Outcomes of COVID-19 in Patients With a History of Cancer and Comorbid Cardiovascular Disease.

BACKGROUND: Cancer and cardiovascular disease (CVD) are independently associated with adverse outcomes in patients with COVID-19. However, outcomes in patients with COVID-19 with both cancer and comorbid CVD are unknown. METHODS: This retrospective study included 2,476 patients who tested positive for SARS-CoV-2 at 4 Massachusetts hospitals between March 11 and May 21, 2020. Patients were stratified by a history of either cancer (n=195) or CVD (n=414) and subsequently by the presence of both cancer and CVD (n=82). We compared outcomes between patients with and without cancer and patients with both cancer and CVD compared with patients with either condition alone. The primary endpoint was COVID-19-associated severe disease, defined as a composite of the need for mechanical ventilation, shock, or death. Secondary endpoints included death, shock, need for mechanical ventilation, need for supplemental oxygen, arrhythmia, venous thromboembolism, encephalopathy, abnormal troponin level, and length of stay. RESULTS: Multivariable analysis identified cancer as an independent predictor of COVID-19-associated severe disease among all infected patients. Patients with cancer were more likely to develop COVID-19-associated severe disease than were those without cancer (hazard ratio [HR], 2.02; 95% CI, 1.53-2.68; P<.001). Furthermore, patients with both cancer and CVD had a higher likelihood of COVID-19-associated severe disease compared with those with either cancer (HR, 1.86; 95% CI, 1.11-3.10; P=.02) or CVD (HR, 1.79; 95% CI, 1.21-2.66; P=.004) alone. Patients died more frequently if they had both cancer and CVD compared with either cancer (35% vs 17%; P=.004) or CVD (35% vs 21%; P=.009) alone. Arrhythmias and encephalopathy were also more frequent in patients with both cancer and CVD compared with those with cancer alone. CONCLUSIONS: Patients with a history of both cancer and CVD are at significantly higher risk of experiencing COVID-19-associated adverse outcomes. Aggressive public health measures are needed to mitigate the risks of COVID-19 infection in this vulnerable patient population.

Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.

Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.

Decreased metalloprotease 9 induction, cardiac fibrosis, and higher autophagy after pressure overload in mice lacking the transcriptional regulator p8.

Left ventricular remodeling, including the deposition of excess extracellular matrix, is key to the pathogenesis of heart failure. The stress-inducible transcriptional regulator p8 is increased in failing human hearts and is required both for agonist-stimulated cardiomyocyte hypertrophy and for cardiac fibroblasts matrix metalloprotease-9 (MMP9) induction. In the heart, upregulation of autophagy is an adaptive response to stress and plays a causative role in cardiomyopathies. We have recently shown that p8 ablation in cardiac cells upregulates autophagy and that, in vivo, loss of p8 results in a decrease of cardiac function. Here we investigated the effects of p8 genetic deletion in mediating adverse myocardial remodeling. Unstressed p8-/- mouse hearts manifested complex alterations in the expression of fibrosis markers. In addition, these mice displayed elevated autophagy and apoptosis compared with p8+/+ mice. Transverse aortic constriction (TAC) induced left ventricular p8 expression in p8+/+ mice. Pressure overload caused left ventricular remodeling in both genotypes, however, p8-/- mice showed less cardiac fibrosis induction. Consistent with this, although MMP9 induction was attenuated in the p8-/- mice, induction of MMP2 and MMP3 were strikingly upregulated while TIMP2 was downregulated. Left ventricular autophagy increased after TAC and was significantly higher in the p8-/- mice. Thus p8-deletion results in reduced collagen fibrosis after TAC, but in turn, is associated with a detrimental higher increase in autophagy. These findings suggest a role for p8 in regulating in vivo key signaling pathways involved in the pathogenesis of heart failure.

Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP.

Parasympathetic stimulation of the heart, which provides protection from arrhythmias and sudden death, involves activation of the G protein-coupled inward rectifying K+ channel GIRK1/4 and results in an acetylcholine-sensitive K+ current, I KACh. We describe a unique relationship between lipid homeostasis, the lipid-sensitive transcription factor SREBP-1, regulation of the cardiac parasympathetic response, and the development of ventricular arrhythmia. In embryonic chick atrial myocytes, lipid lowering by culture in lipoprotein-depleted serum increased SREBP-1 levels, GIRK1 expression, and I KACh activation. Regulation of the GIRK1 promoter by SREBP-1 and lipid lowering was dependent on interaction with 2 tandem sterol response elements and an upstream E-box motif. Expression of dominant negative SREBP-1 (DN-SREBP-1) reversed the effect of lipid lowering on I KACh and GIRK1. In SREBP-1 knockout mice, both the response of the heart to parasympathetic stimulation and the expression of GIRK1 were reduced compared with WT. I KACh, attenuated in atrial myocytes from SREBP-1 knockout mice, was stimulated by SREBP-1 expression. Following myocardial infarction, SREBP-1 knockout mice were twice as likely as WT mice to develop ventricular tachycardia in response to programmed ventricular stimulation. These results demonstrate a relationship between lipid metabolism and parasympathetic response that may play a role in arrhythmogenesis.

Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation.

Left ventricular (LV) hypertrophy commonly develops in response to chronic hypertension and is a significant risk factor for heart failure and death. The serine-threonine phosphatase calcineurin (Cn)A plays a critical role in the development of pathological hypertrophy. Previous experimental studies in murine models show that estrogen limits pressure overload-induced hypertrophy; our purpose was to explore further the mechanisms underlying this estrogen effect. Wild-type, ovariectomized female mice were treated with placebo or 17beta-estradiol (E2), followed by transverse aortic constriction (TAC), to induce pressure overload. At 2 weeks, mice underwent physiological evaluation, immediate tissue harvest, or dispersion of cardiomyocytes. E2 replacement limited TAC-induced LV and cardiomyocyte hypertrophy while attenuating deterioration in LV systolic function and contractility. These E2 effects were associated with reduced abundance of CnA. The primary downstream targets of CnA are the nuclear factor of activated T-cell (NFAT) family of transcription factors. In transgenic mice expressing a NFAT-activated promoter/luciferase reporter gene, E2 limited TAC-induced activation of NFAT. Moreover, the inhibitory effects of E2 on LV hypertrophy were absent in CnA knockout mice, supporting the notion that CnA is an important target of E2-mediated inhibition. In cultured rat cardiac myocytes, E2 inhibited agonist-induced hypertrophy while also decreasing CnA abundance and NFAT activation. Agonist stimulation also reduced CnA ubiquitination and degradation that was prevented by E2; all in vitro effects of estrogen were reversed by an estrogen receptor (ER) antagonist. These data support that E2 reduces pressure overload induced hypertrophy by an ER-dependent mechanism that increases CnA degradation, unveiling a novel mechanism by which E2 and ERs regulate pathological LV and cardiomyocyte growth.

Deletion of cytosolic phospholipase A2 promotes striated muscle growth.

Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A2 (PLA2) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis. Here we report that cytosolic PLA2 is a negative regulator of growth, specifically of striated muscle. We find that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, are exaggerated in Pla2g4a-/- mice, which lack the gene encoding cytosolic PLA2. The mechanism underlying this phenotype is that cytosolic PLA2 negatively regulates insulin-like growth factor (IGF)-1 signaling. Absence of cytosolic PLA2 leads to sustained activation of the IGF-1 pathway, which results from the failure of 3-phosphoinositide-dependent protein kinase (PDK)-1 to recruit and phosphorylate protein kinase C (PKC)-zeta, a negative regulator of IGF-1 signaling. Arachidonic acid restores activation of PKC-zeta, correcting the exaggerated IGF-1 signaling. These results indicate that cytosolic PLA2 and arachidonic acid regulate striated muscle growth by modulating multiple growth-regulatory pathways.

Management of Patients With Giant Cell Myocarditis: JACC Review Topic of the Week.

Giant cell myocarditis is a rare, often rapidly progressive and potentially fatal, disease due to T-cell lymphocyte-mediated inflammation of the myocardium that typically affects young and middle-aged adults. Frequently, the disease course is marked by acute heart failure, cardiogenic shock, intractable ventricular arrhythmias, and/or heart block. Diagnosis is often difficult due to its varied clinical presentation and overlap with other cardiovascular conditions. Although cardiac biomarkers and multimodality imaging are often used as initial diagnostic tests, endomyocardial biopsy is required for definitive diagnosis. Combination immunosuppressive therapy, along with guideline-directed medical therapy, has led to a paradigm shift in the management of giant cell myocarditis resulting in an improvement in overall and transplant-free survival. Early diagnosis and prompt management can decrease the risk of transplantation or death, which remain common in patients who present with cardiogenic shock.

Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program.

BACKGROUND: The postdischarge rehospitalization and death rates are high in patients with acute heart failure (HF) syndromes despite optimization of standard therapy for chronic HF. To the best of our knowledge, there has been no systematic analysis of the causes of death and rehospitalization in this patient population. METHODS: This was a prespecified analysis of adjudicated cause-specific all-cause mortality and cardiovascular (CV) hospitalization in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, a randomized, double-blind, placebo-controlled study in patients hospitalized with worsening HF and left ventricular ejection fraction < or =40% comparing tolvaptan, an oral vasopressin receptor antagonist to placebo, in addition to standard care. RESULTS: Of the 4,133 randomized, there were 5,239 rehospitalizations and 1,080 deaths during a median of 9.9 months. Of all deaths, 41.0% were due to HF, 26.0% due to sudden cardiac death (SCD), 2.6% due to acute myocardial infarction (MI), 2.2% due to stroke, and 13.2% due to non-CV causes. Of all hospitalizations, 39.2% were non-CV, whereas 46.3% were for HF, and a minority of hospitalizations was due to stroke, MI, arrhythmia, or other CV causes. CONCLUSIONS: Despite close follow-up and evidence-based therapy within a clinical trial, rehospitalization and death remain high. Although most deaths were from HF, one quarter of patients had SCD. In addition, there were almost as many non-CV hospitalizations as HF hospitalizations. Knowledge of the causes of death and rehospitalization may be essential for proper management and early initiation of therapy.

Increased FOG-2 in failing myocardium disrupts thyroid hormone-dependent SERCA2 gene transcription.

Reduced expression of sarcoplasmic reticulum calcium ATPase (SERCA)2 and other genes in the adult cardiac gene program has raised consideration of an impaired responsiveness to thyroid hormone (T3) that develops in the advanced failing heart. Here, we show that human and murine cardiomyopathy hearts have increased expression of friend of GATA (FOG)-2, a cardiac nuclear hormone receptor corepressor protein. Cardiac-specific overexpression of FOG-2 in transgenic mice led to depressed cardiac function, activation of the fetal gene program, congestive heart failure, and early death. SERCA2 transcript and protein levels were reduced in FOG-2 transgenic hearts, and FOG-2 overexpression impaired T3-mediated SERCA2 expression in cultured cardiomyocytes. FOG-2 physically interacts with thyroid hormone receptor-alpha1 and abrogated even high levels of T3-mediated SERCA2 promoter activity. These results demonstrate that SERCA2 is an important target of FOG-2 and that increased FOG-2 expression may contribute to a decline in cardiac function in end-stage heart failure by impaired T3 signaling.

Helix-loop-helix protein p8, a transcriptional regulator required for cardiomyocyte hypertrophy and cardiac fibroblast matrix metalloprotease induction.

Cardiomyocyte hypertrophy and extracellular matrix remodeling, primarily mediated by inflammatory cytokine-stimulated cardiac fibroblasts, are critical cellular events in cardiac pathology. The molecular components governing these processes remain nebulous, and few genes have been linked to both hypertrophy and matrix remodeling. Here we show that p8, a small stress-inducible basic helix-loop-helix protein, is required for endothelin- and alpha-adrenergic agonist-induced cardiomyocyte hypertrophy and for tumor necrosis factor-stimulated induction, in cardiac fibroblasts, of matrix metalloproteases (MMPs) 9 and 13-MMPs linked to general inflammation and to adverse ventricular remodeling in heart failure. In a stimulus-dependent manner, p8 associates with chromatin containing c-Jun and with the cardiomyocyte atrial natriuretic factor (anf) promoter and the cardiac fibroblast mmp9 and mmp13 promoters, established activator protein 1 effectors. p8 is also induced strongly in the failing human heart by a process reversed upon therapeutic intervention. Our results identify an unexpectedly broad involvement for p8 in key cellular events linked to cardiomyocyte hypertrophy and cardiac fibroblast MMP production, both of which occur in heart failure.

Risk and predictors of dyssynchrony cardiomyopathy in left bundle branch block with preserved left ventricular ejection fraction.

BACKGROUND: Left bundle branch block (LBBB) and left ventricular (LV) dyssynchrony likely contribute to progressive systolic dysfunction. The evaluation of newly recognized LBBB includes screening for structural heart abnormalities and coronary artery disease (CAD). In patients whose LV ejection fraction (EF) is preserved during initial testing, the incidence of subsequent cardiomyopathy is not firmly established. HYPOTHESIS: The risk of developing LV systolic dysfunction among LBBB patients with preserved LVEF is high enough to warrant serial imaging. METHODS: We screened records of 1000 consecutive patients with LBBB from our ECG database and identified subjects with an initially preserved LVEF (≥45%) without clinically relevant CAD or other cause for cardiomyopathy. Baseline imaging, clinical data, and follow-up imaging were recorded to determine the risk of subsequent LV systolic dysfunction (LVEF ≤40%). RESULTS: (Data are mean + SD) 784 subjects were excluded, the majority for CAD or depressed LVEF upon initial imaging. Of the remaining 216, 37 (17%) developed a decline in LVEF(≤40%) over a mean follow-up of 55 ± 31 months; 94% of these patients had a baseline LVEF≤60% and LV end systolic diameter (ESD) ≥ 2.9 cm indicating that these measures may be useful to define which patients warrant longitudinal follow-up. The negative predictive value of a LVEF>60% and LVESD <2.9 cm was 98%. CONCLUSIONS: Seventeen percent of patients with LBBB and initial preserved LVEF develop dyssynchrony cardiomyopathy. We believe the risk of developing dyssynchrony cardiomyopathy is high enough to warrant serial assessment of LV systolic function in this high-risk population.

Outcomes of Impella CP insertion during cardiac arrest: A single center experience.

OBJECTIVES: We sought to determine the outcomes of patients with an Impella CP percutaneous mechanical circulatory support (MCS) device deployed during a cardiac arrest. BACKGROUND: The Impella CP device is indicated for left ventricular support in patients with cardiogenic shock. The utility of percutaneous MCS in the setting of cardiac arrest during cardiopulmonary resuscitation (CPR) remains unclear. METHODS: We retrospectively examined data from patients supported with an Impella CP device for cardiogenic shock complicated by cardiac arrest between April 2015 and April 2017 at a single academic medical center. Patients with cardiac arrest who underwent Impella CP placement during CPR were compared to those who had return of spontaneous circulation (ROSC) prior to Impella CP placement. RESULTS: We identified 22 patients with cardiogenic shock complicated by cardiac arrest (average age 64 years, 23% female) who underwent placement of an Impella CP device. The majority of patients (68%) underwent support for cardiogenic shock secondary to an acute myocardial infarction. Seven of the 22 patients (32%) underwent Impella CP placement during CPR and 15 (68%) underwent Impella CP insertion following ROSC. The in-hospital mortality was 86% in the group of patients who had the Impella CP placed during CPR and 56% in the group with ROSC prior to Impella CP insertion, (p = 0.19). CONCLUSIONS: Based on our single center retrospective analysis, the mortality rate of patients undergoing placement of an Impella CP during CPR is 86%. Further study is necessary to better understand the utility of the Impella CP mechanical circulatory support device during a cardiac arrest.

Management of Cardiovascular Disease During Coronavirus Disease (COVID-19) Pandemic.

Patients with pre-existing cardiovascular disease and risk factors are more likely to experience adverse outcomes associated with the novel coronavirus disease-2019 (COVID-19). Additionally, consistent reports of cardiac injury and de novo cardiac complications, including possible myocarditis, arrhythmia, and heart failure in patients without prior cardiovascular disease or significant risk factors, are emerging, possibly due to an accentuated host immune response and cytokine release syndrome. As the spread of the virus increases exponentially, many patients will require medical care either for COVID-19 related or traditional cardiovascular issues. While the COVID-19 pandemic is dominating the attention of the healthcare system, there is an unmet need for a standardized approach to deal with COVID-19 associated and other traditional cardiovascular issues during this period. We provide consensus guidance for the management of various cardiovascular conditions during the ongoing COVID-19 pandemic with the goal of providing the best care to all patients and minimizing the risk of exposure to frontline healthcare workers.

Gene 33/RALT is induced by hypoxia in cardiomyocytes, where it promotes cell death by suppressing phosphatidylinositol 3-kinase and extracellular signal-regulated kinase survival signaling.

Ischemia in the heart deprives cardiomyocytes of oxygen, triggering cell death (myocardial infarction). Ischemia and its cell culture model, hypoxia, elicit a stress response program that contributes to cardiomyocyte death; however, the molecular components required to promote this process remain nebulous. Gene 33 is a 50-kDa cytosolic adapter protein that suppresses signaling from receptor Tyr kinases of the epidermal growth factor receptor/ErbB family. Here we show that adenoviral expression of Gene 33 swiftly stimulates cardiomyocyte death coincident with reduced Akt and extracellular signal-regulated kinase (ERK) signaling. Subjecting cardiomyocytes to hypoxia and then reoxygenation induces gene 33 mRNA and Gene 33 protein. RNA interference experiments indicate that endogenous Gene 33 reduces Akt and ERK signaling and is required for maximal hypoxia-induced cardiomyocyte death. Gene 33 levels are also strikingly increased in myocardial ischemic injury and infarction. Our results identify a new role for Gene 33 as a component in the molecular pathophysiology of ischemic injury.

The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy.

In cells capable of entering the cell cycle, including cancer cells, beta-catenin has been termed a master switch, driving proliferation over differentiation. However, its role as a transcriptional activator in terminally differentiated cells is relatively unknown. Herein we utilize conditional, cardiac-specific deletion of the beta-catenin gene and cardiac-specific expression of a dominant inhibitory mutant of Lef-1 (Lef-1Delta20), one of the members of the T-cell factor/lymphocyte enhancer factor (Tcf/Lef) family of transcription factors that functions as a coactivator with beta-catenin, to demonstrate that beta-catenin/Tcf/Lef-dependent gene expression regulates both physiologic and pathological growth (hypertrophy) of the heart. Indeed, the profound nature of the growth impairment of the heart in the Lef-1Delta20 mouse, which leads to very early development of heart failure and premature death, suggests beta-catenin/Tcf/Lef targets are dominant regulators of cardiomyocyte growth. Thus, our studies, employing complementary models in vivo, implicate beta-catenin/Tcf/Lef signaling as an essential growth-regulatory pathway in terminally differentiated cells.

Upfront dexrazoxane for the reduction of anthracycline-induced cardiotoxicity in adults with preexisting cardiomyopathy and cancer: a consecutive case series.

BACKGROUND: Cardiotoxicity associated with anthracycline-based chemotherapies has limited their use in patients with preexisting cardiomyopathy or heart failure. Dexrazoxane protects against the cardiotoxic effects of anthracyclines, but in the USA and some European countries, its use had been restricted to adults with advanced breast cancer receiving a cumulative doxorubicin (an anthracycline) dose > 300 mg/m2. We evaluated the off-label use of dexrazoxane as a cardioprotectant in adult patients with preexisting cardiomyopathy, undergoing anthracycline chemotherapy. METHODS: Between July 2015 and June 2017, five consecutive patients, with preexisting, asymptomatic, systolic left ventricular (LV) dysfunction who required anthracycline-based chemotherapy, were concomitantly treated with off-label dexrazoxane, administered 30 min before each anthracycline dose, regardless of cancer type or stage. Demographic, cardiovascular, and cancer-related outcomes were compared to those of three consecutive patients with asymptomatic cardiomyopathy treated earlier at the same hospital without dexrazoxane. RESULTS: Mean age of the five dexrazoxane-treated patients and three patients treated without dexrazoxane was 70.6 and 72.6 years, respectively. All five dexrazoxane-treated patients successfully completed their planned chemotherapy (doxorubicin, 280 to 300 mg/m2). With dexrazoxane therapy, changes in LV systolic function were minimal with mean left ventricular ejection fraction (LVEF) decreasing from 39% at baseline to 34% after chemotherapy. None of the dexrazoxane-treated patients experienced symptomatic heart failure or elevated biomarkers (cardiac troponin I or brain natriuretic peptide). Of the three patients treated without dexrazoxane, two received doxorubicin (mean dose, 210 mg/m2), and one received daunorubicin (540 mg/m2). Anthracycline therapy resulted in a marked reduction in LVEF from 42.5% at baseline to 18%. All three developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy. Two of them died from cardiogenic shock and multi-organ failure. CONCLUSION: The concomitant administration of dexrazoxane in patients with preexisting cardiomyopathy permitted successful delivery of anthracycline-based chemotherapy without cardiac decompensation. Larger prospective trials are warranted to examine the use of dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require anthracyclines.

17 Beta-estradiol differentially affects left ventricular and cardiomyocyte hypertrophy following myocardial infarction and pressure overload.

BACKGROUND: We have shown previously that 17beta-estradiol (E2) increases left ventricular (LV) and cardiomyocyte hypertrophy after myocardial infarction (MI). However, E2 decreases hypertrophy in pressure overload models. We hypothesized that the effect of estrogen on cardiac hypertrophy was dependent on the type of hypertrophic stimulus. METHODS AND RESULTS: Ovariectomized wild-type female mice (n = 192) were given vehicle or E2 treatment followed by coronary ligation (MI), transverse aortic constriction (TAC), or sham operation. Signaling pathway activation was studied at 3, 24, and 48 hours, whereas echocardiography and hemodynamic studies were performed at 14 days. MI induced early but transient activation of p38 and p42/44 MAPK pathways, whereas TAC induced sustained activation of both pathways. E2 had no effect on these pathways, but increased Stat3 activation after MI while decreasing Stat3 activation after TAC. MI caused LV dilation and decreased fractional shortening (FS) that were unaltered by E2. TAC caused LV dilation, reduced FS, and increased LV mass, but in this model, E2 improved these parameters. After MI, E2 led to increases in myocyte cross-sectional area, atrial natriuretic peptide (ANP) and beta-myosin heavy chain (MHC) gene expression, but E2 diminished TAC-induced increases ANP and beta-MHC gene expression. CONCLUSIONS: These data demonstrate that the effects of E2 on LV and myocyte remodeling depend on the nature of the hypertrophic stimulus. The opposing influence of E2 on hypertrophy in these models may, in part, result from differential effects of E2 on Stat3 activation. Further work will be necessary to explore this and other potential mechanisms by which estrogen affects hypertrophy in these models.

Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure.

BACKGROUND: Heart failure (HF) remains a major cause of morbidity and mortality in North America. With an aging population and an unmet clinical need by current pharmacologic and device-related therapeutic strategies, novel treatment options for HF are being explored. One such promising strategy is gene therapy to target underlying molecular anomalies in the dysfunctional cardiomyocyte. Prior animal and human studies have documented decreased expression of SERCA2a, a major cardiac calcium cycling protein, as a major defect found in HF. METHODS AND RESULTS: We hypothesize that increasing the activity of SERCA2a in patients with moderate to severe HF will improve their cardiac function, disease status, and quality of life. Gene transfer of SERCA2a will be performed via an adeno-associated viral (AAV) vector, derived from a nonpathogenic virus with long-term transgene expression as well as a clinically established favorable safety profile. CONCLUSIONS: We describe the design of a phase 1 clinical trial of antegrade epicardial coronary artery infusion (AECAI) administration of AAVI/SERCA2a (MYDICAR) to subjects with HF divided into 2 stages: in Stage 1, subjects will be assigned open-label MYDICAR in one of up to 4 sequential dose escalation cohorts; in Stage 2, subjects will be randomized in parallel to 2 or 3 doses of MYDICAR or placebo in a double-blinded manner.

Ibrutinib-Associated Atrial Fibrillation.

Ibrutinib, a novel and potent Bruton tyrosine kinase inhibitor, is an effective and well-tolerated treatment for a variety of B-cell lymphomas. However, its use is associated with an increased incidence of atrial fibrillation (AF), ranging from 4% to 16%. We reviewed the original clinical trials that led to the approval of ibrutinib, as well as several other prospective and retrospective studies, to better appreciate the incidence of ibrutinib-associated AF. Based on 16 studies included in our analysis, the incidence of ibrutinib-associated AF was 5.77 per 100 person-years, which is much higher than rates previously reported with ibrutinib and compared with the general adult population. New onset AF in cancer patients is associated with a significantly higher risk of heart failure and thromboembolism, even after adjusting for known risk factors. In addition, ibrutinib poses unique challenges due to its interactions with many medications that are commonly used to manage AF. Ibrutinib also inhibits platelet activation and decisions regarding anticoagulation have to be carefully weighed against this increased risk of bleeding. Ibrutinib's interaction with calcium channel blockers, digoxin, amiodarone, and direct oral anticoagulants can result in either ibrutinib or other drug-related toxicity and careful selection and dose adjustment may be needed. Ibrutinib-associated AF can be a therapy-limiting side effect and physicians should be familiar with the special management considerations imposed by this agent. We review the potential mechanisms and incidence of ibrutinib-associated AF and propose an algorithm for its management.