Bonnie Ky

Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.

Cardiac dysfunction resulting from exposure to cancer therapeutics was first recognized in the 1960s, with the widespread introduction of anthracyclines into the oncologic therapeutic armamentarium. Heart failure (HF) associated with anthracyclines was then recognized as an important side effect. As a result, physicians learned to limit their doses to avoid cardiac dysfunction. Several strategies have been used over the past decades to detect it. Two of them evolved over time to be very useful: endomyocardial biopsies and monitoring of left ven- tricular (LV) ejection fraction (LVEF) by cardiac imaging. Examination of endomyocardial biopsies proved to be the most sensitive and spe- cific parameter for the identification of anthracycline-induced LV dysfunction and became the gold standard in the 1970s. However, the interest in endomyocardial biopsy has diminished over time because of the reduction in the cumulative dosages used to treat ma- lignancies, the invasive nature of the procedure, and the remarkable progress made in noninvasive cardiac imaging. The noninvasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially car- diotoxic cancer treatment.

Assessment of Echocardiography and Biomarkers for the Extended Prediction of Cardiotoxicity in Patients treated with Anthracyclines, Taxanes and Trastuzumab

Background—Because cancer patients survive longer, the impact of cardiotoxicity associated with the use of cancer treatments escalates. The present study investigates whether early alterations of myocardial strain and blood biomarkers predict incident cardiotoxicity in patients with breast cancer during treatment with anthracyclines, taxanes, and trastuzumab. Methods and Results—Eighty-one women with newly diagnosed human epidermal growth factor receptor 2–positive breast cancer, treated with anthracyclines followed by taxanes and trastuzumab were enrolled to be evaluated every 3 months during their cancer therapy (total of 15 months) using echocardiograms and blood samples. Left ventricular ejection fraction, peak systolic longitudinal, radial, and circumferential myocardial strain were calculated. Ultrasensitive troponin I, N-terminal pro–B-type natriuretic peptide, and the interleukin family member (ST2) were also measured. Left ventricular ejection fraction decreased (64 ± 5% to 59 ± 6%; P<0.0001) over 15 months. Twenty-six patients (32%, [22%–43%]) developed cardiotoxicity as defined by the Cardiac Review and Evaluation Committee Reviewing Trastuzumab; of these patients, 5 (6%, [2%–14%]) had symptoms of heart failure. Peak systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines treatment predicted the subsequent development of cardiotoxicity; no significant associations were observed for left ventricular ejection fraction, N-terminal pro–B-type natriuretic peptide, and ST2. Longitudinal strain was <19% in all patients who later developed heart failure. Conclusions—In patients with breast cancer treated with anthracyclines, taxanes, and trastuzumab, systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines therapy are useful in the prediction of subsequent cardiotoxicity and may help guide treatment to avoid cardiac side-effects.

Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

### A. Definition, classification, and mechanisms of toxicity Cardiac dysfunction resulting from exposure to cancer therapeutics was first recognized in the 1960s, with the widespread introduction of anthracyclines into the oncological therapeutic armamentarium.1 Heart failure (HF) associated with anthracyclines was then recognized as an important side effect. As a result, physicians learned to limit their doses to avoid cardiac dysfunction.2 Several strategies have been used over the past decades to detect it. Two of them evolved over time to be very useful: endomyocardial biopsies and monitoring of left ventricular (LV) ejection fraction (LVEF) by cardiac imaging. Examination of endomyocardial biopsies proved to be the most sensitive and specific parameter for the identification of anthracycline-induced LV dysfunction and became the gold standard in the 1970s. However, the interest in endomyocardial biopsy has diminished over time because of the reduction in the cumulative dosages used to treat malignancies, the invasive nature of the procedure, and the remarkable progress made in non-invasive cardiac imaging. The non-invasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially cardiotoxic cancer treatment.3–5 The timing of LV dysfunction can vary among agents. In the case of anthracyclines, the damage occurs immediately after the exposure;6 for others, the time frame between drug administration and detectable cardiac dysfunction appears to be more variable. Nevertheless, the heart has significant cardiac reserve, and the expression of damage in the form of alterations in systolic or diastolic parameters may not be overt until a substantial amount of cardiac reserve has been exhausted. Thus, cardiac damage may not become apparent until years or even decades after receiving the cardiotoxic treatment. This is particularly applicable to …

High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure

Background—Soluble ST2 reflects activity of an interleukin-33–dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches. Methods and Results—We determined the association between ST2 level and risk of death or transplantation in a multicenter, prospective cohort of 1141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2 >36.3 ng/mL) had a markedly increased risk of adverse outcomes compared with the lowest tertile (ST2 ⩽22.3 ng/mL), with an unadjusted hazard ratio of 3.2 (95% confidence interval [CI], 2.2 to 4.7; P<0.0001) that remained significant after multivariable adjustment (adjusted hazard ratio, 1.9; 95% CI, 1.3 to 2.9; P=0.002). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.75 (95% CI, 0.69 to 0.79), which was similar to N-terminal pro-B–type natriuretic peptide (NT-proBNP) (area under the curve, 0.77; 95% CI, 0.72 to 0.81; P=0.24 versus ST2) but lower than the Seattle Heart Failure Model (area under the curve, 0.81 (95% CI, 0.77 to 0.85; P=0.014 versus ST2). Addition of ST2 and NT-proBNP to the Seattle Heart Failure Model reclassified 14.9% of patients into more appropriate risk categories (P=0.017). Conclusions—ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.

Multiple Biomarkers for Risk Prediction in Chronic Heart Failure

Background—Prior studies have suggested using a panel of biomarkers that measure diverse biological processes as a prognostic tool in chronic heart failure. Whether this approach improves risk prediction beyond clinical evaluation is unknown. Methods and Results—In a multicenter cohort of 1513 chronic systolic heart failure patients, we measured a contemporary biomarker panel consisting of high-sensitivity C-reactive protein, myeloperoxidase, B-type natriuretic peptide, soluble fms-like tyrosine kinase receptor-1, troponin I, soluble toll-like receptor-2, creatinine, and uric acid. From this panel, we calculated a parsimonious multimarker score and assessed its performance in predicting risk of death, cardiac transplantation, or ventricular assist device placement in comparison to an established clinical risk score, the Seattle Heart Failure Model (SHFM). During a median follow-up of 2.5 years, there were 317 outcomes: 187 patients died; 99 were transplanted; and 31 had a ventricular assist device placed. In unadjusted Cox models, patients in the highest tertile of the multimarker score had a 13.7-fold increased risk of adverse outcomes compared with the lowest tertile (95% confidence interval, 8.75–21.5). These effects were independent of the SHFM (adjusted hazard ratio, 6.80; 95% confidence interval, 4.18–11.1). Addition of the multimarker score to the SHFM led to a significantly improved area under the receiver operating characteristic curve of 0.803 versus 0.756 (P=0.003) and appropriately reclassified a significant number of patients who had the outcome into a higher risk category (net reclassification improvement, 25.2%; 95% confidence interval, 14.2–36.2%; P<0.001). Conclusions—In ambulatory chronic heart failure patients, a score derived from multiple biomarkers integrating diverse biological pathways substantially improves prediction of adverse events beyond current metrics.

The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans.

OBJECTIVES The aim of this study was to determine the effects of pravastatin and atorvastatin on markers of oxidative stress in plasma. BACKGROUND Hydroxymethylglutaryl coenzyme A reductase inhibitors reduce low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, but their effects on circulating biomarkers of oxidative stress are not well-defined. METHODS Hypercholesterolemic subjects (n = 120, ages 21 to 80 years with LDL-C 130 to 220 mg/dl) were randomized in a double-blind, parallel design to pravastatin 40 mg/day (prava40), atorvastatin 10 mg/day (atorva10), atorvastatin 80 mg/day (atorva80), or placebo. At baseline and 16 weeks, urinary isoprostanes (8, 12-iso-iPF(2 alpha)-VI isoform), plasma lipoprotein-associated phospholipase A2 (Lp-PLA2), Mercodia oxidized LDL (OxLDL) with antibody 4E6, oxidized phospholipids/apolipoprotein B-100 particle (OxPL/apoB) with antibody E06, immunoglobulin (Ig)G/IgM autoantibodies to malondialdehyde (MDA)-LDL, and apolipoprotein B (apoB)-immune complexes (IC) were measured. RESULTS After 16 weeks, there were no significant changes in urinary 8, 12-iso-iPF(2 alpha)-VI. The Lp-PLA2 and OxLDL were reduced in statin-treated groups, but after adjusting for apoB, only prava40 led to a reduction in Lp-PLA2 (-15%, p = 0.008) and atorva10 to a decrease in OxLDL (-12.9%, p = 0.01). The OxPL/apoB increased 25.8% (p < 0.01) with prava40 and 20.2% (p < 0.05) with atorva80. There were no changes in MDA-LDL autoantibodies, but significant decreases in IC were noted. CONCLUSIONS This study suggests that statin therapy results in variable effects on oxidative stress markers in hypercholesterolemic subjects. Future outcome studies should collectively assess various oxidative markers to define clinical utility.

Cancer Therapy–Induced Cardiotoxicity: Basic Mechanisms and Potential Cardioprotective Therapies

The patient is a 63-year-old man with a history of well-controlled hypertension who is diagnosed with diffuse large B-cell lymphoma and treated with a doxorubicin-containing chemotherapy regimen. During therapy, he is continued on hydrochlorothiazide for his hypertension. Three months later, he

Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

Purpose Cardiac dysfunction is a serious adverse effect of certain cancer-directed therapies that can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival of the patient with cancer. The purpose of this effort was to develop recommendations for prevention and monitoring of cardiac dysfunction in survivors of adult-onset cancers. Methods Recommendations were developed by an expert panel with multidisciplinary representation using a systematic review (1996 to 2016) of meta-analyses, randomized clinical trials, observational studies, and clinical experience. Study quality was assessed using established methods, per study design. The guideline recommendations were crafted in part using the Guidelines Into Decision Support methodology. Results A total of 104 studies met eligibility criteria and compose the evidentiary basis for the recommendations. The strength of the recommendations in these guidelines is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms. Recommendations It is important for health care providers to initiate the discussion regarding the potential for cardiac dysfunction in individuals in whom the risk is sufficiently high before beginning therapy. Certain higher risk populations of survivors of cancer may benefit from prevention and screening strategies implemented during cancer-directed therapies. Clinical suspicion for cardiac disease should be high and threshold for cardiac evaluation should be low in any survivor who has received potentially cardiotoxic therapy. For certain higher risk survivors of cancer, routine surveillance with cardiac imaging may be warranted after completion of cancer-directed therapy, so that appropriate interventions can be initiated to halt or even reverse the progression of cardiac dysfunction.

Emerging Paradigms in Cardiomyopathies Associated With Cancer Therapies

The cardiovascular care of cancer patients (cardio-oncology) has emerged as a new discipline in clinical medicine, given recent advances in cancer therapy, and is driven by the cardiovascular complications that occur as a direct result of cancer therapy. Traditional therapies such as anthracyclines and radiation have been recognized for years to have cardiovascular complications. Less expected were the cardiovascular effects of targeted cancer therapies, which were initially thought to be specific to cancer cells and would spare any adverse effects on the heart. Cancers are typically driven by mutations, translocations, or overexpression of protein kinases. The majority of these mutated kinases are tyrosine kinases, though serine/threonine kinases also play key roles in some malignancies. Several agents were developed to target these kinases, but many more are in development. Major successes have been largely restricted to agents targeting human epidermal growth factor receptor-2 (mutated or overexpressed in breast cancer), BCR-ABL (chronic myelogenous leukemia and some cases of acute lymphoblastic leukemia), and c-Kit (gastrointestinal stromal tumor). Other agents targeting more complex malignancies, such as advanced solid tumors, have had successes, but have not extended life to the degree seen with chronic myelogenous leukemia. Years before the first targeted therapy, Judah Folkman correctly proposed that to address solid tumors one had to target the inherent neoangiogenesis. Unfortunately, emerging evidence confirms that angiogenesis inhibitors cause cardiac complications, including hypertension, thrombosis, and heart failure. And therein lies the catch-22. Nevertheless, cardio-oncology has the potential to be transformative as the human cardiomyopathies that arise from targeted therapies can provide insights into the normal function of the heart.

Common variants in HSPB7 and FRMD4B associated with advanced heart failure

Background—Heart failure results from abnormalities in multiple biological processes that contribute to cardiac dysfunction. We tested the hypothesis that inherited variation in genes of known importance to cardiovascular biology would thus contribute to heart failure risk. Methods and Results—We used the ITMAT/Broad/CARe cardiovascular single-nucleotide polymorphism array to screen referral populations of patients with advanced heart failure for variants in ≈2000 genes of predicted importance to cardiovascular biology. Our design was a 2-stage case-control study. In stage 1, genotypes in Caucasian patients with heart failure (n=1590; ejection fraction, 32±16%) were compared with those in unaffected controls (n=577; ejection fraction, 67±8%) who were recruited from the same referral centers. Associations were tested for independent replication in stage 2 (308 cases and 2314 controls). Two intronic single-nucleotide polymorphisms showed replicated associations with all-cause heart failure as follows: rs1739843 in HSPB7 (combined P=3.09×10−6) and rs6787362 in FRMD4B (P=6.09×10−6). For both single-nucleotide polymorphisms, the minor allele was protective. In subgroup analyses, rs1739843 associated with both ischemic and nonischemic heart failure, whereas rs6787362 associated principally with ischemic heart failure. Linkage disequilibrium surrounding rs1739843 suggested that the causal variant resides in a region containing HSPB7 and a neighboring gene, CLCNKA, whereas the causal variant near rs6787362 is probably within FRMD4B. Allele frequencies for these single-nucleotide polymorphisms were substantially different in African Americans (635 cases and 714 controls) and showed no association with heart failure in this population. Conclusions—Our findings identify regions containing HSPB7 and FRMD4B as novel susceptibility loci for advanced heart failure. More broadly, in an era of genome-wide association studies, we demonstrate how knowledge of candidate genes can be leveraged as a complementary strategy to discern the genetics of complex disorders.