Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients.

We have added constitutively active MAP kinase/ERK kinase (MEK), an activator of the mitogen-activated protein kinase (MAPK) signaling pathway, to cycling Xenopus egg extracts at various times during the cell cycle. p42MAPK activation during entry into M-phase arrested the cell cycle in metaphase, as has been shown previously. Unexpectedly, p42MAPK activation during interphase inhibited entry into M-phase. In these interphase-arrested extracts, H1 kinase activity remained low, Cdc2 was tyrosine phosphorylated, and nuclei continued to enlarge. The interphase arrest was overcome by recombinant cyclin B. In other experiments, p42MAPK activation by MEK or by Mos inhibited Cdc2 activation by cyclin B. PD098059, a specific inhibitor of MEK, blocked the effects of MEK(QP) and Mos. Mos-induced activation of p42MAPK did not inhibit DNA replication. These results indicate that, in addition to the established role of p42MAPK activation in M-phase arrest, the inappropriate activation of p42MAPK during interphase prevents normal entry into M-phase.

Background— There remains limited insight into the pathophysiology and therapeutic advances directed at improving prognosis for patients with heart failure with preserved ejection fraction (HFpEF). Recent studies have suggested a role for coronary microvascular dysfunction in HFpEF. Rb-82 cardiac positron emission tomography imaging is a noninvasive, quantitative approach to measuring myocardial flow reserve (MFR), a surrogate marker for coronary vascular health. The aim of this study was to determine whether abnormalities exist in MFR in patients with HFpEF without epicardial coronary artery disease. Methods and Results— A total of 376 patients with ejection fraction ≥50%, no known history of obstructive coronary artery disease, and a confirmed diagnosis of heart failure (n=78) were compared with patients with no evidence of heart failure (n=298), further stratified into those with (n=186) and without (n=112) hypertension. Global and regional left ventricular MFR was calculated as stress/rest myocardial blood flow using Rb-82 positron emission tomography. Patients with HFpEF were more likely to be older, female, and have comorbid hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, anemia, and renal dysfunction. HFpEF was associated with a significant reduction in global MFR (2.16±0.69 in HFpEF versus 2.54±0.80 in hypertensive controls; P <0.02 and 2.89±0.70 in normotensive controls; P <0.001). A diagnosis of HFpEF was associated with 2.62 times greater unadjusted odds of having low global MFR (defined as <2.0) and remained a significant predictor of reduced global MFR after adjusting for comorbidities. Conclusions— HFpEF, in the absence of known history for obstructive epicardial coronary artery disease, is associated with reduced MFR independent of other risk factors.

Background: Cardiogenic shock (CS) is associated with high mortality. We report on a "Shock Team" approach of combined interdisciplinary expertise for decision making, expedited assessment, and treatment. Methods: We reviewed 100 patients admitted in CS over 52 months. Patients managed under a Code Shock Team protocol (n ¼ 64, treatment) from 2016 to 2019 were compared with standard care (n ¼ 36, control) from 2015 to 2016. The cohort was predominantly male (78% treatment, 67% control) with a median age of 55 years (interquartile range [IQR], 43-64) for treatment vs 64 years (IQR, 48-69) for control (P ¼ 0.01). New heart failure was more common in the treatment group: 61% vs 36%, P ¼ 0.02. Acute myocardial infarction comprised 13% of patients in CS. There were no significant differences between treatment and control in markers of clinical acuity, including median left ventricular ejection fraction (18% vs 20%), prevalence of R ESUM E Contexte : Le choc cardiog enique (CC) est associ e à une mortalit e elev ee. Nous d ecrivons une approche où la prise de d ecision, l' evaluation rapide des cas et le traitement sont confi es à une « equipe de choc » interdisciplinaire. M ethodologie : Nous avons examin e les cas de 100 patients hospitalis es en raison d'un CC sur une p eriode de 52 mois. Les patients pris en charge par une equipe interdisciplinaire selon un protocole d'intervention d eclench e par un code-choc (n ¼ 64, groupe trait e) de 2016 à 2019 ont et e compar es à des patients ayant reçu des soins courants (n ¼ 36, groupe t emoin) de 2015 à 2016. Les patients de la cohorte etaient majoritairement de sexe masculin (78 % dans le groupe trait e, 67 % dans le groupe t emoin) et l'âge m edian etait de 55 ans (intervalle interquartile [IIQ]: 43-64) au sein du groupe trait e par rapport à 64 ans (IIQ : 48-69) au sein du groupe t emoin (p ¼ 0,01). Les nou-Cardiogenic shock (CS) is defined as a low cardiac output state with end-organ hypoperfusion. 1 The etiology is broad and includes acute myocardial infarction (AMI), acute decompensated heart failure (ADHF) of preexisting cardiomyopathy, fulminant myocarditis, and tachyarrhythmia. 1 Clinical presentation is variable ranging from rapid hemodynamic deterioration over hours to a more insidious onset over days. Heterogeneity of etiology, presentation, and clinical trajectory have contributed to difficulties standardizing definitions for diagnosis, leading to delayed recognition, management variability, and uncertain optimal practice. Consequently, despite medical advances, clinical outcomes in CS remain poor with up to 50% in-hospital mortality reported in most series. 2,3 An increasing number of institutions are adopting a multidisciplinary team-based strategy for CS and have shown feasibility associated with improved outcomes. [4][5][6][7] In 2016, a Code Shock Team approach was implemented at our institution, which uses an emergent "Code" activation similar to other high-acuity, time-sensitive conditions such as ST-elevation myocardial infarction, cardiac arrest, and...

CAV results in diffuse concentric intimal thickening of the epicardial vessels affecting both the proximal and distal vessels as well as the microcirculation.3 This progressive luminal narrowing and loss of vasodilatory capacity culminates in myocardial ischemia and contractile dysfunction. Immunemediated injury plays a significant role in the development of epicardial vessel stenosis in addition to traditional risk factors. 4 Clinical symptoms such as angina are typically absent in cases of CAV because of allograft denervation, and therefore annual screening is used in most centers.Recent guidelines recommend periodic invasive coronary angiography for at least the first 3 to 5 years after transplantation. 5 However, this is inconvenient and adds risk. Hence, many centers have elected to monitor patients with noninvasive testing, but this strategy may be suboptimal because of the lower sensitivity for the detection of early CAV. 6,7 Rubidium-82 (Rb-82) positron emission tomography (PET) myocardial perfusion imaging is a noninvasive imaging modality that has the ability to quantify myocardial blood flow (MBF) 8 and has been shown to have prognostic value in patients being assessed for ischemia.9-11 This technique may facilitate earlier detection of CAV and thus may have prognostic value in HT patients. The objective of this study was to evaluate the prognostic value of Rb-82 PET in patients with a history of HT.Background-Cardiac allograft vasculopathy is a key prognostic determinant after heart transplant. Detection and risk stratification of patients with cardiac allograft vasculopathy are problematic. Positron emission tomography using rubidium-82 allows quantification of absolute myocardial blood flow and may have utility for risk stratification in this population. Methods and Results-Patients with a history of heart transplant undergoing dipyridamole rubidium-82 positron emission tomography were prospectively enrolled. Myocardial perfusion and left ventricular ejection fraction were recorded. Absolute flow quantification at rest and after dipyridamole stress as well as the ratio of mean global flow at stress and at rest, termed myocardial flow reserve, were calculated. Patients were followed for all-cause death, acute coronary syndrome, and heart failure hospitalization. A total of 140 patients (81% men; median age, 62 years; median follow-up, 18.2 months) were included. There were 14 events during follow-up (9 deaths, 1 acute coronary syndrome, and 4 heart failure admissions). In addition to baseline clinical variables (estimated glomerular filtration rate, previously documented cardiac allograft vasculopathy), relative perfusion defects, mean myocardial flow reserve, and mean stress myocardial blood flow were significant predictors of adverse outcome. Conclusions-Abnormalities on rubidium-82 positron emission tomography were predictors of adverse events in heart transplant patients. Larger prospective studies are required to confirm these findings. (Circ Cardiovasc Imaging. 2014;7:930-937.)

Ten antibody escape mutants of coxsackievirus B3 (CVB3) were used to identify nucleotide substitutions that determine viral virulence for the heart and pancreas. The P1 region, encoding the structural genes of each mutant, was sequenced to identify mutations associated with the lack of neutralization. Eight mutants were found to have a lysine-to arginine mutation in the puff region of VP2, while two had a glutamate-to-glycine substitution in the knob of VP3. Two mutants, EM1 and EM10, representing each of these mutations, were further analyzed, initially by determining their entire sequence. In addition to the mutations in P1, EM1 was found to have two mutations in the 3D polymerase, while EM10 had a mutation in stem-loop II of the 5 nontranslated region (5NTR). The pathogenesis of the mutants relative to that of CVB3 strain RK [CVB3(RK)] then was examined in A/J mice. Both mutants were found to be less cardiotropic than the parental strain, with a 40-fold (EM1) or a 100-to 1,000-fold (EM10) reduction in viral titers in the heart relative to the titers of CVB3(RK). The mutations in VP2, VP3, and the 5NTR were introduced independently into the RK infectious clone, and the phenotypes of the progeny viruses were determined. The results substantiated that the VP2 and VP3 mutations reduced cardiovirulence, while the 5NTR mutation in EM10 was associated with a more virulent phenotype when expressed on its own. Stereographic imaging of the two mutations in the capsomer showed that they lie in close proximity on either side of a narrow cleft between the puff and the knob, forming a conformational epitope that is part of the putative binding site for coreceptor DAF.

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