Canadian Association of Radiologists Cardiovascular Imaging Referral Guideline.

The Canadian Association of Radiologists (CAR) Cardiovascular Expert Panel is made up of physicians from the disciplines of radiology, cardiology, and emergency medicine, a patient advisor, and an epidemiologist/guideline methodologist. After developing a list of 30 clinical/diagnostic scenarios, a rapid scoping review was undertaken to identify systematically produced referral guidelines that provide recommendations for one or more of these clinical/diagnostic scenarios. Recommendations from 48 guidelines and contextualization criteria in the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) for guidelines framework were used to develop 125 recommendation statements across the 30 scenarios (27 unique scenarios as 2 scenarios point to the CAR Thoracic Diagnostic Imaging Referral Guideline and the acute pericarditis subscenario is included under 2 main scenarios). This guideline presents the methods of development and the referral recommendations for acute chest pain syndromes, chronic chest pain, cardiovascular screening and risk stratification, pericardial syndromes, intracardiac/pericardial mass, suspected valvular disease cardiomyopathy, aorta, venous thrombosis, and peripheral vascular disease.

Doxorubicin­induced cardiomyopathy is mitigated by empagliflozin via the modulation of endoplasmic reticulum stress pathways.

Doxorubicin (Dox) exhibits a high efficacy in the treatment of numerous types of cancer. However, the beneficial cytotoxic effects of Dox are often accompanied by an increase in the risk of cardiotoxicity. Oxidative stress (OS) plays a key role in Dox­induced cardiomyopathy (DIC). OS in cardiomyocytes disrupts endoplasmic reticulum (ER) function, leading to the accumulation of misfolded/unfolded proteins known as ER stress. ER stress acts as an adaptive mechanism; however, prolonged ER stress together with OS may lead to the initiation of cardiomyocyte apoptosis. The present study aimed to explore the potential of an anti­diabetic drug, empagliflozin (EMPA), in mitigating Dox­induced ER stress and cardiomyocyte apoptosis. In the present study, the effects of 1 h pretreatment of EMPA on Dox­treated cardiomyocytes isolated from Sprague­Dawley rats were investigated. After 24 h, EMPA pre­treatment promoted cell survival in the EMPA + Dox group compared with the Dox group. Results of the present study also demonstrated that EMPA mitigated overall ER stress, as the increased expression of ER stress markers was reduced in the EMPA + Dox group. Additionally, OS, inflammation and expression of ER stress apoptotic proteins were also significantly reduced following EMPA pre­treatment in the EMPA + Dox group. Thus, EMPA may exert beneficial effects on Dox­induced ER stress and may exhibit potential changes that can be utilised to further evaluate the role of EMPA in mitigating DIC.

Preventing broken hearts in women with breast cancer: a concise review on chemotherapy-mediated cardiotoxicity.

Cancer and cardiovascular disease are the leading causes of death for Canadian women. One in eight Canadian women will receive the life-changing diagnosis of breast cancer (BC) in their lifetime, with 1 in 34 dying from the disease. Although doxorubicin (DOX) and trastuzumab (TRZ) have significantly improved survival in women diagnosed with human epidermal growth factor receptor 2 (HER2)-positive BC, approximately one in four women who receive this treatment are at risk of developing chemotherapy-induced cardiotoxicity. Cardiotoxicity is defined as a decline in left ventricular ejection fraction (LVEF) of >10% to an absolute value of <53%. Current guidelines recommend the serial monitoring of LVEF in this patient population using non-invasive cardiac imaging modalities including transthoracic echocardiography or multi-gated acquisition scan; however, this will only allow for the detection of established cardiotoxicity. Recent studies have demonstrated that a reduction in global longitudinal strain by speckle tracking echocardiography can identify pre-clinical systolic dysfunction prior to a decline in overall LVEF. Implementation of early detection techniques would allow for the prompt initiation of cardioprotective strategies. In addition to the early detection of chemotherapy-mediated cardiotoxicity, the prophylactic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, statins, exercise, and nutraceutical therapies have been studied in the setting of cardio-oncology.

Ventricular tachycardia triggered by electroconvulsive therapy: Case report and review of the literature.

We report a case of a 71-year-old male with severe depression treated with electroconvulsive therapy (ECT) in the operating room complicated by monomorphic ventricular tachycardia (MMVT). The clinical presentation, treatment, and outcomes of this catecholamine-mediated cardiac event are reported with a brief review of the literature.

Correlation of Impedance Cardiography-Derived and Cardiac Magnetic Resonance-Derived Stroke Volumes.

Cardiac output (CO) and other hemodynamic parameter measurements play an important role in the management of cardiovascular conditions; however, due to limitations of current day technologies, such measurements are either not routinely performed or incorporated into clinical practice. Moreover, measurement of these hemodynamic parameters in the outpatient setting at different time points to assess interval change is currently not feasible. We attempted to validate total-body impedance cardiography-based Non-Invasive Cardiac System (NICaS) derived stroke volume (SV) with that from cardiac magnetic resonance (CMR), a current day gold standard method of assessment. We compared SV, as it is the primary unit of measurement utilized by both technologies. Forty-one consecutive patients undergoing CMR were also investigated by NICaS following CMR. The consistency of non-invasive technology-derived SV measurement was validated by NICaS measurement in 10 subjects, both before and after CMR. Of the 41 enrolled patients; data from 38 patients was adequate for comparison (motion artifact prevented CMR measures in 3 patients). Fourteen patients (37%) were female; mean age was 55 ± 15 years (28-87 years) and body-mass index was 28.7 ± 5.5 kg/m2 (20.5-41.9 kg/m2). Hypertrophic cardiomyopathy (9/41) was the most common study indication for CMR. NICaS-derived SV strongly correlated with CMR [NICaS 77 ± 20 ml (31-123 ml) and CMR 84 ± 23 ml (47-132 ml); P < 0.001; r = 0.77; ICC = 0.73]. The Bland-Altman limits of agreement between NICaS and CMR were -26.7% and 39.9%. NICaS-derived SV collected before and after MRI did not differ [80 ± 18 ml (51-102 ml) pre and 76 ± 17 ml (50-99 ml) post; P = 0.0007, Kappa = 1]. Agreement between NICaS-derived and CMR-derived SV was within the acceptable range of boundaries set by the US Food and the Drug Administration. Consistency in SV measurement at different time-points may allow use of this technology to identify interval hemodynamic changes noninvasively.

Chest Pain Evaluation: Diagnostic Testing.

Chest pain/discomfort (CP) is a common symptom and can be a diagnostic dilemma for many clinicians. The misdiagnosis of an acute or progressive chronic cardiac etiology may carry a significant risk of morbidity and mortality. This review summarizes the different options and modalities for establishing the diagnosis and severity of coronary artery disease. An effective test selection algorithm should be individually tailored to each patient to maximize diagnostic accuracy in a timely fashion, determine short- and long-term prognosis, and permit implementation of evidence-based treatments in a cost-effective manner. Through collaboration, a decision algorithm was developed (www.chowmd.ca/cadtesting) that could be adopted widely into clinical practice.

La douleur ou la gêne thoracique sont des symptômes fréquents qui peuvent poser un dilemme diagnostique pour de nombreux médecins. Les erreurs de diagnostic d'une cause aiguë ou chronique progressive d'origine cardiaque peuvent d'ailleurs entraîner un risque considérable de morbidité et de mortalité. La présente synthèse porte sur les différentes options et modalités d'établissement du diagnostic et de la gravité d'une coronaropathie. Un algorithme efficace pour le choix des tests doit être adapté à chaque patient afin de maximiser l'exactitude diagnostique dans les plus brefs délais, de déterminer le pronostic à court et à long terme, et de permettre une mise en œuvre de traitements fondés sur des données probantes tout en tenant compte des coûts. Un algorithme décisionnel a donc été conjointement mis au point (www.chowmd.ca/cadtesting) et pourrait être largement adopté dans la pratique clinique.

Scleraxis and fibrosis in the pressure-overloaded heart.

AIMS: In response to pro-fibrotic signals, scleraxis regulates cardiac fibroblast activation in vitro via transcriptional control of key fibrosis genes such as collagen and fibronectin; however, its role in vivo is unknown. The present study assessed the impact of scleraxis loss on fibroblast activation, cardiac fibrosis, and dysfunction in pressure overload-induced heart failure. METHODS AND RESULTS: Scleraxis expression was upregulated in the hearts of non-ischemic dilated cardiomyopathy patients, and in mice subjected to pressure overload by transverse aortic constriction (TAC). Tamoxifen-inducible fibroblast-specific scleraxis knockout (Scx-fKO) completely attenuated cardiac fibrosis, and significantly improved cardiac systolic function and ventricular remodelling, following TAC compared to Scx+/+ TAC mice, concomitant with attenuation of fibroblast activation. Scleraxis deletion, after the establishment of cardiac fibrosis, attenuated the further functional decline observed in Scx+/+ mice, with a reduction in cardiac myofibroblasts. Notably, scleraxis knockout reduced pressure overload-induced mortality from 33% to zero, without affecting the degree of cardiac hypertrophy. Scleraxis directly regulated transcription of the myofibroblast marker periostin, and cardiac fibroblasts lacking scleraxis failed to upregulate periostin synthesis and secretion in response to pro-fibrotic transforming growth factor ß. CONCLUSION: Scleraxis governs fibroblast activation in pressure overload-induced heart failure, and scleraxis knockout attenuated fibrosis and improved cardiac function and survival. These findings identify scleraxis as a viable target for the development of novel anti-fibrotic treatments.

Olive oil protects against progression of heart failure by inhibiting remodeling of heart subsequent to myocardial infarction in rats.

We examined the beneficial effects of olive oil against heart failure post-myocardial infarction (PMI), induced by coronary artery ligation in rats. Animals were divided into sham and ligated groups and fed either regular chow, olive oil (10% wt/wt), or corn oil (10% wt/wt) and were followed up to 16 weeks. On the echocardiography at 3 days (PMI), in the ligated regular chow (LRC), ligated olive oil (LOO), and ligated corn oil (LCO) left ventricular ejection fraction (LVEF) decrease was 12.14%, 16.42%, and 17.53% from the baseline, respectively. However, only LOO group improved LVEF significantly at 16 weeks PMI and became comparable with all sham groups. Both scar formation and collagen deposition at 16 weeks PMI were less pronounced in the LOO group. Myocardial TNF-α level at 4 weeks of PMI increased by 176%, 11%, and 181% in the LRC, LOO, and LCO groups, respectively. Plasma TNF-α levels in LOO were significantly lower than LRC group after 4 weeks of PMI. Myocardial redox ratio (reduced glutathione/oxidized glutathione) decreased at 4 weeks PMI by 44.4%, 16.4%, and 36.9% in the LRC, LOO, and LCO groups, respectively, compared to the baseline. These changes in the redox ratio at 16 weeks PMI were further exacerbated in the LRC and LCO groups. Lipid hydroperoxides formation increased at 4 weeks PMI by 137.4%, 14.6%, and 97.1% in the LRC, LOO, and LCO groups, respectively. Since coronary artery ligation decreased left ventricular ejection fraction, increased myocardial TNF-α and oxidative stress, and since olive oil was able to inhibit these effects, it is proposed that dietary olive oil modulates cardiac remodeling and heart failure subsequent to myocardial infarction.

Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy.

BACKGROUND: Cytokines such as tumor necrosis factor-α (TNFα) have been implicated in cardiac dysfunction and toxicity associated with doxorubicin (DOX). Although TNFα can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart remain cryptic. The E3 ubiquitin ligase TRAF2 (TNF receptor associated factor 2) provides a critical signaling platform for K63-linked polyubiquitination of RIPK1 (receptor interacting protein 1), crucial for nuclear factor-κB (NF-κB) activation by TNFα and survival. Here, we investigate alterations in TNFα-TRAF2-NF-κB signaling in the pathogenesis of DOX cardiotoxicity. METHODS: Using a combination of in vivo (4 weekly injections of DOX 5 mg·kg-1·wk-1) in C57/BL6J mice and in vitro approaches (rat, mouse, and human inducible pluripotent stem cell-derived cardiac myocytes), we monitored TNFα levels, lactate dehydrogenase, cardiac ultrastructure and function, mitochondrial bioenergetics, and cardiac cell viability. RESULTS: In contrast to vehicle-treated mice, ultrastructural defects, including cytoplasmic swelling, mitochondrial perturbations, and elevated TNFα levels, were observed in the hearts of mice treated with DOX. While investigating the involvement of TNFα in DOX cardiotoxicity, we discovered that NF-κB was readily activated by TNFα. However, TNFα-mediated NF-κB activation was impaired in cardiac myocytes treated with DOX. This coincided with loss of K63- linked polyubiquitination of RIPK1 from the proteasomal degradation of TRAF2. Furthermore, TRAF2 protein abundance was markedly reduced in hearts of patients with cancer treated with DOX. We further established that the reciprocal actions of the ubiquitinating and deubiquitinating enzymes cellular inhibitors of apoptosis 1 and USP19 (ubiquitin-specific peptidase 19), respectively, regulated the proteasomal degradation of TRAF2 in DOX-treated cardiac myocytes. An E3-ligase mutant of cellular inhibitors of apoptosis 1 (H588A) or gain of function of USP19 prevented proteasomal degradation of TRAF2 and DOX-induced cell death. Furthermore, wild-type TRAF2, but not a RING finger mutant defective for K63-linked polyubiquitination of RIPK1, restored NF-κB signaling and suppressed DOX-induced cardiac cell death. Last, cardiomyocyte-restricted expression of TRAF2 (cardiac troponin T-adeno-associated virus 9-TRAF2) in vivo protected against mitochondrial defects and cardiac dysfunction induced by DOX. CONCLUSIONS: Our findings reveal a novel signaling axis that functionally connects the cardiotoxic effects of DOX to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by DOX sensitizes cardiac myocytes to TNFα-mediated necrotic cell death and DOX cardiotoxicity.

Comparing Flaxseed and Perindopril in the Prevention of Doxorubicin and Trastuzumab-Induced Cardiotoxicity in C57Bl/6 Mice.

BACKGROUND: Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the morbidity and mortality of individuals with breast cancer, the use of these agents is limited by adverse cardiotoxic side effects. Both the nutraceutical agent flaxseed (FLX) and the pharmaceutical drug perindopril (PER) have been studied individually in the prevention of chemotherapy-mediated cardiac dysfunction. The objective of this study was to determine whether the prophylactic administration of FLX is comparable and/or synergistic with PER in preventing DOX + TRZ-induced cardiotoxicity. METHODS: Over a six-week period, 81 wild-type C57Bl/6 female mice (8-12 weeks old) were randomized to receive regular chow (RC) or 10% FLX-supplemented diets with or without PER (3 mg/kg/week; oral gavage). Starting at week 4, mice were randomized to receive a weekly injection of saline or DOX (8 mg/kg) + TRZ (3 mg/kg). Serial echocardiography was conducted weekly and histological and biochemical analyses were performed at the end of the study. RESULTS: In mice treated with RC + DOX + TRZ, left ventricular ejection (LVEF) decreased from 75 ± 2% at baseline to 37 ± 3% at week 6. However, prophylactic treatment with either FLX, PER, or FLX + PER partially preserved left ventricular systolic function with LVEF values of 61 ± 2%, 62 ± 2%, and 64 ± 2%, respectively. The administration of FLX, PER, or FLX + PER was also partially cardioprotective in preserving cardiomyocyte integrity and attenuating the expression of the inflammatory biomarker NF-κB due to DOX + TRZ administration. CONCLUSION: FLX was equivalent to PER at preventing DOX + TRZ-induced cardiotoxicity in a chronic in vivo murine model.

Interleukin-10 Mitigates Doxorubicin-Induced Endoplasmic Reticulum Stress as Well as Cardiomyopathy.

The use of doxorubicin (Dox) in cancer patients carries the risk of cardiotoxicity via an increase in oxidative stress, mitochondrial dysfunction, and disturbed endoplasmic reticulum (ER) homeostasis in cardiomyocytes. The present study explores which of the ER transmembrane sensors is involved in Dox-induced apoptosis and whether interleukin-10 (IL-10) has any mitigating effect. There was a time-related increase in apoptosis in cardiomyocytes exposed to 5.43 µg/mL Dox for 0 to 48 h. Dox treatment for 24 h significantly upregulated glucose-regulated proteins 78 and 94, protein disulfide isomerase, cleavage of activating transcription factor 6α, and X-box binding protein 1. These Dox-induced changes in ER stress proteins as well as apoptosis were blunted by IL-10 (10 ng/mL). In Dox-exposed cardiomyocytes, IL-10 also promoted expression of protein kinase-like endoplasmic reticulum kinase and inositol-requiring kinase 1α, which helped in maintaining ER homeostasis. Additionally, under Dox-treatment, IL-10 downregulated caspase-12 activation as well as phosphorylation of c-JUN NH2-terminal kinase, thereby promoting cardiomyocyte survival. IL-10 was able to reduce the overexpression of mitochondrial apoptotic proteins caspase-3 as well as Bax, which were upregulated upon Dox treatment. Thus, a reduction in Dox-induced ER stress as well as apoptosis through IL-10 may provide a significant benefit in improving cardiac function.

COVID-19 Vaccination-Induced Myopericarditis: An Imager's Perspective.

COVID-19 vaccine-induced myocarditis is a rare adverse event in the current pandemic. The following is a case series of 10 individuals with COVID-19 vaccine-related myocarditis confirmed by cardiac magnetic resonance imaging. In this cohort of predominantly male patients, with a mean age of 23 years, chest discomfort and positive cardiac biomarkers occurred at a median of 3 days after the second COVID-19 vaccine dose. Although systolic function was relatively preserved on noninvasive cardiac imaging, evidence was seen of delayed enhancement on cardiac magnetic resonance imaging, confirming myocarditis. As COVID-19 vaccine-induced myocarditis has a relatively benign clinical course, the benefits of vaccination still, by far, outweigh this small risk.

La myocardite induite par le vaccin contre la COVID-19 est un événement indésirable rare de la pandémie actuelle. Voici une série de cas de 10 individus atteints d'une myocardite liée au vaccin de la COVID-19 confirmée par l'imagerie par résonance magnétique cardiaque (RMC). Dans cette cohorte principalement composée d'hommes, dont l'âge moyen était de 23 ans, qui ont manifesté un inconfort à la poitrine et montré des biomarqueurs cardiaques positifs à une médiane de trois jours après la deuxième dose du vaccin contre la COVID-19. Bien que l'imagerie cardiaque non invasive a montré une fonction systolique relativement préservée, la RMC mettait en évidence un rehaussement tardif qui confirmait la myocardite. Puisque la myocardite induite par le vaccin contre la COVID-19 a une évolution clinique relativement bénigne, les avantages de la vaccination restent de loin supérieurs à ce risque minime.

Cardiac and cardiometabolic phenotyping of trastuzumab-mediated cardiotoxicity: a secondary analysis of the MANTICORE trial.

AIMS: An improved understanding of the pathophysiology of trastuzumab-mediated cardiotoxicity is required to improve outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to characterize the cardiac and cardiometabolic phenotype of trastuzumab-mediated toxicity and potential interactions with cardiac pharmacotherapy. METHODS AND RESULTS: This study was an analysis of serial magnetic resonance imaging (MRI) and circulating biomarker data acquired from patients with HER2-positive early-stage breast cancer participating in a randomized-controlled clinical trial for the pharmaco-prevention of trastuzumab-associated cardiotoxicity. Circulating biomarkers (B-type natriuretic peptide, troponin I, MMP-2 and -9, GDF-15, neuregulin-1, and IGF-1) and MRI of cardiac structure and function and abdominal fat distribution were acquired prior to trastuzumab, post-cycle 4 and post-cycle 17. Ninety-four participants (51 ± 8 years) completed the study with 30 on placebo, 33 on perindopril, and 31 on bisoprolol. Post-cycle 4, global longitudinal strain deteriorated from baseline in both placebo (+2.0 ± 2.7%, P = 0.002) and perindopril (+0.9 ± 2.5%, P = 0.04), but not with bisoprolol (-0.2 ± 2.1%, P = 0.55). In all groups combined, extracellular volume fraction and GDF-15 increased post-cycle 4 (+1.3 ± 4.4%, P = 0.004; +130 ± 150%, P ≤ 0.001, respectively). However, no significant change in troponin I was detected throughout trastuzumab. In all groups combined, visceral and intermuscular fat volume increased post-cycle 4 (+7 ± 17%, P = 0.02, +8 ± 23%, P = 0.02, respectively), while muscle volume and IGF-1 decreased from post-cycle 4 to 17 (-2 ± 10%, P = 0.008, -18 ± 28%, P < 0.001, respectively). CONCLUSION: Trastuzumab results in impaired cardiac function and early myocardial inflammation. Trastuzumab is also associated with deleterious changes to the cardiometabolic phenotype which may contribute to the increased cardiovascular risk in this population.

Endoplasmic Reticulum Stress Promotes iNOS/NO and Influences Inflammation in the Development of Doxorubicin-Induced Cardiomyopathy.

Doxorubicin (Dox) is known to cause heart failure in some cancer patients. Despite extensive studies over the past half century, the subcellular basis of Dox-induced cardiomyopathy (DIC) is still elusive. Earlier, we suggested that Dox causes a delayed activation of unfolded protein response (UPR) which may promote mitochondrial Bax activity leading to cardiomyocyte death. As a follow up, using NO donor, S-Nitroso-N-acetyl-d,l-penicillamine (SNAP), and/or NOS inhibitor, N(ω)-nitro-L-arginine methyl ester (L-NAME), we now show that endoplasmic reticulum (ER) stress promotes inflammation through iNOS/NO-induced TLR2 activation. In vivo Dox treatment increased mitochondrial iNOS to promote ER stress as there was an increase in Bip (Grp78) response, proapoptotic CHOP (DDIT3) and ER-mediated Caspase 12 activation. Increased iNOS activity is associated with an increase in TLR2 and TNF-α receptor associated factor 2 (TRAF2). These two together with NF-κB p105/50 expression and a synergistic support through ER stress, promote inflammatory response in the myocardium leading to cell death and ultimately fostering DIC conditions. In the presence of NOS inhibitor, such detrimental effects of Dox were inhibited, suggesting iNOS/NO as key mediators of Dox-induced inflammatory as well as apoptotic responses.

Exercise to Reduce Anthracycline-Mediated Cardiovascular Complications in Breast Cancer Survivors.

While developments in cancer therapeutics have greatly reduced morbidity and mortality in females with breast cancer, it comes at a cost of an increased risk of cardiovascular complications. In particular, anthracyclines, like doxorubicin, which are a mainstay of current chemotherapy regimens, are associated with dose-dependent cardiotoxicity. Exercise has been widely accepted as an effective intervention in reducing cardiovascular risk in a variety of different clinical conditions. However, the benefits of exercise in anthracycline-mediated cardiotoxicity are not clearly understood. First, this review discusses the pre-clinical studies which have elucidated the cardioprotective mechanisms of aerobic and resistance exercise in improving cardiovascular function in the setting of anthracycline treatment. Next, it aims to summarize the results of aerobic and resistance exercise clinical trials conducted in females with breast cancer who received anthracycline-based chemotherapy. The review further discusses the current exercise guidelines for women undergoing chemotherapy and contraindications for exercise. Finally, the review addresses gaps in research, specifically the need for further clinical trials to establish a recommended exercise prescription within this patient population.

Long COVID-19: A Primer for Cardiovascular Health Professionals, on Behalf of the CCS Rapid Response Team.

It is now widely recognized that COVID-19 illness can be associated with significant intermediate and potentially longer-term physical limitations. The term, "long COVID-19" is used to define any patient with persistent symptoms after acute COVID-19 infection (ie, after 4 weeks). It is postulated that cardiac injury might be linked to symptoms that persist after resolution of acute infection, as part of this syndrome. The Canadian Cardiovascular Society Rapid Response Team has generated this document to provide guidance to health care providers on the optimal management of patients with suspected cardiac complications of long COVID-19.

Prevalence and Functional Implication of Silent Coronary Artery Disease in Marathon Runners Over 40 Years of Age: The MATCH-40 Study.

BACKGROUND: Marathon participation is becoming increasingly popular among individuals ≥40 years of age. Little is known about the prevalence of subclinical coronary artery disease (CAD) and corresponding ischemia in this patient population. The study objectives are: (1) to characterize the prevalence of silent CAD in marathoners ≥ 40 years old using cardiac computed tomography angiography (CCT); and (2) if subclinical CAD was detected, to determine the functional significance of occult lesions by stress echocardiography (SE). METHODS: Marathoners aged ≥ 40 years who completed a full marathon between 2018 and 2019 were recruited to undergo a prospective CCT. Coronary artery stenosis was graded as zero, mild (1%-49%), moderate (50%-69%), or severe (> 70%). All study participants diagnosed with mild-to-severe atherosclerotic CAD on CCT further underwent functional imaging with exercise treadmill SE. RESULTS: A total of 65 individuals (53 ± 7 years, 65% males, 24 ± 3 kg/m2) underwent a prospective CCT within 12 months of marathon completion. Of the total study population, 13 participants (20%) were diagnosed with CAD, of whom 10 (77%) had mild disease, 1 (8%) had moderate disease, and 2 (15%) had severe disease by CCT. Despite the identification of subclinical CAD on CCT, none of the 13 patients had any evidence of inducible ischemia on SE. CONCLUSIONS: This is the first study to incorporate both CCT and SE in the evaluation of subclinical CAD in marathoners ≥40 years old. Although the overall prevalence of anatomic CAD was 20%, there was no evidence of functional ischemia in this highly competitive cohort.

CONTEXTE: Les marathons ont gagné en popularité auprès des individus âgés de 40 ans ou plus. On en sait toutefois peu sur la prévalence de la coronaropathie subclinique et de l'ischémie qui lui est associée dans cette population de patients. L'étude visait à 1) caractériser la prévalence de la coronaropathie silencieuse chez les marathoniens âgés de 40 ans ou plus à l'aide d'une angiographie cardiaque par tomodensitométrie (ACTDM) si une coronaropathie subclinique était détectée, à déterminer l'importance fonctionnelle des lésions occultes par une échocardiographie d'effort (EE). MÉTHODOLOGIE: Des marathoniens âgés de 40 ans ou plus ayant réalisé un marathon entre 2018 et 2019 ont été recrutés et soumis à une ACTDM prospective. Les sténoses des artères coronaires étaient classées selon une échelle allant de zéro, légère (1 à 49 %), modérée (50 à 69 %) à sévère (> 70 %). Tous les participants à l'étude ayant reçu un diagnostic de coronaropathie athéroscléreuse légère à sévère à la suite de l'ACTDM ont été soumis à une imagerie fonctionnelle avec EE sur tapis roulant. RÉSULTATS: Au total, 65 sujets (53 ± 7 ans, 65 % d'hommes, 24 ± 3 kg/m2) ont été soumis à une ACTDM prospective dans un délai de 12 mois à la suite de leur dernier marathon. Dans l'ensemble de la population à l'étude, 13 participants (20 %) ont reçu un diagnostic de coronaropathie; 10 (77 %) présentaient une maladie bénigne, 1 (8 %) présentait une maladie modérée et 2 (15 %) présentaient une maladie sévère selon l'ACTDM. Même si une coronaropathie subclinique a été diagnostiquée lors de l'ACTDM, aucun des 13 patients ne présentait de signe d'ischémie inductible à l'EE. CONCLUSIONS: Il s'agit de la première étude à utiliser l'ACTDM et l'EE pour évaluer la présence d'une coronaropathie chez des marathoniens âgés de 40 ou plus. Même si la prévalence globale de la coronaropathie anatomique était de 20 %, il n'y avait aucun signe d'ischémie fonctionnelle au sein de cette cohorte hautement compétitive.

Elimination of endogenous high molecular weight FGF2 prevents pressure-overload-induced systolic dysfunction, linked to increased FGFR1 activity and NR1D1 expression.

Fibroblast growth factor 2 (FGF2), produced as high (Hi-) and low (Lo-) molecular weight isoforms, is implicated in cardiac response to injury. The role of endogenous FGF2 isoforms during chronic stress is not well defined. We investigated the effects of endogenous Hi-FGF2 in a mouse model of simulated pressure-overload stress achieved by transverse aortic constriction (TAC) surgery. Hi-FGF2 knockout mice, expressing only Lo-FGF2, FGF2(Lo), and wild-type mice, FGF2(WT), expressing both Hi-FGF2 and Lo-FGF2, were used. By echocardiography, a decline in systolic function was observed in FGF2(WT) but not FGF2(Lo) mice compared to corresponding sham-operated animals at 4-8 weeks post-TAC surgery. TAC surgery increased markers of myocardial stress/damage including B-type natriuretic peptide (BNP) and the pro-cell death protein BCL2/adenovirus E1B 19 kDa protein-interacting protein-3 (Bnip3) in FGF2(WT) but not FGF2(Lo) mice. In FGF2(Lo) mice, cardiac levels of activated FGF receptor 1 (FGFR1), and downstream signals, including phosphorylated mTOR and p70S6 kinase, were elevated post-TAC. Finally, NR1D1 (nuclear receptor subfamily 1 group D member 1), implicated in cardioprotection from pressure-overload stress, was downregulated or upregulated in the presence or absence, respectively, of Hi-FGF2 expression, post-TAC surgery. In wild-type cardiomyocyte cultures, endothelin-1 (added to simulate pressure-overload signals) caused NR1D1 downregulation and BNP upregulation, similar to the effect of TAC surgery on the FGF2(WT) mice. The NR1D1 agonist SR9009 prevented BNP upregulation, simulating post-TAC findings in FGF2(Lo) mice. We propose that elimination of Hi-FGF2 is cardioprotective during pressure-overload by increasing FGFR1-associated signaling and NR1D1 expression.