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Sex Differences in Revascularization, Treatment Goals, and Outcomes of Patients With Chronic Coronary Disease: Insights From the ISCHEMIA Trial

Reynolds, Harmony R; Cyr, Derek D; Merz, C Noel Bairey; Shaw, Leslee J; Chaitman, Bernard R; Boden, William E; Alexander, Karen P; Rosenberg, Yves D; Bangalore, Sripal; Stone, Gregg W; Held, Claes; Spertus, John; Goetschalckx, Kaatje; Bockeria, Olga; Newman, Jonathan D; Berger, Jeffrey S; Elghamaz, Ahmed; Lopes, Renato D; Min, James K; Berman, Daniel S; Picard, Michael H; Kwong, Raymond Y; Harrington, Robert A; Thomas, Boban; O'Brien, Sean M; Maron, David J; Hochman, Judith S; ,
BACKGROUND:Women with chronic coronary disease are generally older than men and have more comorbidities but less atherosclerosis. We explored sex differences in revascularization, guideline-directed medical therapy, and outcomes among patients with chronic coronary disease with ischemia on stress testing, with and without invasive management. METHODS AND RESULTS/RESULTS:=0.49), with no significant sex-by-treatment-group interactions. CONCLUSIONS:Women had less extensive coronary artery disease and, therefore, lower revascularization rates in the invasive group. Despite lower risk factor goal attainment, women with chronic coronary disease experienced similar risk-adjusted outcomes to men in the ISCHEMIA trial. REGISTRATION/BACKGROUND:URL: Unique identifier: NCT01471522.
PMID: 38410945
ISSN: 2047-9980
CID: 5645612

Body Mass Index and Clinical and Health Status Outcomes in Chronic Coronary Disease and Advanced Kidney Disease in the ISCHEMIA-CKD Trial

Mathew, Roy O; Kretov, Evgeny I; Huang, Zhen; Jones, Philip G; Sidhu, Mandeep S; O'Brien, Sean M; Prokhorikhin, Aleksei A; Rangaswami, Janani; Newman, Jonathan; Stone, Gregg W; Fleg, Jerome L; Spertus, John A; Maron, David J; Hochman, Judith S; Bangalore, Sripal; ,
OBJECTIVE:This study aimed to assess whether an obesity paradox (lower event rates with higher body mass index [BMI]) exists in participants with advanced chronic kidney disease (CKD) and chronic coronary disease in the International Study of Comparative Health Effectiveness of Medical and Invasive Approaches (ISCHEMIA)-CKD, and whether BMI modified the effect of initial treatment strategy. METHODS:). Associations between BMI and the primary outcome of all-cause death or myocardial infarction (D/MI), and all-cause death, cardiovascular death, and MI individually were estimated. Associations with health status were also evaluated using the Seattle Angina Questionnaire-7, the Rose Dyspnea Scale, and the EuroQol-5D Visual Analog Scale. RESULTS:was marginally associated with D/MI (HR 1.43 [1.00-2.04]) and greater dyspnea throughout follow-up (P < .05 at all time points). Heterogeneity of treatment effect between baseline BMI was not evident for any outcome. CONCLUSIONS:In the ISCHEMIA-CKD trial, an obesity paradox was not detected. Higher BMI was associated with worse dyspnea, and a trend toward increased D/MI and MI risk. Larger studies to validate these findings are warranted.
PMID: 37925061
ISSN: 1555-7162
CID: 5607182

Platelet RNA Biomarker of Ticagrelor-Responsive Genes Is Associated With Platelet Function and Cardiovascular Events

Myers, Rachel A; Ortel, Thomas L; Waldrop, Alexander; Cornwell, MacIntosh; Newman, Jonathan D; Levy, Natalie K; Barrett, Tessa J; Ruggles, Kelly; Sowa, Marcin A; Dave, Sandeep; Ginsburg, Geoffrey S; Berger, Jeffrey S; Voora, Deepak
BACKGROUND/UNASSIGNED:Identifying patients with the optimal risk:benefit for ticagrelor is challenging. The aim was to identify ticagrelor-responsive platelet transcripts as biomarkers of platelet function and cardiovascular risk. METHODS/UNASSIGNED:Healthy volunteers (n=58, discovery; n=49, validation) were exposed to 4 weeks of ticagrelor with platelet RNA data, platelet function, and self-reported bleeding measured pre-/post-ticagrelor. RNA sequencing was used to discover platelet genes affected by ticagrelor, and a subset of the most informative was summarized into a composite score and tested for validation. This score was further analyzed (1) in CD34+ megakaryocytes exposed to an P2Y12 inhibitor in vitro, (2) with baseline platelet function in healthy controls, (3) in peripheral artery disease patients (n=139) versus patient controls (n=30) without atherosclerosis, and (4) in patients with peripheral artery disease for correlation with atherosclerosis severity and risk of incident major adverse cardiovascular and limb events. RESULTS/UNASSIGNED:Ticagrelor exposure differentially expressed 3409 platelet transcripts. Of these, 111 were prioritized to calculate a Ticagrelor Exposure Signature score, which ticagrelor reproducibly increased in discovery and validation cohorts. Ticagrelor's effects on platelets transcripts positively correlated with effects of P2Y12 inhibition in primary megakaryocytes. In healthy controls, higher baseline scores correlated with lower baseline platelet function and with minor bleeding while receiving ticagrelor. In patients, lower scores independently associated with both the presence and extent of atherosclerosis and incident ischemic events. CONCLUSIONS/UNASSIGNED:Ticagrelor-responsive platelet transcripts are a biomarker for platelet function and cardiovascular risk and may have clinical utility for selecting patients with optimal risk:benefit for ticagrelor use.
PMID: 38059352
ISSN: 1524-4636
CID: 5591292

A Clinical Perspective on Arsenic Exposure and Development of Atherosclerotic Cardiovascular Disease

Kaur, Gurleen; Desai, Karan P; Chang, Isabella Y; Newman, Jonathan D; Mathew, Roy O; Bangalore, Sripal; Venditti, Ferdinand J; Sidhu, Mandeep S
Cardiovascular risk has traditionally been defined by modifiable and non-modifiable risk factors, such as tobacco use, hyperlipidemia, and family history. However, chemicals and pollutants may also play a role in cardiovascular disease (CVD) risk. Arsenic is a naturally occurring element that is widely distributed in the Earth's crust. Inorganic arsenic (iAs) has been implicated in the pathogenesis of atherosclerosis, with chronic high-dose exposure to iAs (> 100 µg/L) being linked to CVD; however, whether low-to-moderate dose exposures of iAs (< 100 µg/L) are associated with the development of CVD is unclear. Due to limitations of the existing literature, it is difficult to define a threshold for iAs toxicity. Studies demonstrate that the effect of iAs on CVD is far more complex with influences from several factors, including diet, genetics, metabolism, and traditional risk factors such as hypertension and smoking. In this article, we review the existing data of low-to-moderate dose iAs exposure and its effect on CVD, along with highlighting the potential mechanisms of action.
PMID: 35029799
ISSN: 1573-7241
CID: 5119142

Biomarkers and cardiovascular events in patients with stable coronary disease in the ISCHEMIA Trials

Newman, Jonathan D; Anthopolos, Rebecca; Ruggles, Kelly V; Cornwell, Macintosh; Reynolds, Harmony R; Bangalore, Sripal; Mavromatis, Kreton; Held, Claes; Wallentin, Lars; Kullo, Iftikar J; McManus, Bruce; Newby, L Kristin K; Rosenberg, Yves; Hochman, Judith S; Maron, David J; Berger, Jeffrey S; ,
IMPORTANCE:Biomarkers may improve prediction of cardiovascular events for patients with stable coronary artery disease (CAD), but their importance in addition to clinical tests of inducible ischemia and CAD severity is unknown. OBJECTIVES:To evaluate the prognostic value of multiple biomarkers in stable outpatients with obstructive CAD and moderate or severe inducible ischemia. DESIGN AND SETTING:The ISCHEMIA and ISCHEMIA CKD trials randomized 5,956 participants with CAD to invasive or conservative management from July 2012 to January 2018; 1,064 participated in the biorepository. MAIN OUTCOME MEASURES:Primary outcome was cardiovascular death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. Secondary outcome was cardiovascular death or MI. Improvements in prediction were assessed by cause-specific hazard ratios (HR) and area under the receiver operating characteristics curve (AUC) for an interquartile increase in each biomarker, controlling for other biomarkers, in a base clinical model of risk factors, left ventricular ejection fraction (LVEF) and ischemia severity. Secondary analyses were performed among patients in whom core-lab confirmed severity of CAD was ascertained by computed cardiac tomographic angiography (CCTA). EXPOSURES:Baseline levels of interleukin-6 (IL-6), high sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), lipoprotein a (Lp[a]), high sensitivity C-reactive protein (hsCRP), Cystatin C, soluble CD 40 ligand (sCD40L), myeloperoxidase (MPO), and matrix metalloproteinase 3 (MMP3). RESULTS:Among 757 biorepository participants, median (IQR) follow-up was 3 (2-5) years, age was 67 (61-72) years, and 144 (19%) were female; 508 had severity of CAD by CCTA available. In an adjusted multimarker model with hsTnT, GDF-15, NT-proBNP and sCD40L, the adjusted HR for the primary outcome per interquartile increase in each biomarker was 1.58 (95% CI 1.22, 2.205), 1.60 (95% CI 1.16, 2.20), 1.61 (95% 1.22, 2.14), and 1.46 (95% 1.12, 1.90), respectively. The adjusted multimarker model also improved prediction compared with the clinical model, increasing the AUC from 0.710 to 0.792 (P < .01) and 0.714 to 0.783 (P < .01) for the primary and secondary outcomes, respectively. Similar findings were observed after adjusting for core-lab confirmed atherosclerosis severity. CONCLUSIONS AND RELEVANCE:Among ISCHEMIA biorepository participants, biomarkers of myocyte injury/distension, inflammation, and platelet activity improved cardiovascular event prediction in addition to risk factors, LVEF, and assessments of ischemia and atherosclerosis severity. These biomarkers may improve risk stratification for patients with stable CAD.
PMID: 37604357
ISSN: 1097-6744
CID: 5598422

SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels

Eberhardt, Natalia; Noval, Maria Gabriela; Kaur, Ravneet; Amadori, Letizia; Gildea, Michael; Sajja, Swathy; Das, Dayasagar; Cilhoroz, Burak; Stewart, O'Jay; Fernandez, Dawn M; Shamailova, Roza; Guillen, Andrea Vasquez; Jangra, Sonia; Schotsaert, Michael; Newman, Jonathan D; Faries, Peter; Maldonado, Thomas; Rockman, Caron; Rapkiewicz, Amy; Stapleford, Kenneth A; Narula, Navneet; Moore, Kathryn J; Giannarelli, Chiara
Patients with coronavirus disease 2019 (COVID-19) present increased risk for ischemic cardiovascular complications up to 1 year after infection. Although the systemic inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques remains unknown. Here we report that SARS-CoV-2 viral RNA is detectable and replicates in coronary lesions taken at autopsy from severe COVID-19 cases. SARS-CoV-2 targeted plaque macrophages and exhibited a stronger tropism for arterial lesions than adjacent perivascular fat, correlating with macrophage infiltration levels. SARS-CoV-2 entry was increased in cholesterol-loaded primary macrophages and dependent, in part, on neuropilin-1. SARS-CoV-2 induced a robust inflammatory response in cultured macrophages and human atherosclerotic vascular explants with secretion of cytokines known to trigger cardiovascular events. Our data establish that SARS-CoV-2 infects coronary vessels, inducing plaque inflammation that could trigger acute cardiovascular complications and increase the long-term cardiovascular risk.
PMID: 38076343
ISSN: 2731-0590
CID: 5589542

Portable Air Cleaners and Home Systolic Blood Pressure in Adults With Hypertension Living in New York City Public Housing [Letter]

Wittkopp, Sharine; Anastasiou, Elle; Hu, Jiyuan; Liu, Mengling; Langford, Aisha T; Brook, Robert D; Gordon, Terry; Thorpe, Lorna E; Newman, Jonathan D
PMID: 37382099
ISSN: 2047-9980
CID: 5537272

Timing of Antihypertensive Drug Therapy: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Maqsood, Muhammad Haisum; Messerli, Franz H; Skolnick, Adam H; Newman, Jonathan D; Berger, Jeffrey S; Bangalore, Sripal
BACKGROUND:The timing of antihypertensive drugs administration is controversial. The aim was to compare the efficacy of dosing of antihypertensive drugs in the morning versus evening. METHODS:A PubMed, EMBASE, and databases search for randomized clinical trials of antihypertensive therapies where patients were randomized to morning versus evening dosing. The outcomes were ambulatory blood pressure parameters (day-time, night-time, and 24/48-hour systolic blood pressure [SBP] and diastolic blood pressure [DBP]) and cardiovascular outcomes. RESULTS: CONCLUSIONS:Evening dosing of antihypertensive drugs significantly reduced ambulatory blood pressure parameters and lowered cardiovascular events but the effect was mainly driven by trials by Hermida group. Unless the intention is to specifically lower night-time blood pressure, antihypertensive drugs should be taken at a time of day that is convenient, optimizes adherence, and minimizes undesirable effects.
PMID: 37212152
ISSN: 1524-4563
CID: 5480232

Contemporary use of cardiovascular risk reduction strategies in type 2 diabetes. Insights from the diabetes collaborative registry

Arnold, Suzanne V; Gosch, Kensey; Kosiborod, Mikhail; Wong, Nathan D; Sperling, Laurence S; Newman, Jonathan D; Gamble, Cory L; Hamersky, Carol; Rajpura, Jigar; Vaduganathan, Muthiah
BACKGROUND:Cardiovascular disease remains the primary source of morbidity and mortality in type 2 diabetes (T2D). We characterized the change over time in the use of evidence-based therapies to reduce cardiovascular risk in US patients with T2D. METHODS:Data from a longitudinal outpatient diabetes registry were used to calculate the prescription of SGLT2i or GLP-1RA over time and among those with high-risk comorbidities (atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], chronic kidney disease [CKD]) and a diabetes cardiovascular composite score (DCCS; calculated as: #eligible medications prescribed/#eligible medications x 100 for SGLT2i, GLP-1RA, statin, antiplatelet/anticoagulant therapy, ACEi/ARB/ARNI). Scores ranged from 0% to 100% (higher=more optimal care). RESULTS:Among 1,001,542 outpatients from 391 US sites, 51.7% patients had ASVCD, 17.7% HF, and 23.0% CKD. The percentage of patients prescribed an SGLT2i or GLP-1RA increased over time (7.3% in 2013 to 28.8% in 2019), and 18.3% of patients with ASCVD, HF, or CKD were on at least one of these medications at last follow-up vs 25.5% of patients without any of these comorbidities. Mean DCCS was 54±36%; 54±25% in patients with ASCVD, HF, or CKD vs 52±50% in patients without any of these comorbidities (P<0.001 for both). In a hierarchical linear model, male sex, and a diagnosis of CKD were independently associated with higher DCCS whereas a diagnosis of HF or ASCVD was associated with a lower DCCS. CONCLUSIONS:In a large, contemporary cohort of patients with T2D, we found improvement in the use of SGLT2i and GLP-1RA but unexpectedly lower use in patients with ASCVD, heart failure, and CKD, highlighting a treatment-risk paradox. Further education is needed to shift the understanding of these medications as tools for glucose-lowering to cardiovascular risk reduction and to improve their implementation in clinical practice.
PMID: 37164146
ISSN: 1097-6744
CID: 5544582

Health Status and Clinical Outcomes in Older Adults With Chronic Coronary Disease: The ISCHEMIA Trial

Nguyen, Dan D; Spertus, John A; Alexander, Karen P; Newman, Jonathan D; Dodson, John A; Jones, Philip G; Stevens, Susanna R; O'Brien, Sean M; Gamma, Reto; Perna, Gian P; Garg, Pallav; Vitola, João V; Chow, Benjamin J W; Vertes, Andras; White, Harvey D; Smanio, Paola E P; Senior, Roxy; Held, Claes; Li, Jianghao; Boden, William E; Mark, Daniel B; Reynolds, Harmony R; Bangalore, Sripal; Chan, Paul S; Stone, Gregg W; Arnold, Suzanne V; Maron, David J; Hochman, Judith S
BACKGROUND:Whether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown. OBJECTIVES/OBJECTIVE:The goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. METHODS:One-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure. RESULTS: = 0.29). CONCLUSIONS:Older patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).
PMID: 37100486
ISSN: 1558-3597
CID: 5465192