Emerging Medical Therapies for the Treatment of Obesity in Women with Cardiovascular Diseases.

PURPOSE OF REVIEW: In this review, the impact of obesity on cardiovascular disease in women and emerging anti-obesity pharmacologic treatments are discussed. RECENT FINDINGS: Robust evidence demonstrates the burden of obesity across the lifespan in women and links obesity to a diverse set of cardiovascular diseases. Female-specific risk factors including sex hormones and pregnancy factors intersect with obesity and cardiovascular risk. Sustained weight loss has potential for cardiovascular benefits. Recent trials demonstrate cardiovascular benefits of emerging agents with weight loss effects including GLP-1 RA and SGLT2 inhibitors in women. Treatment and prevention strategies for cardiovascular disease in obese women should include integration of weight management strategies including the targeted use of emerging pharmacologic therapies.

Innovations in Cardio-oncology Resulting from the COVID-19 Pandemic.

OPINION STATEMENT: The COVID pandemic has transformed our approach to patient care, research, and training in cardio-oncology. While the early phases of the COVID pandemic were exceptionally frightening, we now can reflect on the innovative changes that brought more effective and patient-centered care to our doorsteps: expansion of telemedicine, integration of digital health, wider adoption of cardiac biomarkers, consolidation, and coordination of cardio-oncology testing. Normally, it takes years for health care systems to adopt new technology or modify patient care pathways; however, COVID pushed healthcare providers and the health systems to change at warp speed. All of these innovations have improved our efficacy and provided a more "patient-centered" approach for our cardio-oncology patients. The changes we have made in cardio-oncology will likely remain well beyond the pandemic and continue to grow improving the cardiovascular care of oncology patients.

Childhood cancer survivors: The integral role of the cardiologist and cardiovascular imaging.

IMPORTANCE: With 80% of childhood cancer survivors (CCS) alive 30 years after diagnosis, preventable causes of death, such as cardiovascular disease resulting from initial cancer therapy, becomes an important metric. This leads to a more pronounced role for cardiologists in the care of CCS. OBSERVATIONS: While routine cardiovascular screening has been traditionally performed by the hematologist/oncologist or primary care provider, our understanding of cardiovascular disease in CCS has advanced. The measurement of left ventricular ejection fraction (LVEF) can now be complemented with additional assessments of strain, LV mass, right ventricular function, diastolic function, valve function, the pericardium, coronary perfusion, and biomarkers. Risk factor modification, prophylaxis, and timing of treatment are also critical. CONCLUSIONS AND RELEVANCE: Early cardiovascular screening and treatment in asymptomatic CCS can be nuanced and complex. As a result, there is a renewed opportunity for the cardiologist to play an integral role in the care of CCS. KEY POINTS: Question/Purpose: Review cardiovascular disease and the role of the cardiologist in the care of asymptomatic childhood cancer survivors (CCS). FINDINGS: Cardiovascular care in CCS benefits from a multi-faceted approach that does not overly rely on LVEF. Meaning: Adequate screening and treatment of cardiovascular disease in asymptomatic CCS may often be optimized by the involvement of a cardiologist.

Collaborative cardiovascular management of patients with chronic myeloid leukemia on tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) of the BCR-ABL fusion protein have dramatically changed the mortality of chronic myeloid leukemia (CML) but they carry a risk of serious vascular morbidity. While TKIs do not cure CML, daily oral administration of a TKI can control CML and TKIs are chronic medications. Interestingly, vascular complications can occur at any time a patient is on a TKI. Therefore, it is imperative that all care team members and patients are aware of and watching for possible vascular complications. In the following review, a case of arterial thrombosis secondary to the TKI ponatinib is presented as well as a discussion of thrombotic and vascular adverse events reported with TKIs. TKIs are metabolized through the cytochrome P450 system and important drug interactions to consider are reviewed. Finally, we present a multidisciplinary approach to the management of patients with CML on TKIs.

Strategies to Prevent Cardiotoxicity.

OPINION STATEMENT: Cardiovascular disease is a leading cause of death among cancer survivors. While the field of cardiology as a whole is driven by evidence generated through robust clinical trials, data in cardio-oncology is limited to a relatively small number of prospective clinical trials with heterogeneous groups of cancer patients. In addition, many pharmaceutical trials in oncology are flawed from a cardiovascular perspective because they exclude patients with significant cardiovascular (CV) history and have wide variation in the definitions of CV events and cardiotoxicity. Ultimately, oncology trials often underrepresent the possibility of cardiovascular events in a "real world" population. Thus, the signal for CV toxicity from a cancer treatment is often not manifested until phase IV studies; where we are often caught trying to mitigate the CV effects rather than preventing them. Most of the data about cardiotoxicity from cancer therapy and cardioprotective strategies has been developed from our experience in using anthracyclines for over 50 years with dramatic improvement in cancer survivorship. However, as we are in an era where cancer drug discovery is moving at lightning pace with increasing survival rates, it is imperative to move beyond anthracyclines and commit to research on the cardiovascular side effects of all aspects of cancer therapy with a focus on prevention. We emphasize the role of pre-cancer treatment CV assessment to anticipate cardiac issues and ultimately optimizing CV risk prior to cancer therapy as an opportunity to mitigate cardiovascular risk from cancer therapy.

Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial.

OBJECTIVES: SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC). BACKGROUND: AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium. METHODS: The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP). CONCLUSIONS: This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome.

Cardio-Oncology: An Update on Cardiotoxicity of Cancer-Related Treatment.

Through the success of basic and disease-specific research, cancer survivors are one of the largest growing subsets of individuals accessing the healthcare system. Interestingly, cardiovascular disease is the second leading cause of morbidity and mortality in cancer survivors after recurrent malignancy. This recognition has helped stimulate a collaboration between oncology and cardiology practitioners and researchers, and the portmanteau cardio-oncology (also known as onco-cardiology) can now be found in many medical centers. This collaboration promises new insights into how cancer therapies impact cardiovascular homeostasis and long-term effects on cancer survivors. In this review, we will discuss the most recent views on the cardiotoxicity related to various classes of chemotherapy agents and radiation. We will also discuss broadly the current strategies for treating and preventing cardiovascular effects of cancer therapy.

Getting the SCOOP-Survey of Cardiovascular Outcomes From Oncology Patients During Survivorship.

BACKGROUND: Cardiovascular (CV) disease is the second most common cause of mortality and morbidity in cancer survivors (CS). Limited data exist on the knowledge and awareness of CS about CV effects of cancer therapies and its effect on lifestyle of survivors. It is important to identify gaps in CV care of CS. MATERIALS AND METHODS: A brief voluntary, anonymous, web-based questionnaire was designed to assess the awareness of CS about the interaction between CV disease, CV symptoms and lifestyle changes from cancer treatment. RESULTS: A total of 213 volunteers (181 women) with mean age of 56 years responded to the survey. Breast cancer was the most prevalent cancer diagnosis. In all, 15% reported CV disease before therapy with a higher incidence of CV disease in survivors more than 5 years from diagnosis (20% >5 years versus 10% <5 years of survivorship, P = 0.05). The reported use of beta blockers (9%) and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (9%) was rare despite the high incidence of CV disease. Only one-fourth of survivors were offered CV screening during treatment, whereas 36% of survivors had unanswered questions about CV symptoms from therapy. The CV symptoms adversely affected lifestyle in 27% of CS. One-fifth of survivors received exercise counseling even though half would have liked counseling. CONCLUSIONS: The survey demonstrates that CS have self-reported CV symptoms and there may be unmet needs for CV preventive services. Further work is needed to develop collaborative patient counseling and management strategies between oncology and cardiology for improving CV health and symptoms of CS.

Sympathetic nervous system alterations with HER2+ antagonism: an early marker of cardiac dysfunction with breast cancer treatment?

BACKGROUND: HER2 antagonists (anti-HER2; e.g., trastuzumab and lapatinib) are effective in treating an aggressive form of breast cancer (BC), but can cause cardiotoxicity due to the disruption in neuregulin (NRG)/HER2+ ligand receptor signalling. The recent data show that NRG-HER2 receptors located in the medulla oblongata are important regulators of vasomotor tone. Disrupting the NRG-HER2 signalling in mouse medulla results in increased sympathetic nerve output and blood pressure. We hypothesized that anti-HER2 agents would cause increased sympathetic tone with changes in plasma catecholamines and NRG. METHODS: In 15 newly diagnosed HER2+ BC patients receiving anti-HER2 agents, vital signs were measured along with supine plasma epinephrine (EPI), norepinephrine (NE), and NRG at baseline and three months. Serial echocardiography was performed. RESULTS: With three months of anti-HER2 treatment, NE increased (2.334 ± 1.294 nmol/L vs. 3.262 ± 2.103 nmol/L; p = 0.004) and NRG decreased (12.7±15.7 ng/ml vs. 10.9 ± 13.3 ng/ml; p = 0.036) with a corresponding increase in systolic blood pressure (110 ± 10 mmHg vs. 120 ± 16 mmHg, p = 0.049) and diastolic blood pressure (67 ± 14 vs. 77 ± 10, p = 0.009). There was no change, however, in EPI (0.183 ± 0.151 nmol/L vs. 0.159 ± 0.174 nmol/L; p = 0.519) or heart rate (73 ± 12 bpm vs. 77 ± 10 bpm, p = 0.146). Left ventricular ejection function declined over the follow-up period (baseline 63 ± 6% vs. follow-up 56 ± 5%). CONCLUSIONS: Anti-HER2 treatment results in increased NE, blood pressure, and decreased NRG; this suggests that the inhibition of NRGHER2 signalling leads to increased sympathoneural tone. Larger studies are needed to determine if these observations have prognostic value and may be offset with medical interventions, such as beta-blockers. CLINICAL TRIAL REGISTRATION: The study was registered with www.clinicaltrials.gov (NCT00875238).

Reproducibility of intracardiac and transpulmonary biomarkers in the evaluation of pulmonary hypertension.

Intracardiac and transpulmonary levels of natriuretic peptides (NPs) and cyclic guanosine monophosphate (cGMP) provide insight into the pathophysiology of pulmonary hypertension (PH) secondary to left-heart failure but have not been evaluated in established or suspected pulmonary arterial hypertension (PAH). Demonstrating adequate reproducibility of these markers is an important precursor to further study. We hypothesized that the reproducibility of intracardiac and transpulmonary NPs and cGMP is similar to the reproducibility of these markers sampled from the peripheral venous circulation. In outpatients undergoing right-heart catheterization for PH, blood samples were obtained from a peripheral venous site, superior vena cava, inferior vena cava, coronary sinus, pulmonary artery, and pulmonary capillary wedge position. At each site, a repeat sample was collected approximately 60 seconds after the initial measurement. Reproducibility was assessed using the slope of the regression line between initial and follow-up levels. We enrolled 10 patients: Six had PAH, two had pulmonary venous hypertension, and two had normal pulmonary pressure. At all sites, the slopes of the regression lines for BNP were close to identity. BNP was generally more reproducible than NT-pro-BNP. For the NPs and cGMP, reproducibility at intracardiac and transpulmonary sites was similar to the peripheral venous site. Reproducibility of NPs was not influenced by PH severity, access site, or time between measurements. The two patients with the highest transpulmonary pressure gradients had high transpulmonary BNP uptake, but their transpulmonary cGMP gradients were negative. In patients evaluated for PH, reproducibility of NPs and cGMP at intracardiac and transpulmonary sites is high and is comparable to that of peripheral venous measurements.

Heart transplant survival outcomes for adriamycin-dilated cardiomyopathy.

In 2015, there will be an estimated 11.3 million cancer survivors. With an increasing population of cancer survivors, it is imperative to understand the treatment options available and outcomes for chemotherapy-related cardiomyopathy. Anthracycline-based chemotherapy causes heart failure in approximately 5% of patients. Orthotopic heart transplantation (OHT) is an option for cancer survivors in complete remission who develop end-stage heart failure. We examined retrospective OHT data collected from the United Network of Organ Sharing from 1987 to 2011. The primary aim was to characterize the survival in patients with either the primary diagnosis of "dilated cardiomyopathy: Adriamycin" (DCA) versus "all other" causes of cardiomyopathy. The secondary aim was to define the differences in the primary cause of death and to describe the temporal relationship of DCA OHT. The United Network of Organ Sharing database identified 453 OHTs for the diagnosis of DCA and 51,312 OHTs for all other causes of cardiomyopathy. The DCA group was significantly younger with a greater percentage of women. After adjusting for age, gender, and history of malignancy, the 10-year survival curves showed that patients with DCA have an improved survival compared to those with all other causes of cardiomyopathy (hazard ratio 1.28, p = 0.026). No difference was found in the primary cause of death between the 2 groups. A statistically significant increasing temporal trend was seen in the number of OHTs for the diagnosis DCA. In conclusion, patients who undergo OHT for DCA have favorable 10-year survival, making OHT a good therapeutic option for end-stage heart failure due to anthracyclines. Additionally, no increased risk of cancer-related deaths was found in the DCA group, demonstrating that recurrent malignancy does not affect long-term survival. The temporal trends demonstrated that DCA remains a significant problem for cancer survivors.

Intravenous glial growth factor 2 (GGF2) isoform of neuregulin-1ß improves left ventricular function, gene and protein expression in rats after myocardial infarction.

AIMS: Recombinant Neuregulin (NRG)-1ß has multiple beneficial effects on cardiac myocytes in culture, and has potential as a clinical therapy for heart failure (HF). A number of factors may influence the effect of NRG-1ß on cardiac function via ErbB receptor coupling and expression. We examined the effect of the NRG-1ß isoform, glial growth factor 2 (GGF2), in rats with myocardial infarction (MI) and determined the impact of high-fat diet as well as chronicity of disease on GGF2 induced improvement in left ventricular systolic function. Potential mechanisms for GGF2 effects on the remote myocardium were explored using microarray and proteomic analysis. METHODS AND RESULTS: Rats with MI were randomized to receive vehicle, 0.625 mg/kg, or 3.25 mg/kg GGF2 in the presence and absence of high-fat feeding beginning at day 7 post-MI and continuing for 4 weeks. Residual left ventricular (LV) function was improved in both of the GGF2 treatment groups compared with the vehicle treated MI group at 4 weeks of treatment as assessed by echocardiography. High-fat diet did not prevent the effects of high dose GGF2. In experiments where treatment was delayed until 8 weeks after MI, high but not low dose GGF2 treatment was associated with improved systolic function. mRNA and protein expression analysis of remote left ventricular tissue revealed a number of changes in myocardial gene and protein expression altered by MI that were normalized by GGF2 treatment, many of which are involved in energy production. CONCLUSIONS: This study demonstrates that in rats with MI induced systolic dysfunction, GGF2 treatment improves cardiac function. There are differences in sensitivity of the myocardium to GGF2 effects when administered early vs. late post-MI that may be important to consider in the development of GGF2 in humans.