Prevention Of Cardiac Dysfunction Research Articles

Impact of the ESC Cardio-Oncology Guidelines Biomarker Criteria on Incidence of Cancer Therapy–Related Cardiac Dysfunction

BackgroundThe impact of recent consensus definitions of cancer therapy–related cardiac dysfunction (CTRCD) from the European Society of Cardiology cardio-oncology guidelines on the reported incidence of CTRCD has not yet been assessed. ObjectivesThe aim of this study was to assess the: 1) cumulative incidence; 2) point prevalence during and after adjuvant therapy; and 3) prognostic value of CTRCD as defined by different asymptomatic CTRCD guideline criteria. MethodsThe cumulative incidence and point prevalence of CTRCD were retrospectively assessed in 118 patients participating in the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial. Asymptomatic CTRCD was assessed using alternative cardiac troponin (cTn) 99th percentile upper reference limits (URLs) to define cTnT and cTnI elevation. ResultsThe cumulative incidence of moderate or severe CTRCD was low (1.7%), whereas the cumulative incidence of mild asymptomatic CTRCD was higher and differed markedly according to the biomarker criteria applied, ranging from 49.2% of patients when cTnT greater than the sex-specific 99th percentile URL was used to define cTn elevation to 9.3% when sex-neutral cTnI was used. The point prevalence of CTRCD was highest at the end of anthracycline therapy (47.8%) and was driven primarily by asymptomatic cTn elevation. CTRCD during adjuvant therapy was not prognostic for CTRCD at extended follow-up of 24 months (Q1-Q3: 21-29 months) after randomization. ConclusionsMild asymptomatic CTRCD during adjuvant breast cancer therapy was frequent and driven mainly by cTn elevation and was not prognostic of subsequent CTRCD. The incidence of mild, asymptomatic CTRCD differed markedly depending on the cTn assay and whether sex-neutral or sex-dependent URLs were applied. (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy [PRADA]; NCT01434134)

Living with brain cancer: From researcher to patient

As an academic researcher, my work-life revolves around testing the efficaciousness of pharmaceutical drugs on the prevention of cardiac dysfunction, arrhythmias, and sudden cardiac death in animal models of heart disease. I never thought I would go from someone studying a life-threatening disease to a patient living with one in twenty-four hours. Yet, that transformation occurred October 8, 2019. I was just appointed to Assistant Professor at Johns Hopkins University School of Medicine (JHUSOM), yet after sitting for my professional headshot I had a grand mal seizure. I cannot recall this event, but I bit the tip of my tongue off, dislocated my right shoulder, and underwent violent contractions. I was rushed to the Emergency Department, thankfully within the same building (JHUSOM). A few scans later, I was told I had ‘a mass’ in my brain that needed to be removed immediately. Fearing the worst, I followed the advice of my newly appointed neurosurgeon and scheduled surgery for October 19, 2019. I had no time to process what had and what was about to happen. What followed was two years of post-surgical recovery during a global pandemic, my own personal awe in the power of medicine, resurgence of my seizures and tumors, and now – my road to recovery through chemotherapy and radiation. These two years have taught me so much about the day-to-day difficulties patients with chronic diseases live with, strategies I use to cope with my new normal, and most importantly, the necessity of caregivers.

Prediction of anthracycline-induced cardiotoxicity as assessed by global longitudinal strain in women with early breast cancer: insights from the PRADA trial

Abstract Background Early recognition of anthracycline-induced cardiotoxicity is essential to prevent and treat left ventricular dysfunction before permanent damage ensues. Echocardiographic global longitudinal strain (GLS) may be a more sensitive indicator of decline in left ventricular systolic function than measurement left ventricular ejection fraction (LVEF). Many factors have been associated with cardiotoxicity defined by LVEF criteria, but less is known about predictors of early and late cardiotoxicity expressed as GLS. Objective The purpose of this study was to identify factors associated with cardiotoxicity, defined as absolute GLS <18% (a) after completion of anthracycline treatment and (b) at extended follow up after completion of adjuvant therapy for early breast cancer. Methods 120 women with early breast cancer undergoing adjuvant treatment with anthracyclines and/or trastuzumab, were included in the PRADA (PRevention of cArdiac Dysfunction during Adjuvant breast cancer) trial and randomized in a 2x2 factorial fashion to concomitant treatment with candesartan cilexetil, metoprolol succinate or matching placebo. Serial measurements of cardiovascular biomarkers (high sensitivity cardiac troponin I (hs-cTnI), B-type natriuretic peptide (BNP) and Galectin-3), cardiovascular magnetic resonance and echocardiography were performed at baseline, after anthracycline treatment and at extended follow-up median 23 months (interquartile range 21–28 months) after initiation of adjuvant therapy for early breast cancer. To identify potential predictors of cardiotoxicity defined by GLS criteria, associations between demographic, clinical, cancer therapy and biochemical and imaging biomarker data were evaluated by logistic regression analysis. Results 89 patients had GLS measurements performed at baseline, 87 at completed anthracycline therapy and 81 at extended follow-up. An overall decline in absolute GLS of 0.75% was observed at extended follow-up. One patient had absolute GLS <18 prior to anthracycline therapy whereas, 7 out of 87 (8.0%) and 7 out of 81 (8.6%) patients had GLS levels <18 after completion of anthracycline treatment and at extended follow up, respectively. Variables associated with absolute GLS <18% after anthracycline treatment and at extended follow-up are summarized in Tables 1a and 1b. Conclusion In this subanalysis of the PRADA trial, higher age, higher hs-cTnI, lower LVEF, lower E' and higher GLS at baseline predicted subsequent reduced systolic function expressed as reduced absolute GLS after anthracycline treatment. Higher age, hypertension, higher body mass index and higher hs-cTnI concentrations predicted absolute GLS <18 at extended follow up. Assessment of cardiac troponin I, cardiac imaging biomarkers and patient age may assist in the identification of patients at risk for developing cardiotoxicity. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by The South-Eastern Norway Regional Health Authority, The University of Oslo, The Extra Foundation for Health and Rehabilitation, The Norwegian Cancer Society, and Akershus University Hospital. Study medications and matching placebos were provided free of charge by AstraZeneca. Reagents for the analysis of high-sensitivity cardiac troponin I on the Architect platform were provided by Abbott Diagnostics.

Abstract LB515: Cardiovascular risk assessed by aptamer-based proteomics is increased in early breast cancer

Abstract Background: Cancer patients with a high risk for cardiovascular (CV) disease may be susceptible to cardiotoxic injury during cancer therapy. Accordingly, CV risk assessment may help in identifying candidates for preventive cardioprotective treatment. Since existing CV risk scores may lack the sensitivity and granularity to reflect the changes in CV risk that is associated with early cancer, we hypothesized that a CV risk score based on aptamer-based proteomics would permit discrimination of CV risk between patients with early breast cancer and age-, sex- and risk factor-matched healthy subjects. Moreover, we hypothesized that CV risk as assessed by aptamer-based proteomics first increases during and subsequently decreases after anthracycline-containing chemotherapy. Methods: We included 120 women with early breast cancer participating in the 2x2 factorial, randomized, placebo-controlled Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA) trial who were assigned to candesartan vs placebo and metoprolol vs placebo. Blood samples were obtained serially at: Visit 1 (ie, post-surgery but prior to epirubicin), following the first cycle of epirubicin (Visit 2), after the completion of epirubicin therapy (Visit 3), following adjuvant therapy (Visit 4), and 1-2 years after completion of adjuvant and blinded therapy (Visit 5). Age-, sex-, and risk factor-matched subjects (n = 500) from the Fenland study served as controls. We used highly multiplexed modified aptamer-based proteomics to measure ~5000 plasma proteins. A validated 27-protein CV risk model (CVD) that provides information on absolute risk of myocardial infarction, stroke, heart failure or mortality over a 4-year period was used as the dependent variable. Results: The CVD risk probability was significantly higher at Visit 1 than in the age-, sex- and risk-factor matched control group (p < 0.001). The CVD risk probability increased significantly from baseline to completion of epirubicin therapy (p < 0.001) and dropped below baseline levels for subsequent timepoints after the completion of epirubicin treatment. The mean CVD risk increased from 15.9% at Visit 2 to 24.6% at Visit 3, resulting in the percentage of subjects in the medium-high risk bin increasing from 9% at Visit 2 to 28% at Visit 3. The CVD risk distribution at the end of study was similar to the initial distribution at baseline and Visit 2. Conclusion: Using a novel CVD risk proteomics model, we observed that (1) The CVD risk of patients with early breast cancer is increased compared to age-, sex- and risk factor-matched individuals from the general population; (2) CVD risk increases during adjuvant epirubicin-containing chemotherapy, and (3) after completed adjuvant cancer therapy CVD risk returns to pre-chemotherapy level. Use of the CVD risk score may represent a novel tool to identify and monitor cancer patients who may benefit from preventive cardioprotective therapy. Citation Format: Torbjørn Omland, Jessica Chadwick, Ragnhild Røysland, Geeta Gulati, David Astling, Siri L. Heck, Victoria Vinje, Rachel Ostroff, Peter Ganz, Jürgen Geisler, Steve Williams. Cardiovascular risk assessed by aptamer-based proteomics is increased in early breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB515.

Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial

BackgroundRecent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested.ObjectiveTo assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction.MethodsPRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations.ResultsThe study is ongoing. Results will be published when the study is completed.ConclusionPRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy.Trial registrationThe trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588). Registered 30 November 2018.

The brain-heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention.

The influence of the central nervous system and autonomic system on cardiac activity is being intensively studied, as it contributes to the high rate of cardiologic comorbidities observed in people with epilepsy. Indeed, neuroanatomic connections between the brain and the heart provide links that allow cardiac arrhythmias to occur in response to brain activation, have been shown to produce arrhythmia both experimentally and clinically. Moreover, seizures may induce a variety of transient cardiac effects, which include changes in heart rate, heart rate variability, arrhythmias, asystole, and other ECG abnormalities, and can trigger the development of Takotsubo syndrome. People with epilepsy are at a higher risk of death than the general population, and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy‐related cause of death. Although the cause of SUDEP is still unknown, cardiac abnormalities during and between seizures could play a significant role in its pathogenesis, as highlighted by studies on animal models of SUDEP and registration of SUDEP events. Recently, genetic mutations in genes co‐expressed in the heart and brain, which may result in epilepsy and cardiac comorbidity/increased risk for SUDEP, have been described. Recognition and a better understanding of brain–heart interactions, together with new advances in sequencing techniques, may provide new insights into future novel therapies and help in the prevention of cardiac dysfunction and sudden death in epileptic individuals.

Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol.

Adjuvant breast cancer therapy containing anthracyclines with or without anti-human epidermal growth factor receptor-2 antibodies and radiotherapy is associated with cancer treatment-related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the β-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury. In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations. A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (P=0.021) and attenuated decline in global longitudinal strain (P=0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.

BRG1 protects the heart from acute myocardial infarction by reducing oxidative damage through the activation of the NRF2/HO1 signaling pathway

Brahma-related gene 1 (BRG1) regulates the chromatin structure and expression of cardiac genes. Although BRG1 is downregulated in adult cardiomyocytes, it is reactivated during cardiac stress. The role of BRG1 in acute myocardial infarction (AMI) has not been clearly defined. This study assessed the protective role of BRG1 in AMI using cell cultures and an animal model and explored the underlying molecular events. The results showed that in the peri-infarct zone, expression of BRG1 protein was significantly increased relative to the sham group, which was accompanied by NRF2 and HO1 upregulation and KEAP1 downregulation. BRG1 overexpression through adenoviral intramyocardial injection into AMI mice reduced the infarct size and improved cardiac functions with upregulation of NRF2 and its target HO1 and attenuated oxidative damage and cell apoptosis. However, shRNA-mediated Brg1 knockdown had the opposite effects. These results were further confirmed in cultured primary neonatal rat cardiomyocytes (NRCMs) with oxygen-glucose deprivation (OGD). Moreover, the selective NRF2 inhibitor brusatol could partially reverse cardiomyocyte antioxidant ability and BRG1 overexpression-induced cardiac protection in vitro. In addition, co-immunoprecipitation and immunofluorescence data showed that BRG1 overexpression significantly promoted the BRG1/NRF2 co-localization in cardiomyocytes. The chromatin immunoprecipitation-qPCR revealed BRG1 interaction with the Ho1 promoter and BRG1 overexpression could induce BRG1 binding to the Ho1 promoter during the OGD. In conclusion, this study demonstrated that BRG1 upregulation during AMI in vitro and in vivo increased the NRF2 level and NRF2 nuclear accumulation for HO1 expression to alleviate cardiac myocyte oxidative stress and upregulate cardiomyocyte viability. The BRG1-NRF2-HO1 pathway may represent a novel therapeutic target in the prevention of cardiac dysfunction in AMI patients.

P3120Prevention of heart failure in treatments with trastuzumab and anthracyclines: a meta-analysis

Abstract Background Trastuzumab and anthracyclines are conventional chemotherapies used in breast cancer. Unfortunately, they are associated with a decrease in left ventricular function potentially leading to heart failure (HF). In order to prevent this, randomised controlled trials (RCTs) assess the preventive effect of concomitant beta-blocker (BB), angiotensin receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) therapy during chemotherapy. Purpose To assess the preventive effect of BB, ARB or ACEIs on left ventricular ejection fraction (LVEF) during trastuzumab and anthracycline treatment in patients without HF. Methods Our primary outcomes were the effect of BBs or ARB/ACEIs during 1) trastuzumab and 2) anthracycline treatment. Secondary outcomes were the distinct effects of 1) BBs and 2) ARB/ACEIs in either trastuzumab or anthracycline treatments. Through the search term “(RCTs), prevention, cancer chemotherapy and cardiotoxicity” in PubMed, studies were selected, excluding those without randomising to a BB, ARB/ACEI and a placebo control group during chemotherapy. Means of the LVEF and the standard deviation (SD) post-chemotherapy were applied. Meta-analyses estimated the standardised mean difference (SMD) in the LVEF. Heterogeneity was calculated as the I2. Results A total of 7 studies (Table 1) were included in the analysis. Between 93 and 100% were woman. Age varied from 41 to 51 years. Treatment time varied from 12 to 52 weeks. Concomitant BB or ARB/ACEI therapy during trastuzumab treatment was not associated with the LVEF, significantly (Fig. 1A; p=0.07). Oppositely, in the anthracycline regime the LVEF remained significant higher in the concomitant BB and ARB/ACEI groups as compared to controls (Fig. 1B). BB and ARB/ACEI separation in the analysis showed both to influence the LVEF positively independent of chemotherapy (P=0.03 & p=0.005). Table 1 Study reference Year Chemotherapies Preventive drugs Pituskin et al., “Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity.” 2017 Trastuzumab Perindopril. bisoprolol Gulati et al., “Prevention of Cardiac Dysfunction during Adjuvant Breast Cancer Therapy (PRADA).” 2016 Trastuzumab Candesartan, metoprolol Boekhout et al., “Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial.” 2016 Trastuzumab Candesartan Janbabai et al., “Effect of Enalapril on Preventing Anthracycline-Induced Cardiomyopathy.” 2017 Anthracycline Enalapril Nabati et al., “Cardioprotective Effects of Carvedilol in Inhibiting Doxorubicin-Induced Cardiotoxicity.” 2017 Anthracycline Carvedilol Tashakori Beheshti et al., “Carvedilol Administration Can Prevent Doxorubicin-Induced Cardiotoxicity: A Double-Blind Randomized Trial.” 2016 Anthracycline Carvedilol Kaya et al., “Protective Effects of Nebivolol against Anthracycline-Induced Cardiomyopathy: A Randomized Control Study.” 2013 Anthracycline Nebivolol Figure 1 Conclusions Concomitant BB and ARB/ACEI therapy both favoured maintenance of the LVEF during trastuzumab and anthracyclines regimens as compared to controls.

1836P - High-sensitivity troponin as a cardiotoxicity biomarker in breast cancer treatment

BackgroundCardiotoxicity is one of the effects described with anthracyclines (AC) or antiHER2 therapies. Monitoring is usually performed with an echocardiogram and the main effect is the left ventricular ejection fraction reduction. On the other hand, cardiotoxicity biomarkers, such as high-sensitivity troponin (TropHS), can be evaluated at shorter intervals and have been described as an early diagnosis indicator of myocardial injury. MethodsRetrospective analysis of 83 breast cancer patients undergoing neoadjuvant or adjuvant chemotherapy with AC, with or without antiHER2 therapy, from January 2017 to July 2018. All patients were evaluated with cardiotoxicity biomarkers, electrocardiogram and transthoracic echocardiogram prior to treatment, and 3, 6, 9 and 12 months thereafter. After assessment of the cardiovascular risk, cardioprotective therapy has been initiated in patients with TropHS elevation. Cardiotoxicity was defined by a decline in LVEF> 10% of baseline or LVEF <50%. ResultsThe median age was 49 years (26-76) and 14.5% of the patients had history of cardiovascular disease (namely arterial hypertension). Almost 29% (n=24) were treated with association of antiHER2 therapy and the median chemotherapy treatment time was 3.8 months (1-6). About 84% (n=70) were submitted to adjuvant radiotherapy. Eight percent had a very high (7) Cardiotoxicity Risk Score, being most of them of the group with TropHS elevation. Almost 57% (n=47) of the patients presented TropHS elevation and we observed a major elevation at 3 months treatment, with a median of 21.25 (1.90-209.0). Approximately 5% (n=4) of the patients had cardiotoxicity, all of them treated with combination of antiHER2 therapy, and this was more frequent in patients with TropHS elevation (p=0.215). Among 15 patients who presented TropHs elevation and started cardioprotective therapy, only three developed cardiotoxicity. The median follow-up was 12 months (3-23). ConclusionsRecently, the role of TropHS, as a biomarker in the early identification of cardiotoxicity, has been affirmed. The consequent use of cardioprotective agents has emerged as an effective approach in the prevention of cardiac dysfunction. For the moment, more studies are needed to validate this biomarker in clinical practice. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

A12686 The sirtuin 6 attenuates myocardial injury and dysfunction by regulating ADAM17/ACE2 pathway in hypertensive rats

Objectives: The sirtuin 6 (SIRT6) is an important modulator of cardiovascular functions in health and diseases. However, the exact role of SIRT6 in hypertension is poorly defined. Methods: The male Sprague-Dawley rats were used to the normal control or randomized to preparation of hypertensive rats by Ang II (200 ng/kg/min) infusion with treatment of recombinant pAAV-SIRT6 or pAAV-GFP for 4 weeks. Results: There were reduced expression of SIRT6 and ACE2, and augmented levels of TGF-β, osteopontin (OPN), MMP-2 and MMP-9 in hypertensive rats, contributing to elevated cardiac fibrosis and exacerbated ultrastructural injury. Enhanced phosphorylation of ADAM-17 and impaired heart function were observed in both hypertensive rats and ACE2 knockout rats, characterized by increased LVPWT. Treatment of pAAV-SIRT6 significantly prevented Ang II-mediated pressor response and attenuated myocardial fibrosis and ultrastructural injury in hypertensive rats. These changes were associated with marked increases in LVEF and LVFS as well as downregulated levels of OPN, MMP-2 and MMP-9 in hypertensive rats. In cultured neonatal rat cardiac fibroblasts, exposure of Ang II resulted in reduction in ACE2 expression and phosphorylation of p-ADAM-17 as well as increases in cellular proliferation and migration, which were rescued by treatment of pAAV-SIRT6. Conclusion: The SIRT6 prevents hypertension-mediated pathological hypertrophy, impaired heart function and ultrastructural injury in hypertensive rats. These results indicate cardiac protective roles of SIRT6 in the prevention of cardiac dysfunction and injury via activation of ADAM-17-ACE2 pathway and suppression of the TGF-β-OPN signaling. Targeting SIRT6 and ACE2 has potential therapeutic importance for controlling myocardial injury and dysfunction in hypertension.

Neurohormonal Blockade and Circulating Cardiovascular Biomarkers During Anthracycline Therapy in Breast Cancer Patients: Results From the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) Study.

BackgroundAnthracyclines are associated with cardiotoxic effects. Cardiovascular biomarkers may reflect myocardial injury, dysfunction, inflammation, and fibrosis and may precede and predict the development of left ventricular impairment. The aim of this study was to assess: (1) longitudinal change in circulating cardiovascular biomarkers, (2) the effect of metoprolol succinate and candesartan cilexetil on the biomarker response, and (3) the associations between on‐treatment changes in biomarker concentrations and subsequent left ventricular dysfunction in patients with early breast cancer receiving anthracyclines.Methods and ResultsThis report encompasses 121 women included in the 2×2 factorial, placebo‐controlled, double‐blind PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial with metoprolol and candesartan given concomitantly with anticancer therapy containing the anthracycline, epirubicin (total cumulative dose, 240–400 mg/m2). Cardiovascular magnetic resonance, echocardiography images, and circulating levels of biomarkers were obtained before and after anthracycline treatment. Cardiac troponins I and T, B‐type natriuretic peptide, N‐terminal pro‐B‐type natriuretic peptide, C‐reactive protein, and galectin‐3 increased during anthracycline therapy (all P<0.05). The troponin response was attenuated by metoprolol (P<0.05), but not candesartan. There was no association between change in biomarker concentrations and change in cardiac function during anthracycline therapy.ConclusionsTreatment with contemporary anthracycline doses for early breast cancer is associated with increase in circulating cardiovascular biomarkers. This increase is, however, not associated with early decline in ventricular function. Beta‐blockade may attenuate early myocardial injury, but whether this attenuation translates into reduced risk of developing ventricular dysfunction in the long term remains unclear.Clinical Trial Registration URL: http://www.clinicaltrial.gov. Unique identifier: NCT01434134.

Prevention of cardiac dysfunction, kidney fibrosis and lipid metabolic alterations in l-NAME hypertensive rats by sinapic acid—Role of HMG-CoA reductase

The present study was designed to evaluate the effect of sinapic acid, a bioactive phenolic acid on high blood pressure associated cardiac dysfunction, kidney fibrosis and lipid alterations in Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME) induced hypertensive rats. Sinapic acid was administered to rats orally at a dosage of 40mg/kg everyday for a period of 4 weeks. Sinapic acid treatment significantly decreased mean arterial pressure, left ventricular end diastolic pressure, organ weights (liver and kidney), lipid peroxidation products in tissues (liver and kidney), activities of hepatic marker enzymes and the levels of renal function markers in serum of l-NAME rats. Sinapic acid treatment also significantly increased the level of plasma nitric oxide metabolites, and enzymatic and non-enzymatic antioxidants in tissues of l-NAME rats. Tissue damage was assessed by histopathological examination. Alterations in plasma angiotensin-converting enzyme activity, level of plasma lipoproteins and tissue lipids were corrected by sinapic acid treatment in l-NAME rats. Sinapic acid treatment significantly decreased the activity of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase in plasma and liver, whereas the activity of lecithin cholesterol acyl transferase was significantly increased in the plasma of hypertensive rats. Docking result showed the interaction between sinapic acid and HMG-CoA reductase. Sinapic acid has shown best ligand binding energy of −5.5kcal/M. Moreover, in chick embryo model, sinapic acid improved vessel density on chorioallantoic membrane. These results of the present study concludes that sinapic acid acts as a protective agent against hypertension associated cardiac dysfunction, kidney fibrosis and lipid alterations.

Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol.

AimsContemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the β-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation.Methods and resultsIn a 2 × 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the β-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed.ConclusionIn patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function.

Regular exercise modulates cardiac mast cell activation in ovariectomized rats.

It is well accepted that regular exercise is a significant factor in the prevention of cardiac dysfunction; however, the cardioprotective mechanism is as yet not well defined. We have examined whether regular exercise can modulate the activity of cardiac mast cells (CMC) after deprivation of female sex hormones, as well as the density and percentage degranulation of mast cells, in ventricular tissue of ovariectomized (OVX) rats after an 11-week running program. A significant increase in CMC density with a greater percentage degranulation was induced after ovarian sex hormone deprivation. Increased CMC density was prevented by estrogen supplements, but not by regular training. To the contrary, increased CMC degranulation in the OVX rat heart was attenuated by exercise training, but not by estrogen supplement. These findings indicate a significant correlation between the degree of CMC degranulation and myocyte cross-section area. However, no change in the expression of inflammatory mediators, including chymase, interleukin-6, and interleukin-10, was detected. Taken together, these results clearly indicate one of the cardioprotective mechanisms of regular aerobic exercise is the modulation of CMC activation.

Effects of the olive tree leaf constituents on myocardial oxidative damage and atherosclerosis.

The olive (Olea europaea) leaf is considered an important traditional herbal medicine utilized against infectious diseases, and for the treatment of diabetes and hypertension. Moreover, olive leaf constituents have been related to cardioprotection, probably due to their association with cellular redox modulating effects. The pathogenesis of certain common diseases, including those of the cardiovascular system, involves oxidative stress and tissue inflammation. Olive polyphenolic compounds, such as oleuropein, hydroxytyrosol, or tyrosol, possess antioxidant, anti-inflammatory, antiatherosclerotic, anti-ischemic, and hypolipidemic effects on the myocardium as demonstrated by various in vitro and in vivo studies. In this review article, we summarize the current knowledge on the role of the olive leaf constituents in the prevention of cardiac dysfunction and highlight future perspectives in their use as cardioprotective agents in therapeutics.

Abstract CT321: Prevention of cardiac dysfunction during adjuvant breast cancer therapy: the PRADA study

Abstract Purpose: Breast cancer is the most common malignancy in women worldwide. Treatment modalities include chemotherapeutic regimens containing anthracyclines, radiotherapy, and if HER-2 positive, the monoclonal antibody trastuzumab. Anthracyclines and trastuzumab are known to cause cardiac dysfunction, which may interrupt the anticancer treatment and thus increase the risk of cancer relapse. In previous observational trials, of patients with established left ventricular dysfunction following high-dose chemotherapy, treatment with angiotensin converting enzyme inhibitors and beta-blockers appeared to be associated with beneficial effects. Experimental design: A randomized, placebo-controlled, 2x2-factorial, double-blinded study is currently conducted at Akershus University Hospital, Lørenskog, Norway. In total, 120 women receiving adjuvant breast cancer therapy including anthracyclines and, if indicated, trastuzumab and/or radiation will be enrolled. Inclusion criteria comprise age between 18-70 years, Eastern Cooperative Oncology Group performance status ≤1, serum creatinine &amp;lt;140umol/L or estimated creatinine clearance &amp;gt;60 ml/min, systolic blood pressure ≥110 and ≤170 mmHg and left ventricular ejection fraction ≥ 50%. Cardiac magnetic resonance imaging (cMRI) with gadolinium contrast, echocardiography, cardiovascular biomarkers, and electrocardiogram are used to monitor cardiac function and injury. Objective: To assess the prophylactic effect of candesartan and metoprolol monotherapy, or their combination on global left ventricular systolic function, as assessed by cMRI of the heart, during postoperative, adjuvant chemotherapy with or without anti-HER-2 treatment and/or radiotherapy for early breast cancer. Secondary objectives include assessment of cardiac function and injury by echocardiography and cardiovascular biomarkers. Status: At our institution, postoperative, adjuvant chemotherapy was considered for 261 women in the period of September 2011 through November 2013. Among these, 105 (40%) were randomized for the PRADA-study. So far, 27 of 105 (26%) women included have received trastuzumab. The inclusion is estimated to continue through March 2014. Study value: The PRADA study addresses an important clinical problem in the early breast cancer population. The study will provide novel and clinically important data concerning the potential prevention of cardiac dysfunction during adjuvant breast cancer treatment. Our first experience with repeated cardial cMRIs and echocardiography during adjuvant therapy in early breast cancer patients on cardioprotective therapy will be presented and discussed. Citation Format: Geeta Gulati, Siri Lagethon Heck, Anne Hansen Ree, Åse Bratland, Kjetil Steine, Jeanette Schulz-Menger, Berit Gravdehaug, Pavel Hoffmann, Helge Røsjø, Jürgen Geisler, Torbjørn Omland. Prevention of cardiac dysfunction during adjuvant breast cancer therapy: the PRADA study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT321. doi:10.1158/1538-7445.AM2014-CT321

Protective Effects of Crocin on Hemodynamic Parameters and Infarct Size in Comparison with Vitamin E after Ischemia Reperfusion in Isolated Rat Hearts

Although reperfusion is a useful method for the survival of ischemic heart, harmful effects have been observed. This study was carried out to investigate the preconditioning and cardioprotective potential effects of crocin and vitamin E on the hemodynamic and infarct size in the ischemia-reperfusion model of isolated rat hearts. Animals were divided into a control group, an ischemia-reperfusion control group and three treatment groups: crocin (10, 20, and 40 mg/kg), vitamin E (100 mg/kg), and combination (crocin 40 mg/kg with vitamin E 100 mg/kg). The hearts were excised, quickly transferred to a Langendorff apparatus, and subjected to 30 min of global ischemia followed by 60 min of reperfusion. Left ventricular developed pressure, coronary perfusion pressure, left ventricular systolic pressure, myocardial contractility, rate pressure product, coronary flow, and infarct size were assessed. The successful induction of ischemia was determined by ST elevation on the electrocardiogram.The results showed that crocin significantly improved cardiac dysfunction and also reduced infarct size in the rat hearts. However, the combination of crocin 40 mg/kg and vitamin E 100 mg/kg had an even more significantly improved effect on the hemodynamic parameters and infarct size.Therefore, it can be suggested that the protective role of crocin may be due to the stability or reinforcement of antioxidant systems, and crocin could be useful for the treatment or prevention of cardiac dysfunction.

Cancer therapy-induced autonomic dysfunction in early breast cancer: Implications for aerobic exercise training

Breast cancer is the most common malignancy affecting women and the second leading cause of cancer death in women in the United States [1]. Due to improvements in detection and adjuvant therapy, breast cancer specific mortality has decreased significantly in women with early stage disease, and the five-year relative survival rate for early stage disease has increased from 80% in 1950 to 89% today [1]. Increased breast cancer specific survival, however, is at risk of being offset by the potential late occurring cardiovascular toxic effects of oncologic therapy. Indeed, among women with early breast cancer, particularly those over age 65, cardiovascular disease (CVD) is now the predominant cause of mortality, and these women are also at increased risk of CVD compared with age-matched women without a history of breast cancer [2].

Effects of Olmesartan Medoxomil, an Angiotensin II Type 1 Receptor Antagonist, on Plasma Concentration of B-Type Natriuretic Peptide, in Hypertensive Patients with Type 2 Diabetes Mellitus

Angiotensin II type 1 (AT1) receptor antagonists (angiotensin receptor blockers [ARBs]) are widely used for the treatment of not only hypertension but also cardiac dysfunction. B-type natriuretic peptide (BNP) is secreted mainly by the cardiac ventricle and plays an important role in the regulation of blood pressure (BP) and body fluid. It has been established that the plasma level of BNP is increased in patients with chronic heart failure in proportion to the severity of cardiac dysfunction. Because cardiac dysfunction is closely associated with a high risk of mortality in patients with diabetes mellitus, early identification and prevention of cardiac dysfunction are important. The objective of this study was to determine the effects of olmesartan medoxomil, a novel ARB, on the plasma level of BNP in hypertensive patients with type 2 diabetes. This was a preliminary, prospective, observational, open-label study. Sixty-eight type 2 diabetic patients with hypertension (systolic BP [SBP]≥140 mmHg or diastolic BP [DBP]≥90 mmHg) received olmesartan medoxomil 10–20 mg/day for 24 weeks. Plasma levels of BNP, as well as several clinical parameters of glycaemic control and lipid metabolism, were compared before and after 24 weeks of treatment. Another group consisting of 22 age- and body mass index-matched subjects not treated with olmesartan medoxomil was observed for reference purposes. In the olmesartan medoxomil group, mean±SD SBP decreased from 152.8±16.4 at baseline to 146.8±14.4 mmHg after 24 weeks' treatment (p<0.05); similarly, mean±SD DBP decreased from 85.6±10.5 to 81.3±11.6 mmHg (p<0.05). In 53 subjects in whom plasma levels of BNP could be measured both before and after treatment, mean±SD BNP decreased from 41.3±49.9 to 32.5±36.3 pg/mL (p<0.05). Change in plasma BNP level over the 24-week treatment period in the olmesartan medoxomil group was not correlated with change in SBP or DBP. Multiple regression analysis revealed that change in plasma BNP level was not correlated with baseline value of or change in any other parameters. No other parameters in the olmesartan medoxomil group, and no parameters in the non-olmesartan medoxomil reference group, showed significant changes. The current preliminary study showed that olmesartan medoxomil treatment might decrease plasma BNP levels, independent of its BP-lowering effect, in hypertensive patients with type 2 diabetes.