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Cardiotoxicity is a growing concern in the oncology population. Transthoracic echocardiography and multigated acquisition scans have been used for surveillance but are relatively insensitive and resource intensive. Innovative imaging techniques are constrained by cost and availability. More sensitive, cost-effective cardiotoxicity surveillance strategies are needed. Circulating cardiovascular biomarkers could provide a sensitive, low-cost solution. Biomarkers such as troponins, natriuretic peptides (NPs), novel upstream signals of oxidative stress, inflammation, and fibrosis as well as panomic technologies have shown substantial promise, and guidelines recommend baseline measurement of troponins and NPs in all patients receiving potential cardiotoxins. Nonetheless, supporting evidence has been hampered by several limitations. Previous reviews have provided valuable perspectives on biomarkers in cancer populations, but important analytic aspects remain to be examined in depth. This review provides comprehensive assessment of critical challenges and solutions in this field, with focus on analytical issues relating to biomarker measurement and interpretation. Examination of evidence pertaining to common and serious forms of cardiotoxicity reveals that improved study designs incorporating larger, more diverse populations, registry-based approaches, and refinement of current definitions are key. Further efforts to harmonize biomarker methodologies including centralized biobanking and analyses, novel decision limits, and head-to-head comparisons are needed. Multimarker algorithms incorporating machine learning may allow rapid, personalized risk assessment. These improvements will not only augment the predictive value of circulating biomarkers in cardiotoxicity but may elucidate both direct and indirect relationships between cardiovascular disease and cancer, allowing biomarkers a greater role in the development and success of novel anticancer therapies.

The development of cardiovascular toxicity attributable to anticancer drugs is a pivotal event that is associated with cardiovascular morbidity as well as with worse cancer-specific and overall outcomes. Although broad consensus exists regarding the importance of cardiovascular safety assessment in cancer drug development, real-world data suggest that cardiovascular events are significantly underestimated in oncology trials. This drug safety discrepancy has profound implications on drug development decisions, risk-benefit evaluation, formulation of surveillance and prevention protocols, and survivorship. In this article, we review the contemporary cardiovascular safety evaluation of new pharmaceuticals in hematology and oncology, spanning from in vitro pharmacodynamic testing to randomized clinical trials. We argue that cardiovascular safety assessment of anticancer drugs should be reformed and propose practical strategies, including development and validation of preclinical assays, expansion of oncology trial eligibility, incorporation of cardiovascular end points in early-phase studies, and design of longitudinal multi-institutional cardiotoxicity registries.

Background Myocarditis attributable to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune-related adverse event. Limited data have suggested an association between baseline and on-treatment absolute lymphocyte count (ALC) and neutrophil/lymphocyte ratio (NLR) and the development of other immune-related adverse events; there are no data characterizing the role of ALC and NLR in ICI-associated myocarditis. Methods and Results This was a case control study of 55 patients with ICI myocarditis and 55 controls without any post-ICI immune-related adverse events. We leveraged clinical testing, where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events was also tested. In cases, there was a statistically significant decrease in ALC with myocarditis from baseline (1.6 thousands per cubic milliliter (K/μL); interquartile range, 1.1-1.9 K/μL) to admission (1.1 K/μL; interquartile range, 0.7-1.3 K/μL; P <0.001). Similarly, there was an increase in NLR from baseline (3.5; interquartile range, 2.3-5.4) to admission (6.6; interquartile range, 4.5-14.1; P <0.001). There was no statistically significant change in controls. In follow-up, there were 20 events; larger decreases in ALC (44.6% versus 18.2%; P <0.001) or increases in NLR (156.5% versus 65.1%; P =0.019) were associated with major adverse cardiac events. Conclusions A reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR was associated with subsequent major adverse cardiac events.

Background This study aimed to explore whether statins reduce radiation-induced vascular complications in cancer patients postradiotherapy to the thorax, head, and neck. Methods and Results We conducted a retrospective cohort study within a provincial linked database of 5718 cardiac patients with thorax and head or neck cancer having undergone radiotherapy between 2000 and 2011. One thousand five hundred fifty-two patients were identified as nonstatin users and 4166 as statin users. The primary outcome of interest was the composite of cerebrovascular (transient ischemic attack, and fatal or nonfatal stroke) or cardiovascular events (fatal or nonfatal myocardial infarction). Time-dependent Cox proportional hazard analyses were performed. The crude event rate was 10.31% for nonusers and 9.03% for statin users (hazard ratio of 0.92 [95% CI 0.76-1.10, P=0.3451]), over a mean time to event/censoring of 534±687 days for nonusers and 594±706 days for the statin users. After adjusting for age, sex, prior history of stroke/transient ischemic attack or myocardial infarction, diabetes mellitus, dyslipidemia, atrial fibrillation, chronic kidney disease, heart failure, and hypertension, statin use postradiotherapy was associated with a nonsignificant 15% relative risk reduction, but a strong trend toward reducing the primary outcome (hazard ratio=0.85 95% CI 0.69-1.04, P=0.0811). The use of statins was associated with a significant reduction of 32% for the outcome of stroke alone (hazard ratio=0.68, 95% CI 0.48-0.98, P=0.0368). Conclusions Statin use post radiation therapy was associated with a significant reduction in stroke, with a trend toward significantly reducing cardiovascular and cerebrovascular events.

Background People living with HIV ( PHIV ) are at an increased risk for sudden cardiac death, and implantable cardioverter-defibrillators ( ICDs ) prevent SCD . There are no data on the incidence, predictors, and effects of ICD therapies among PHIV . Methods and Results We compared ICD discharge rates between 59 PHIV and 267 uninfected controls. For PHIV , we tested the association of traditional cardiovascular risk factors and HIV -specific parameters with an ICD discharge and then tested whether an ICD discharge among PHIV was associated with cardiovascular mortality or an admission for heart failure. The indication for ICD insertion was similar among groups. Compared with controls, PHIV with an ICD were more likely to have coronary artery disease and to use cocaine. In follow-up, PHIV had a higher ICD discharge rate (39% versus 20%; P=0.001; median follow-up period, 19 months). Among PHIV , cocaine use, coronary artery disease, QRS duration, and higher New York Heart Association class were associated with an ICD discharge. An ICD discharge had a prognostic effect, with a subsequent 1.7-fold increase in heart failure admission and a 2-fold increase in cardiovascular mortality, an effect consistent across racial/ethnic and sex categories. Conclusions ICD discharge rates are higher among PHIV compared with uninfected controls. Among PHIV , cocaine use and New York Heart Association class are associated with increased ICD discharge, and an ICD discharge is associated with a subsequent increase in admission for heart failure and cardiovascular mortality.

Background: Radiation therapy (RT) is a standard treatment for head and neck cancer; however, it is associated with inflammation, accelerated atherosclerosis, and cerebrovascular events (CVEs; stroke or transient ischemic attack). Human papillomavirus (HPV) is found in nearly half of head and neck cancers and is associated with inflammation and atherosclerosis. Whether HPV confers an increased risk of CVEs after RT is unknown., Methods and Results: Using an institutional database, we identified all consecutive patients treated with RT from 2002 to 2012 for head and neck cancer who were tested for HPV. The outcome of interest was the composite of ischemic stroke and transient ischemic attack, and the association between HPV and CVEs was assessed using Cox proportional hazard models, competing risk analysis, and inverse probability weighting. Overall, 326 participants who underwent RT for head and neck cancer were tested for HPV (age 59±12 years, 75% were male, 9% had diabetes mellitus, 45% had hypertension, and 61% were smokers), of which 191 (59%) were tumor HPV positive. Traditional risk factors for CVEs were similar between HPV-positive and -negative patients. Over a median follow-up of 3.4 years, there were 18 ischemic strokes and 5 transient ischemic attacks (event rate of 1.8% per year). The annual event rate was higher in the HPV-positive patients compared with the HPV-negative patients (2.6% versus 0.9%, P =0.002). In a multivariable model, HPV-positive status was associated with a >4 times increased risk of CVEs (hazard ratio: 4.4; 95% confidence interval, 1.5-13.2; P =0.008)., Conclusions: In this study, HPV-positive status is associated with an increased risk of stroke or transient ischemic attack following RT for head and neck cancer., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The factors that predict recovery of left ventricular (LV) systolic dysfunction among patients with atrial fibrillation (AF) are not completely understood. Late gadolinium enhancement (LGE) of the LV has been reported among patients with AF, and we aimed to test whether the presence LGE was associated with subsequent recovery of LV systolic function among patients with AF and LV dysfunction., Methods and Results: From a registry of 720 consecutive patients undergoing a cardiac magnetic resonance study prior to pulmonary vein isolation (PVI), patients with LV systolic dysfunction (ejection fraction [EF] <50%) were identified. The primary outcome was recovery of LVEF defined as an EF >50%; a secondary outcome was a combined outcome of subsequent heart failure (HF), admission, and death. Of 720 patients, 172 (24%) had an LVEF of <50% prior to PVI. The mean LVEF pre-PVI was 41±6% (median 43%, range 20% to 49%). Forty-three patients (25%) had LGE (25 [58%] ischemic), and the extent of LGE was 7.5±4% (2% to 19%). During follow-up (mean 42 months), 91 patients (53%) had recovery of LVEF, 68 (40%) had early recurrence of AF, 65 (38%) had late AF, 18 (5%) were admitted for HF, and 23 died (13%). Factors associated with nonrecovery of LVEF were older age, history of myocardial infarction, early AF recurrence, late AF recurrence, and LGE. In a multivariable model, the presence of LGE and any recurrence of AF had the strongest association with persistence of LV dysfunction. Additionally, all patients without recurrence of AF and LGE had normalization of LVEF, and recovery of LVEF was associated with reduced HF admissions and death., Conclusions: In patients with AF and LV dysfunction undergoing PVI, the absence of LGE and AF recurrence are predictors of LVEF recovery and LVEF recovery in AF with associated reduction in subsequent death and heart failure., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Nearly 50% of patients with heart failure (HF) have preserved LV ejection fraction, with interstitial fibrosis and cardiomyocyte hypertrophy as early manifestations of pressure overload. However, methods to assess both tissue characteristics dynamically and noninvasively with therapy are lacking. We measured the effects of mineralocorticoid receptor blockade on tissue phenotypes in LV pressure overload using cardiac magnetic resonance (CMR)., Methods and Results: Mice were randomized to l-nitro-ω-methyl ester (l-NAME, 3 mg/mL in water; n=22), or l-NAME with spironolactone (50 mg/kg/day in subcutaneous pellets; n=21). Myocardial extracellular volume (ECV; marker of diffuse interstitial fibrosis) and the intracellular lifetime of water (τic; marker of cardiomyocyte hypertrophy) were determined by CMR T1 imaging at baseline and after 7 weeks of therapy alongside histological assessments. Administration of l-NAME induced hypertensive heart disease in mice, with increases in mean arterial pressure, LV mass, ECV, and τic compared with placebo-treated controls, while LV ejection fraction was preserved (>50%). In comparison, animals receiving both spironolactone and l-NAME ("l-NAME+S") showed less concentric remodeling, and a lower myocardial ECV and τic, indicating decreased interstitial fibrosis and cardiomyocyte hypertrophy (ECV: 0.43 ± 0.09 for l-NAME versus 0.25 ± 0.03 for l-NAME+S, P<0.001; τic: 0.42 ± 0.11 for l-NAME groups versus 0.12 ± 0.05 for l-NAME+S group). Mice treated with a combination of l-NAME and spironolactone were similar to placebo-treated controls at 7 weeks., Conclusions: Spironolactone attenuates interstitial fibrosis and cardiomyocyte hypertrophy in hypertensive heart disease. CMR can phenotype myocardial tissue remodeling in pressure-overload, furthering our understanding of HF progression., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Sleep apnea (SA) is associated with an increased risk of atrial fibrillation (AF). We sought to determine the effect of SA on cardiac structure in patients with AF, whether therapy for SA was associated with beneficial cardiac structural remodelling, and whether beneficial cardiac structural remodelling translated into a reduced risk of recurrence of AF after pulmonary venous isolation (PVI)., Methods and Results: A consecutive group of 720 patients underwent a cardiac magnetic resonance study before PVI. Patients with SA (n=142, 20%) were more likely to be male, diabetic, and hypertensive and have an increased pulmonary artery pressure, right ventricular volume, atrial dimensions, and left ventricular mass. Treated SA was defined as duration of continuous positive airway pressure therapy of >4 hours per night. Treated SA patients (n=71, 50%) were more likely to have paroxysmal AF, a lower blood pressure, lower ventricular mass, and smaller left atrium. During a follow-up of 42 months, AF recurred in 245 patients. The cumulative incidence of AF recurrence was 51% in patients with SA, 30% in patients without SA, 68% in patients with untreated SA, and 35% in patients with treated SA. In a multivariable model, the presence of SA (hazard ratio 2.79, CI 1.97 to 3.94, P<0.0001) and untreated SA (hazard ratio 1.61, CI 1.35 to 1.92, P<0.0001) were highly associated with AF recurrence., Conclusions: Patients with SA have an increased blood pressure, pulmonary artery pressure, right ventricular volume, left atrial size, and left ventricular mass. Therapy with continuous positive airway pressure is associated with lower blood pressure, atrial size, and ventricular mass, and a lower risk of AF recurrence after PVI.

Background: Childhood obesity is a significant risk factor for cardiovascular disease in adulthood. Although ventricular remodeling has been reported in obese youth, early tissue-level markers within the myocardium that precede organ-level alterations have not been described., Methods and Results: We studied 21 obese adolescents (mean age, 17.7±2.6 years; mean body mass index [BMI], 41.9±9.5 kg/m(2), including 11 patients with type 2 diabetes [T2D]) and 12 healthy volunteers (age, 15.1±4.5 years; BMI, 20.1±3.5 kg/m(2)) using biomarkers of cardiometabolic risk and cardiac magnetic resonance imaging (CMR) to phenotype cardiac structure, function, and interstitial matrix remodeling by standard techniques. Although left ventricular ejection fraction and left atrial volumes were similar in healthy volunteers and obese patients (and within normal body size-adjusted limits), interstitial matrix expansion by CMR extracellular volume fraction (ECV) was significantly different between healthy volunteers (median, 0.264; interquartile range [IQR], 0.253 to 0.271), obese adolescents without T2D (median, 0.328; IQR, 0.278 to 0.345), and obese adolescents with T2D (median, 0.376; IQR, 0.336 to 0.407; P=0.0001). ECV was associated with BMI for the entire population (r=0.58, P<0.001) and with high-sensitivity C-reactive protein (r=0.47, P<0.05), serum triglycerides (r=0.51, P<0.05), and hemoglobin A1c (r=0.76, P<0.0001) in the obese stratum., Conclusions: Obese adolescents (particularly those with T2D) have subclinical alterations in myocardial tissue architecture associated with inflammation and insulin resistance. These alterations precede significant left ventricular hypertrophy or decreased cardiac function.

Background: Abnormal tissue Doppler (TD)-derived indices during dobutamine stress echocardiography (DSE) can predict the presence of coronary artery disease (CAD) in patients with normal renal function. These indices include a reduction in annular systolic velocity (S'), a decrease in early diastolic annular velocity (E'), and prolongation of the time to E'. However, the ability of these indices to detect or exclude CAD in patients with chronic renal failure (CRF) is unclear., Objective: To examine the ability of TD-derived indices to detect or exclude the presence of CAD in patients with CRF., Methods: We evaluated a total of 30 patients (13 males, mean age 57 +/- 15 years) using both DSE and coronary angiography. This cohort consisted of 12 control patients with normal renal function (mean creatinine 0.5 mg/dL) and 18 patient with CRF (mean creatinine 2.5 mg/dL). At each stage of the DSE, left ventricular (LV) diastolic function was assessed using conventional (peak early (E) and late (A) transmitral, E/A ratio, E-wave deceleration time (DT), and isovolumic relaxation time (IVRT)) and TD-derived indices (lateral annular systolic (S'), early diastolic (E'), and late atrial velocities (A'), time to E' and E/E')., Results: All 30 patients had a normal DSE based on systolic regional function and a normal coronary angiogram. There was no difference in E, A, E/A, DT or IVRT between the two groups at each stage. Despite normal coronaries, patients with CRF demonstrated lower S' and E' velocities at peak stress compared to the control patients (8.0 +/- 2.2 cm/sec vs 15.1 +/- 2.6, P < 0.05 and 6.7 +/- 1.6 cm/sec vs 13.3 +/- 3.1, P < 0.05, respectively). During DSE, the time to E' at peak stress in CRF patients was also prolonged compared to control (400 +/- 44 ms vs 329 +/- 51, P < 0.05). Patients with CRF also had increased filling pressures (as estimated by E/E') as compared to controls at peak stress (14.7 +/- 5.2 vs 7.4 +/- 1.5, P < 0.05, respectively)., Conclusion: In patients with CRF, a reduction in TD derived indices does not predict the presence of obstructive CAD.

A 61-year-old male with a history of a mechanical Bjork-Shiley aortic valve replacement in 1977 and repair of an ascending aortic root dissection in 1993, presented with a 2-week history of fatigue and exertional dyspnea. Echocardiography confirmed the presence of an aortic pseudoaneurysm with a fistulous connection between the aorta and right atrium, which subsequently underwent successful repair. Although there have been several cases describing the development of an aortic pseudoaneurysm after aortic dissection repair, our case is the first to describe an aorta-atrial fistula as a long-term complication of a previous aortic dissection repair.