Hal Skopicki

Cancer Therapy–Related Cardiac Dysfunction and Heart Failure Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging

Advances in cancer therapy have resulted in significant improvement in long-term survival for many types of cancer but have also resulted in untoward side effects associated with treatment. One such complication that has become increasingly recognized is the development of cardiomyopathy and heart failure. Whether a previously healthy person from a cardiovascular perspective develops cancer therapy–related cardiac dysfunction or a high-risk cardiovascular patient requires cancer therapy, the team of oncologists and cardiologists must be better equipped with an evidence-based approach to care for these patients across the spectrum. Although the toxicities associated with various cancer therapies are well recognized, limitations to our understanding of the appropriate course of action remain. In this first of a 2-part review, we discuss the epidemiologic, pathophysiologic, risk factors, and imaging aspects of cancer therapy–related cardiac dysfunction and heart failure. In a subsequent second part, we discuss the prevention and treatment aspects, concluding with a section on evidence gap and future directions. We focus on adult patients in all stages of cancer therapy from pretreatment surveillance, to ongoing therapy, and long-term follow-up.

Embryonic Expression of the Gax Homeodomain Protein in Cardiac, Smooth, and Skeletal Muscle

Gax is a homeobox-containing gene that has been detected in adult cardiovascular tissues and exhibits a growth arrest-specific pattern of expression in cultured vascular myocytes. To study the regulation of gax during development, we performed immunohistochemistry and in situ hybridization on mouse embryos. Gax was present in mesodermally and, as with other homeobox genes, neuroectodermally derived tissues. Early mesodermal protein expression was limited to the lateral plate and somitic mesoderm. Gax in the cardiac muscle lineage exhibited a biphasic pattern of expression. Expression was prominent in the heart tube of the earliest cardiomyocytes and remained prominent through the looping stage (day 12.5 post coitum [pc]) but fell below the threshold of detection in atria and ventricles by day 13.5 pc. At day 15.5 pc, Gax protein was again detectable but restricted to cells within the compact layer of the ventricular myocardium. Gax expression was also noted in smooth muscle cells as early as day 9.5 pc. In the skeletal muscle lineage, Gax protein was expressed at the onset of somitogenesis before the expression of the myogenic basic helix-loop-helix and MEF2/RSRF family proteins. Subsequently, it was noted at day 9.5 pc in premyogenic cells migrating into head, trunk, and limb buds. Gax was detected in myotomes, premuscle masses, and mature muscle groups. These data suggest an important developmental role for Gax in all muscle lineages.

Cancer Therapy–Related Cardiac Dysfunction and Heart Failure Part 2: Prevention, Treatment, Guidelines, and Future Directions

Success with oncologic treatment has allowed cancer patients to experience longer cancer-free survival gains. Unfortunately, this success has been tempered by unintended and often devastating cardiac complications affecting overall patient outcomes. Cardiac toxicity, specifically the association of several cancer therapy agents with the development of left ventricular dysfunction and cardiomyopathy, is an issue of growing concern. Although the pathophysiologic mechanisms behind cardiac toxicity have been characterized, there is currently no evidence-based approach for monitoring and management of these patients. In the first of a 2-part review, we discuss the epidemiologic, pathophysiologic, risk factors, and imaging aspects of cancer therapy–related cardiac dysfunction and heart failure. In this second part, we discuss the prevention and treatment aspects in these patients and conclude with highlighting the evidence gaps and future directions for research in this area.

Utility of positron emission tomography for drug development for heart failure

Only about 1 in 5,000 investigational agents in a preclinical stage acquires Food and Drug Administration approval. Among many reasons for this includes an inefficient transition from preclinical to clinical phases, which exponentially increase the cost and the delays the process of drug development. Positron emission tomography (PET) is a nuclear imaging technique that has been used for the diagnosis, risk stratification, and guidance of therapy. However, lately with the advance of radiochemistry and of molecular imaging technology, it became evident that PET could help novel drug development process. By using a PET radioligand to report on receptor occupancy during novel agent therapy, it may help assess the effectiveness, efficacy, and safety of such a new medication in an early preclinical stage and help design successful clinical trials even at a later phase. In this article, we explore the potential implications of PET in the development of new heart failure therapies and review PETs application in the respective pathophysiologic pathways such as myocardial perfusion, metabolism, innervation, inflammation, apoptosis, and cardiac remodeling.

Comparing Sodium Intake Strategies in Heart Failure

In the past 2 decades, heart failure (HF) research has focused primarily on drugs and devices. In contrast, evidence remains scarce and mostly observational for dietary sodium restriction,1–3 arguably the most widely recommended self-care measure for patients with HF. In recent studies, patients with HF consumed an average of 3600 to 4200 mg sodium daily by 24-hour urinary sodium excretion,4 with 65% consuming >3000 mg.5 Although the evidence suggests that high-sodium intake worsens outcomes, the level of sodium intake that achieves optimal outcomes for patients with HF is unknown.6–12 All current guidelines emphasize sodium intake restriction; however, there is no consensus on the actual level. Recommendations are either nonspecific or ranging between 2000 and 3000 mg/d,9 largely based on opinions or observational studies. In explicit acknowledgment of the evidence gap, the recent European Society of Cardiology guidelines for HF12 have not assigned a level of evidence to sodium intake recommendations. The recent American College of Cardiology Foundation and American Heart Association guidelines recommend (class IIa) that sodium restriction is reasonable for patients with HF with congestive symptoms, but do not recommend a specific target level.13 The inconsistency of guidelines underlines the weak database that supports this cornerstone treatment. Current data indicate limited adherence with recommended sodium restriction among patients with HF. In a recent interventional study, when instructed to limit sodium intake to 2500 mg/d, patients with HF averaged a daily intake of 2700 to 3900 mg/d by 24-hour urinary sodium, depending on the assigned arm, after 8 months of intervention.4 Sodium intake reduction is difficult to adhere to even among patients with symptomatic HF, with less than one third of patients reporting sodium intake ≤2500 mg/d by 3-day food diaries, which underestimate actual sodium intake.4 Congruent …

Hemodynamic profiles of ED patients with acute decompensated heart failure and their association with treatment.

BACKGROUND The hemodynamic profile of patients presenting to the emergency department (ED) with acutely decompensated heart failure (ADHF) provides the basis for initial management. We characterized the hemodynamic profiles of patients presenting to the ED with ADHF and their association with treatments and outcomes. METHODS We conducted a retrospective analysis of the National Hospital Ambulatory Medical Care Survey (2006-2010) including ED subjects presenting with ADHF. Patients were classified into 3 groups based on their presenting systolic blood pressure (SBP): hypertensive (HTN) (SBP, ≥ 160), normotensive (NT) (SBP, 100-159), or hypotensive (HYPO) (SBP, <100). Univariate and multivariate analyses were used to determine associations between age, sex, race, and medications administered vs hemodynamic profiles using χ(2) test and logistic regression. RESULTS There were an estimated 3.4 million ED patient visits for ADHF. Mean age was 69 years, 51% were men, and 65% were white. Hemodynamic profiles at presentation were HTN (32%), NT (48%), and HYPO (21%). Age, sex, and ethnicity were similar across hemodynamic profiles. Rates of admission (HTN [78%], NT [75%], and HYPO [72%]; P = .39) and ED mortality (HYPO, 0.8%; HTN and HYPO, 0% each; P = .12) were not associated with hemodynamic group. Although administration of loop diuretics was similar across groups (approximately 60%-70% each), vasodilator use (mostly nitroglycerin) was greatest in the HTN group (42%, HTN; 23%, NT; 12%, HYPO; P < .001). CONCLUSIONS Of HTN ADHF patients, less than half received vasodilators, and approximately one-third did not receive diuretics, in the ED. The development of stratified protocols for therapy based on these profiles should be considered.

Comparing Sodium Intake Strategies in Heart Failure Rationale and Design of the Prevent Adverse Outcomes in Heart Failure by Limiting Sodium (PROHIBIT) Study

In the past 2 decades, heart failure (HF) research has focused primarily on drugs and devices. In contrast, evidence remains scarce and mostly observational for dietary sodium restriction,1–3 arguably the most widely recommended self-care measure for patients with HF. In recent studies, patients with HF consumed an average of 3600 to 4200 mg sodium daily by 24-hour urinary sodium excretion,4 with 65% consuming >3000 mg.5 Although the evidence suggests that high-sodium intake worsens outcomes, the level of sodium intake that achieves optimal outcomes for patients with HF is unknown.6–12 All current guidelines emphasize sodium intake restriction; however, there is no consensus on the actual level. Recommendations are either nonspecific or ranging between 2000 and 3000 mg/d,9 largely based on opinions or observational studies. In explicit acknowledgment of the evidence gap, the recent European Society of Cardiology guidelines for HF12 have not assigned a level of evidence to sodium intake recommendations. The recent American College of Cardiology Foundation and American Heart Association guidelines recommend (class IIa) that sodium restriction is reasonable for patients with HF with congestive symptoms, but do not recommend a specific target level.13 The inconsistency of guidelines underlines the weak database that supports this cornerstone treatment. Current data indicate limited adherence with recommended sodium restriction among patients with HF. In a recent interventional study, when instructed to limit sodium intake to 2500 mg/d, patients with HF averaged a daily intake of 2700 to 3900 mg/d by 24-hour urinary sodium, depending on the assigned arm, after 8 months of intervention.4 Sodium intake reduction is difficult to adhere to even among patients with symptomatic HF, with less than one third of patients reporting sodium intake ≤2500 mg/d by 3-day food diaries, which underestimate actual sodium intake.4 Congruent …

Rationale and design of a randomized controlled trial of allogeneic mesenchymal stem cells in patients with nonischemic cardiomyopathy.

Aims This article describes an ongoing study investigating the safety and efficacy of ischemia-tolerant mesenchymal stem cell (MSC) therapy in patients with nonischemic heart failure and dysfunctional viable myocardium without scarring. This study will follow principles of the previously described mechanistic translational-phase concept whereby the effect of the study agent on laboratory and imaging markers of cardiac structure and function will be tested in a small homogenous cohort with the goal to enhance the understanding of the effect of interventions on cardiac remodeling and performance. Study design This single-blind, placebo-controlled, crossover, multicenter, randomized study will assess the safety, tolerability, and preliminary efficacy of a single intravenous (i.v.) dose of allogeneic ischemia-tolerant MSCs in individuals with heart failure of nonischemic cause, ejection fraction 40% or less, and dysfunctional viable myocardium who have been receiving guideline-directed medical therapy. Eligible patients will have no evidence of baseline replacement scarring on delayed-enhancement cardiac magnetic resonance (CMR). Approximately 20 patients will be randomized in a 1 : 1 ratio to receive an i.v. infusion of ischemia-tolerant MSCs or placebo. At 90 days, the two groups will undergo crossover and received the alternative treatment. The primary endpoint is safety, as evaluated through at least 1-year post-MSC infusion. Additional efficacy endpoints will include measures of cardiac structure and function, as evaluated by serial cine-CMR and transthoracic echocardiography at 90 and 180 days post-initial infusion. Conclusion This pilot study will explore the safety and effects on cardiac structure and function of i.v. injection of ischemia-tolerant MSCs in a small homogenous cohort of nonischemic heart failure patients with reduced ejection fraction and absent replacement scarring on CMR. This study also represents a prospective mechanistic translational-phase study using baseline and serial CMR imaging in heart failure patients and serves as a potential model for design of future heart failure trials (ClinicalTrials.gov identifier: NCT02467387).

Intravenous Allogeneic Mesenchymal Stem Cells for Non-Ischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial.

Rationale: Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role. Objective: To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy. Methods and Results: This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ≤40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×106 cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98–66.97; P =0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70–9.74; P =0.02) and functional status scores (+5.65, 95% confidence interval −0.11 to 11.41; P =0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction. Conclusions: In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity. Clinical Trial Registration: URL: . Unique identifier: [NCT02467387][1]. # Novelty and Significance {#article-title-23} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02467387&atom=%2Fcircresaha%2F120%2F2%2F332.atomRationale: Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role. Objective: To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy. Methods and Results: This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ⩽40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×106 cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98–66.97; P=0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70–9.74; P=0.02) and functional status scores (+5.65, 95% confidence interval −0.11 to 11.41; P=0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction. Conclusions: In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02467387.

Heart Failure: An Exploration of Recent Advances in Research and Treatment (A).

Article types include original clinical and basic research articles, case reports, commentaries, meeting reports, methodology, perspective, research proposal, reviews, software/ database reviews, and technical advance. The supplement aims to provide readers with an exploration of recent advances in research on and treatment of heart failure. This includes but is not limited to the following topics: Pathophysiology § § Evaluation § § Management § § Diagnosis § § Prognosis § § Treatment § § Screening § § Prevention § § Epidemiology § § Risk factor modification § §