻辑回归分析共享多基因风险，以及(3)使用2样本孟德尔随机化（反方差加权法、孟德尔随机化- egger法和中位数法）进行工具变量分析，确定潜在的可改变危险因素，探讨G1DD状态。没有与G1DD状态显著相关的常见单核苷酸多态性。BMI的多基因风险评分与G1DD风险增加显著相关(BMI增加1-SD的优势比[OR]为1.20 [95% CI, 1.08-1.32]；P = 0.0003)。反方差加权法证实了这种关联（OR, 1.89 [95% CI, 1.37-2.61]）。在BMI的候选介质中，通过反方差加权方法，只有空腹血糖与G1DD状态显著相关（空腹血糖升高1-SD的OR为4.14）[95% CI, 1.55-11.02]；P = 0.005)。多变量孟德尔随机化显示，当调整空腹血糖时，BMI相关性适度衰减（OR, 1.84 [95% CI, 1.35-2.52]）。结论：这些数据表明，BMI升高的遗传易感性增加了G1DD的风险。部分影响可能是通过改变葡萄糖稳态介导的。

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引用次数: 0

Subcutaneous Versus Transvenous Implantable Defibrillator Therapy: A Systematic Review and Meta-Analysis of Randomized Trials and Propensity Score-Matched Studies. 皮下与经静脉植入式除颤器治疗：随机试验和倾向评分匹配研究的系统回顾和荟萃分析。

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Pub Date : 2022-06-07 Epub Date: 2022-06-03 DOI: 10.1161/JAHA.121.024756

Khi Yung Fong, Colin Jun Rong Ng, Yue Wang, Colin Yeo, Vern Hsen Tan

Background Subcutaneous implantable cardioverter-defibrillators (S-ICDs) have been of great interest as an alternative to transvenous implantable cardioverter-defibrillators (TV-ICDs). No meta-analyses synthesizing data from high-quality studies have yet been published. Methods and Results An electronic literature search was conducted to retrieve randomized controlled trials or propensity score-matched studies comparing S-ICD against TV-ICD in patients with an implantable cardioverter-defibrillator indication. The primary outcomes were device-related complications and lead-related complications. Secondary outcomes were inappropriate shocks, appropriate shock, all-cause mortality, and infection. All outcomes were pooled under random-effects meta-analyses and reported as risk ratios (RRs) and 95% CIs. Kaplan-Meier curves of device-related complications were digitized to retrieve individual patient data and pooled under a 1-stage meta-analysis using Cox models to determine hazard ratios (HRs) of patients undergoing S-ICD versus TV-ICD. A total of 5 studies (2387 patients) were retrieved. S-ICD had a similar rate of device-related complications compared with TV-ICD (RR, 0.59 [95% CI, 0.33-1.04]; P=0.070), but a significantly lower lead-related complication rate (RR, 0.14 [95% CI, 0.07-0.29]; P<0.0001). The individual patient data-based 1-stage stratified Cox model for device-related complications across 4 studies yielded no significant difference (shared-frailty HR, 0.82 [95% CI, 0.61-1.09]; P=0.167), but visual inspection of pooled Kaplan-Meier curves suggested a divergence favoring S-ICD. Secondary outcomes did not differ significantly between both modalities. Conclusions S-ICD is clinically superior to TV-ICD in terms of lead-related complications while demonstrating comparable efficacy and safety. For device-related complications, S-ICD may be beneficial over TV-ICD in the long term. These indicate that S-ICD is likely a suitable substitute for TV-ICD in patients requiring implantable cardioverter-defibrillator implantation without a pacing indication.

皮下植入式心律转复除颤器（S-ICDs）作为经静脉植入式心律转复除颤器（TV-ICDs）的替代方案已经引起了人们的极大兴趣。目前尚未发表综合高质量研究数据的荟萃分析。方法和结果通过电子文献检索检索随机对照试验或倾向评分匹配研究，比较S-ICD和TV-ICD在植入式心律转复除颤器适应症患者中的应用。主要结局是器械相关并发症和导联相关并发症。次要结局为不适当休克、适当休克、全因死亡率和感染。所有结果在随机效应荟萃分析中汇总，并以风险比（rr）和95% ci报告。将器械相关并发症的Kaplan-Meier曲线数字化以检索个体患者数据，并使用Cox模型进行一期荟萃分析，以确定S-ICD患者与TV-ICD患者的风险比（hr）。共检索了5项研究（2387例患者）。与TV-ICD相比，S-ICD的器械相关并发症发生率相似(RR, 0.59 [95% CI, 0.33-1.04]；P=0.070)，但与导联相关的并发症发生率显著降低(RR, 0.14 [95% CI, 0.07-0.29]；PP=0.167)，但合并Kaplan-Meier曲线的目视检查显示偏向S-ICD的散度。两种治疗方式的次要结果无显著差异。结论S-ICD在铅相关并发症方面优于TV-ICD，且具有相当的疗效和安全性。从长远来看，S-ICD可能比TV-ICD更有利。这表明S-ICD可能是需要植入式心律转复除颤器植入而无起搏指征的患者电视- icd的合适替代品。

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引用次数: 0

Is There an Obesity Paradox in Cardiogenic Shock? 心源性休克是否存在肥胖悖论?

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Pub Date : 2022-06-06 DOI: 10.1161/JAHA.122.026088

C. Lavie, A. daSilva-deAbreu, H. Ventura, M. Mehra

Obesity has reached epidemic levels in the United States and in much of the Westernized world.1– 3 The majority of the US population is now either overweight or obese (75%), and 42% meet the current body mass index criteria (BMI ≥30 kg/m2) for obesity, with 9% meeting criteria for severe, class III obesity (formerly called morbid obesity with a BMI ≥40 kg/ m2 or a BMI of 35 kg/m2 or higher and experiencing obesityrelated health conditions).1 Obesity adversely influences cardiovascular diseases (CVD) by its intersection with major CVD risk factors, including worsening of arterial pressure and glucose intolerance, thus leading to metabolic syndrome and diabetes and worsening lipids, especially triglyceride levels. Not only is obesity associated with worsening inflammation, but it also increases the prevalence of hypertension and coronary heart disease, all of which conspire to cause heart failure (HF). Thus, obesity increases the risk of HF, especially HF with preserved ejection fraction (EF) more so than HF with reduced EF. As reviewed elsewhere3,4 obesity is associated with development of atrial fibrillation, worsened renal function, venous thromboembolism, and respiratory illness, all of which alone and together can worsen HF prognosis. Despite the increased health risks associated with obesity, considerable focus has centered on the “obesity paradox” (wherein individuals with overweight or obesity and CVD have a better shortand mediumterm prognosis than do leaner patients with the same degree of disease) among patients with CVD, endstage renal disease, pulmonary diseases (including chronic obstructive pulmonary disease), and complications from infections.2,3,5– 8 Particularly, an obesity paradox has been noted with both HF with reduced EF and HF with preserved EF, manifest by a lower overall and CVDmortality in people who are overweight or mildly obese, whereas hospitalizations seem to be increased as obesity progresses to severe.9,10 In advanced stages of HF and especially in states of therapy for such a condition such as use of left ventricular assist devices or heart transplantation, the presence of obesity perpetuates complications and worsens survival.11,12 Similarly, an obesity paradox has not been demonstrated in cardiogenic shock. Recently, Sreenivasan and colleagues13 did not find an obesity paradox in a large US population of cardiogenic shock (CS) compared with those who were nonobese, and moderate and severe obesity had progressively higher mortality.13,14 In this issue of the Journal of the American Heart Association (JAHA), Kwon and colleagues15 studied 1227 patients with CS from a South Korean registry and classified patients as obese (BMI ≥25 kg/m2 based

肥胖在美国和大部分西化国家已经达到了流行病的程度。1 - 3目前，大多数美国人口要么超重，要么肥胖(75%)，42%符合当前肥胖的体重指数标准(BMI≥30 kg/m2)， 9%符合严重的III类肥胖标准(以前称为病态肥胖，BMI≥40 kg/m2或BMI为35 kg/m2或更高，并经历与肥胖相关的健康状况)肥胖通过与主要心血管疾病危险因素(包括动脉压恶化和葡萄糖耐受不良)的交叉对心血管疾病(CVD)产生不利影响，从而导致代谢综合征和糖尿病，并导致血脂，特别是甘油三酯水平恶化。肥胖不仅与炎症恶化有关，而且还会增加高血压和冠心病的患病率，所有这些都会导致心力衰竭(HF)。因此，肥胖增加HF的风险，尤其是保留射血分数(EF)的HF比射血分数降低的HF更明显。如其他文献所述3,4肥胖与房颤、肾功能恶化、静脉血栓栓塞和呼吸系统疾病的发生有关，所有这些单独或共同可使心衰预后恶化。尽管与肥胖相关的健康风险增加，但在患有心血管疾病、终末期肾病、肺部疾病(包括慢性阻塞性肺病)和感染并发症的患者中，相当多的焦点集中在“肥胖悖论”上(超重或肥胖合并心血管疾病的个体比患有相同疾病程度的苗条患者有更好的短期和中期预后)。2,3,5 - 8特别值得一提的是，对于心力衰竭降低的心衰和心力衰竭保留的心衰，肥胖悖论已经被注意到，表现为超重或轻度肥胖患者的总体和心血管死亡率较低，而随着肥胖进展到严重，住院治疗似乎增加。9,10在心衰晚期，特别是在使用左心室辅助装置或心脏移植等治疗阶段，肥胖的存在使并发症持续存在并恶化生存。11,12同样，肥胖悖论在心源性休克中也未得到证实。最近，Sreenivasan和他的同事们在美国的心源性休克(CS)人群中与非肥胖者相比，并没有发现肥胖悖论，而且中度和重度肥胖的死亡率逐渐升高。13,14在本期的《美国心脏协会杂志》(JAHA)上，Kwon及其同事研究了1227名来自韩国的CS患者，并将患者分类为肥胖(BMI≥25 kg/m2)

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引用次数: 1

Methadone Blockade of Cardiac Inward Rectifier K+ Current Augments Membrane Instability and Amplifies U Waves on Surface ECGs: A Translational Study 美沙酮阻断心脏向内整流K+电流增加膜不稳定性并放大表面心电图上的U波:一项转化研究

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Pub Date : 2022-06-06 DOI: 10.1161/JAHA.121.023482

Michael G Klein, M. Krantz, N. Fatima, A. Watters, Dayan Colon-Sanchez, R. Geiger, R. Goldstein, S. Solhjoo, P. Mehler, T. Flagg, M. Haigney

Background Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K+ current (I Kr), the principal mechanism of drug‐associated arrhythmia. Congenital defects of inward rectifier K+ current (I K1) have been linked to increased U‐wave amplitude on ECG and fatal arrhythmia. We hypothesized that methadone may also be a potent inhibitor of I K1, contributing to delayed repolarization and manifesting on surface ECGs as augmented U‐wave integrals. Methods and Results Using a whole‐cell voltage clamp, methadone inhibited both recombinant and native I K1 with a half‐maximal inhibitory concentration IC50) of 1.5 μmol/L, similar to that observed for I Kr block (half‐maximal inhibitory concentration of 2.9 μmol/L). Methadone modestly increased the action potential duration at 90% repolarization and slowed terminal repolarization at low concentrations. At higher concentrations, action potential duration at 90% repolarization lengthening was abolished, but its effect on terminal repolarization rose steadily and correlated with increased fluctuations of diastolic membrane potential. In parallel, patient ECGs were analyzed before and after methadone initiation, with 68% of patients having a markedly increased U‐wave integral compared with premethadone (lead V3; mean +38%±15%, P=0.016), along with increased QT and TPeak to TEnd intervals, likely reflective of I Kr block. Conclusions Methadone is a potent I K1 inhibitor that causes augmentation of U waves on surface ECG. We propose that increased membrane instability resulting from I K1 block may better explain methadone’s arrhythmia risk beyond I Kr inhibition alone. Drug‐induced augmentation of U waves may represent evidence of blockade of multiple repolarizing ion channels, and evaluation of the effect of that agent on I K1 may be warranted.

背景美沙酮与猝死和室性心动过速的不成比例的风险相关，尽管延迟整流K+电流(I Kr)只有适度的抑制作用，这是药物相关性心律失常的主要机制。先天性内向整流K+电流(I K1)缺陷与ECG上U波振幅增加和致命性心律失常有关。我们假设美沙酮也可能是ik1的有效抑制剂，有助于延迟复极化，并在表面心电图上表现为增强的U波积分。方法和结果在全细胞电压钳下，美沙酮对重组I K1和原生I K1均有抑制作用，半数最大抑制浓度IC50为1.5 μmol/L，与对I Kr阻滞的半数最大抑制浓度IC50相似(2.9 μmol/L)。美沙酮适度地增加了90%复极时的动作电位持续时间，并减缓了低浓度的末端复极。在较高浓度下，90%复极延长时的动作电位持续时间被消除，但其对终末复极的影响稳步上升，并与舒张膜电位波动增加相关。同时，对美沙酮治疗前后患者的心电图进行了分析，68%的患者与预美沙酮相比U波积分明显增加(导联V3;平均+38%±15%，P=0.016)， QT和TPeak至TEnd间隔增加，可能反映了I - Kr阻滞。结论美沙酮是一种有效的I K1抑制剂，可引起体表心电图U波增强。我们认为，ik1阻断导致的膜不稳定性增加可能更好地解释美沙酮的心律失常风险，而不仅仅是ik1抑制。药物诱导的U波增强可能是阻断多个复极化离子通道的证据，并且可能有必要评估该药物对I K1的影响。

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引用次数: 4

Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center 心包炎和自身炎症:国家转诊中心特发性复发性心包炎和单基因自身炎症患者的临床和遗传分析

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Pub Date : 2022-06-06 DOI: 10.1161/JAHA.121.024931

Claire J Peet, D. Rowczenio, E. Omoyinmi, C. Papadopoulou, B. R. Mapalo, Michael R. Wood, F. Capon, H. Lachmann

Background Idiopathic recurrent pericarditis (IRP) is an orphan disease that carries significant morbidity, partly driven by corticosteroid dependence. Innate immune modulators, colchicine and anti‐interleukin‐1 agents, pioneered in monogenic autoinflammatory diseases, have demonstrated remarkable efficacy in trials, suggesting that autoinflammation may contribute to IRP. This study characterizes the phenotype of patients with IRP and monogenic autoinflammatory diseases, and establishes whether autoinflammatory disease genes are associated with IRP. Methods and Results We retrospectively analyzed the medical records of patients with IRP (n=136) and monogenic autoinflammatory diseases (n=1910) attending a national center (London, UK) between 2000 and 2021. We examined 4 genes (MEFV, MVK, NLRP3, TNFRSF1A) by next‐generation sequencing in 128 patients with IRP and compared the frequency of rare deleterious variants to controls obtained from the Genome Aggregation Database. In this cohort of patients with IRP, corticosteroid dependence was common (39/136, 28.7%) and was associated with chronic pain (adjusted odds ratio 2.8 [95% CI, 1.3–6.5], P=0.012). IRP frequently manifested with systemic inflammation (raised C‐reactive protein [121/136, 89.0%] and extrapericardial effusions [68/136, 50.0%]). Pericarditis was observed in all examined monogenic autoinflammatory diseases (0.4%–3.7% of cases). Rare deleterious MEFV variants were more frequent in IRP than in ancestry‐matched controls (allele frequency 9/200 versus 2932/129 200, P=0.040). Conclusions Pericarditis is a feature of interleukin‐1 driven monogenic autoinflammatory diseases and IRP is associated with variants in MEFV, a gene involved in interleukin‐1β processing. We also found that corticosteroid dependence in IRP is associated with chronic noninflammatory pain. Together these data implicate autoinflammation in IRP and support reducing reliance on corticosteroids in its management.

背景:特发性复发性心包炎(IRP)是一种发病率很高的孤儿病，部分由皮质类固醇依赖引起。先天免疫调节剂，秋水仙碱和抗白细胞介素- 1药物，在单基因自身炎症疾病中率先出现，在试验中显示出显著的疗效，表明自身炎症可能有助于IRP。本研究确定了IRP和单基因自身炎症性疾病患者的表型特征，并确定了自身炎症性疾病基因是否与IRP相关。方法和结果我们回顾性分析了2000年至2021年间在英国伦敦国家中心就诊的IRP (n=136)和单基因自身炎症性疾病(n=1910)患者的病历。我们对128例IRP患者的4个基因(MEFV、MVK、NLRP3、TNFRSF1A)进行了下一代测序，并比较了从基因组聚集数据库中获得的罕见有害变异与对照的频率。在这组IRP患者中，皮质类固醇依赖很常见(39/136,28.7%)，并与慢性疼痛相关(校正优势比为2.8 [95% CI, 1.3-6.5]， P=0.012)。IRP常表现为全身性炎症(C反应蛋白升高[121/ 136,89.0%]和心包外积液[68/ 136,50.0%])。在所有检查的单基因自身炎症性疾病中均观察到心包炎(0.4%-3.7%)。罕见的有害MEFV变异在IRP中比在祖先匹配的对照组中更常见(等位基因频率为9/200比2932/129 200,P=0.040)。心包炎是白介素- 1驱动的单基因自身炎症性疾病的一个特征，IRP与MEFV变异有关，MEFV是参与白介素- 1β加工的基因。我们还发现IRP中的皮质类固醇依赖与慢性非炎症性疼痛有关。综上所述，这些数据暗示了IRP中的自身炎症，并支持减少对皮质类固醇的依赖。

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引用次数: 8

Impact of the Obesity Paradox Between Sexes on In‐Hospital Mortality in Cardiogenic Shock: A Retrospective Cohort Study 性别肥胖悖论对心源性休克住院死亡率的影响:一项回顾性队列研究

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Pub Date : 2022-06-06 DOI: 10.1161/JAHA.121.024143

W. Kwon, Seung Hun Lee, Jeong Hoon Yang, K. Choi, T. Park, J. Lee, Y. Song, J. Hahn, Seung‐Hyuk Choi, C. Ahn, Y. Ko, C. Yu, W. Jang, Hyun-Joong Kim, S. Kwon, J. Jeong, Sang-Don Park, Sungsoo Cho, J. Bae, H. Gwon

Background Several studies have shown that obesity is associated with better outcomes in patients with cardiogenic shock (CS). Although this phenomenon, the “obesity paradox,” reportedly manifests differently based on sex in other disease entities, it has not yet been investigated in patients with CS. Methods and Results A total of 1227 patients with CS from the RESCUE (Retrospective and Prospective Observational Study to Investigate Clinical Outcomes and Efficacy of Left Ventricular Assist Device for Korean Patients With Cardiogenic Shock) registry in Korea were analyzed. The study population was classified into obese and nonobese groups according to Asian Pacific criteria (BMI ≥25.0 kg/m2 for obese). The clinical impact of obesity on in‐hospital mortality according to sex was analyzed using logistic regression analysis and restricted cubic spline curves. The in‐hospital mortality rate was significantly lower in obese men than nonobese men (34.2% versus 24.1%, respectively; P=0.004), while the difference was not significant in women (37.3% versus 35.8%, respectively; P=0.884). As a continuous variable, higher BMI showed a protective effect in men; conversely, BMI was not associated with clinical outcomes in women. Compared with patients with normal weight, obesity was associated with a decreased risk of in‐hospital death in men (multivariable‐adjusted odds ratio [OR], 0.63; CI, 0.43–0.92 [P=0.016]), but not in women (multivariable‐adjusted OR, 0.94; 95% CI, 0.55–1.61 [P=0.828]). The interaction P value for the association between BMI and sex was 0.023. Conclusions The obesity paradox exists and apparently occurs in men among patients with CS. The differential effect of BMI on in‐hospital mortality was observed according to sex. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02985008.

几项研究表明，肥胖与心源性休克(CS)患者的预后较好相关。尽管这种现象，即“肥胖悖论”，据报道在其他疾病实体中因性别而表现不同，但尚未在CS患者中进行研究。方法和结果对韩国RESCUE(调查韩国心源性休克患者左心室辅助装置临床结果和疗效的回顾性和前瞻性观察性研究)登记的1227例CS患者进行分析。研究人群按照亚太标准(BMI≥25.0 kg/m2为肥胖)分为肥胖组和非肥胖组。采用logistic回归分析和限制性三次样条曲线分析肥胖症对不同性别住院死亡率的临床影响。肥胖男性的住院死亡率显著低于非肥胖男性(分别为34.2%和24.1%);P=0.004)，而在女性中差异不显著(分别为37.3%对35.8%;P = 0.884)。作为一个连续变量，较高的BMI对男性有保护作用;相反，BMI与女性的临床结果无关。与体重正常的患者相比，肥胖与男性院内死亡风险降低相关(多变量校正优势比[OR]， 0.63;CI, 0.43-0.92 [P=0.016])，但女性没有(多变量校正OR, 0.94;95% ci, 0.55-1.61 [p =0.828])。BMI与性别相关的交互P值为0.023。结论肥胖悖论在男性CS患者中明显存在。根据性别观察BMI对住院死亡率的不同影响。注册网址:https://www.clinicaltrials.gov;唯一标识符:NCT02985008。

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引用次数: 9

Idiopathic Recurrent Pericarditis: Not Really So Idiopathic? 特发性复发性心包炎:真的不是特发性的吗?

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Pub Date : 2022-06-06 DOI: 10.1161/JAHA.122.026218

F. Roubille, C. Delmas, C. Roubille

In this issue of the Journal of the American Heart Association (JAHA), Peet1 challenges the current concept of idiopathic recurrent pericarditis (IRP). Indeed, “idiopathic” means “arising spontaneously or from an obscure or unknown cause,” which implies that the pathophysiology is not established, and the treatment should remain empirical. In 2 words, behind this learned word, we hide our ignorance.

在这一期的《美国心脏协会杂志》(JAHA)上，Peet1挑战了目前特发性复发性心包炎(IRP)的概念。事实上，“特发性”意味着“自发或由一个模糊或未知的原因引起的”，这意味着病理生理学不确定，治疗应保持经验。两个字，在这个博学的字后面，隐藏着我们的无知。

引用次数: 1