Michel G. Khouri

A 4-tiered classification of left ventricular hypertrophy based on Left ventricular geometry the dallas Heart study

Background—Left ventricular hypertrophy (LVH) is traditionally classified as concentric or eccentric, based on the ratio of LV wall thickness to chamber dimension. We propose a 4-tiered LVH classification based on LV concentricity0.67 (mass/end-diastolic volume0.67) and indexed LV end-diastolic volume (EDV). Methods and Results—Cardiac MRI was performed in 2803 subjects and LVH (n=895) was defined by increased LV mass/height2.7. Increased concentricity0.67 and indexed EDV were defined at the 97.5th percentile of a healthy subpopulation. Four geometric patterns resulted: increased concentricity without increased EDV (“thick hypertrophy,” n=361); increased EDV without increased concentricity (“dilated hypertrophy,” n=53); increased concentricity with increased EDV (“both thick and dilated hypertrophy,” n=13); and neither increased concentricity nor increased EDV (“indeterminate hypertrophy,” n=468). Compared with subjects with isolated thick hypertrophy, those with both thick and dilated hypertrophy had a lower LV ejection fraction and higher NT-pro-BNP and BNP levels (P≤0.001 for all). Subjects with dilated hypertrophy had a lower LV ejection fraction and higher troponin T, NT-pro-BNP, and BNP levels versus those with indeterminate hypertrophy (P<0.001 for all). Subjects with indeterminate LVH versus those without LVH had increased LV mass (by definition) but also a higher LV ejection fraction and no increase in troponin or natriuretic peptide levels. Conclusions—Concentric or eccentric LVH can each be subclassified into 2 subgroups, yielding 4 distinct geometric patterns. Many subjects currently classified with eccentric LVH can be reclassified into an indeterminate subgroup that has better LV function and comparable levels of biomarkers reflecting cardiac stress as compared with those without LVH.

Cancer Therapy–Induced Cardiac Toxicity in Early Breast Cancer Addressing the Unresolved Issues

The landscape of early breast cancer has changed dramatically with significant advancements in early screening and diagnosis and curative-intent therapies. Indeed, breast cancer–specific survival has improved by 20% during the past 30 years, and 5-year survival is now 98% for early-stage disease.1 As a consequence, the risk and nature of adjuvant therapy–induced immediate and late-occurring cardiovascular injury have similarly evolved. In women with early breast cancer, particularly those >65 years of age, cardiovascular disease (CVD) is now the predominant cause of mortality as indicated by Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.2 Additionally, these women are also at increased risk of CVD compared with age-matched women without a history of breast cancer.3 Significant cardiac safety concerns about anticancer therapy were first described by Von Hoff and colleagues,4 identifying dose-dependent and progressive left ventricular (LV) dysfunction manifesting as symptomatic heart failure in patients receiving anthracyclines. From this work and others,5,6 anthracycline-induced cardiac toxicity7,8 is now a well-recognized adverse side effect. More recently, randomized trials have demonstrated that human epidermal growth factor receptor 2 (HER2)–directed monoclonal antibodies (ie, trastuzumab) and newer multitargeted small-molecule inhibitors interfere with molecular pathways crucial to normal cardiac homeostasis,9 resulting in relatively high incidences of subclinical and overt cardiac toxicity.10 Although cardiac toxicity with newer therapies has demonstrated reversibility,11 recovery of LV function after treatment cessation is uncertain at this time.12 Thus, to identify those individuals at high risk of cardiac toxicity, baseline measurement of LV ejection fraction (LVEF) is recommended by the American College of Cardiology (ACC) and American Heart Association (AHA) as standard of care for all breast cancer patients being considered for potentially cardiac-toxic treatment regimens.13,14 In addition, measurement …

Mechanical dyssynchrony evaluated by tissue Doppler cross-correlation analysis is associated with long-term survival in patients after cardiac resynchronization therapy

AIMS Pre-implant assessment of longitudinal mechanical dyssynchrony using cross-correlation analysis (XCA) was tested for association with long-term survival and compared with other tissue Doppler imaging (TDI)-derived indices. METHODS AND RESULTS In 131 patients referred for cardiac resynchronization therapy (CRT) from two international centres, mechanical dyssynchrony was assessed from TDI velocity curves using time-to-peak opposing wall delay (OWD) ≥80 ms, Yu index ≥32 ms, and the maximal activation delay (AD-max) >35 ms. AD-max was calculated by XCA of the TDI-derived myocardial acceleration curves. Outcome was a composite of all-cause mortality, cardiac transplantation, or implantation of a ventricular assist device (left ventricular assist device) and modelled using the Cox proportional hazards regression. Follow-up was truncated at 1460 days. Dyssynchrony by AD-max was independently associated with improved survival when adjusted for QRS > 150 ms and aetiology {hazard ratio (HR) 0.35 [95% confidence interval (CI) 0.16-0.77], P = 0.01}. Maximal activation delay performed significantly better than Yu index, OWD, and the presence of left bundle branch block (P < 0.05, all, for difference between parameters). In subgroup analysis, patients without dyssynchrony and QRS between 120 and 150 ms showed a particularly poor survival [HR 4.3 (95% CI 1.46-12.59), P < 0.01, compared with the group with dyssynchrony and QRS between 120 and 150 ms]. CONCLUSION Mechanical dyssynchrony assessed by AD-max was associated with long-term survival after CRT and was significantly better associated compared with other TDI-derived indices. Patients without dyssynchrony and QRS between 120 and 150 ms had a particularly poor prognosis. These results indicate a valuable role for XCA in selection of CRT candidates.

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].

Running on Empty: Cardiovascular Reserve Capacity and Late Effects of Therapy in Cancer Survivorship

Seminal investigations by Frank 1 and Starling 2 provided thefirst evidence that the heart possesses inherent reserve capacity—a key principle that is a pillar of modern cardiology research and practice. After 150 years of research, we now understand that cardiovascular reserve capacity (CVRC) is determined by the integrative ability of cross-system mechanisms (eg, neurohormonal, central, and peripheral oxygen delivery 3 ), which collectively possess remarkable adaptive capacity. Sequential as well as concurrent pathologic perturbations to either one or more of these mechanisms are offset by initial compensatory adaptive responses in other component systems to maintain whole-body homeostatic regulation—a process termed coordinated adaptation. 4 Unfortunately, CVRC is finite, and continued insults ultimately lead to overt dysfunction (eg, acute coronary syndromes, left ventricular dysfunction). Pathologic impairments in CVRC are etiologicinmanychronicdiseaseconditionsandarethusanintegralconsiderationindailypractice.Thepurposeofthiscommentaryistoprovidean overviewoftheguidingprinciplesandapplicationofCVRCintheoncology setting using early breast cancer as an illustrative model. Measurement of CVRC

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

Background Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF). Methods and Results We identified HFpEF cases, HFrEF controls, and no‐HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No‐HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long‐chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no‐HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance. Conclusions We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.

Effects of Nonlinear Aerobic Training on Erectile Dysfunction and Cardiovascular Function Following Radical Prostatectomy for Clinically Localized Prostate Cancer

UNLABELLED Erectile dysfunction (ED) is a major adverse effect of radical prostatectomy (RP). We conducted a randomized controlled trial to examine the efficacy of aerobic training (AT) compared with usual care (UC) on ED prevalence in 50 men (n=25 per group) after RP. AT consisted of five walking sessions per week at 55-100% of peak oxygen uptake (VO2peak) for 30-60 min per session following a nonlinear prescription. The primary outcome was change in the prevalence of ED, as measured by the International Index of Erectile Function (IIEF), from baseline to 6 mo. Secondary outcomes were brachial artery flow-mediated dilation (FMD), VO2peak, cardiovascular (CV) risk profile (eg, lipid profile, body composition), and patient-reported outcomes (PROs). The prevalence of ED (IIEF score ≤ 21) decreased by 20% in the AT group and by 24% in the UC group (difference: p=0.406). There were no significant between-group differences in any erectile function subscale (p>0.05). Significant between-group differences were observed for changes in FMD and VO2peak, favoring AT. There were no group differences in other markers of CV risk profile or PROs. In summary, nonlinear AT does not improve ED in men with localized prostate cancer in the acute period following RP. TRIAL REGISTRATION Clinicaltrials.gov identifier NCT00620932.

Exercise therapy as treatment for cardiovascular and oncologic disease after a diagnosis of early-stage cancer.

Advances in early detection and adjuvant therapy have led to dramatic improvements in longevity after a cancer diagnosis. As a result, there are ~13.7 million cancer survivors alive in the United States, with this figure projected to increase to 18 million in 2022. Despite improvements in the 5-year relative survival rates, cancer patients with early-stage disease not only remain at high risk of cancer recurrence but also have sufficient longevity to now be at risk for late effects of adjuvant therapy, particularly cardiovascular disease (CVD). Against this background, we review here the risk factors common to cancer and CVD as well as the extant evidence supporting the potential efficacy of exercise therapy to modify the risk of cancer-specific and CVD-specific mortality in persons with cancer. We also evaluate evidence from clinical studies investigating the effects of structured exercise therapy to modify risk factors common to cancer and CVD. Findings of this review indicate that several major biomarkers/risk factors are predictive of both recurrence as well as non-cancer mortality in persons diagnosed with cancer. Such information is important to health professionals providing disease-risk screening as well as informing effective management strategies in long-term cancer survivors. In terms of the latter, there is growing but preliminary evidence that exercise may be efficacious in lowering both recurrence and CVD risk in cancer patients.

Safety and Efficacy of Aerobic Training in Patients With Cancer Who Have Heart Failure: An Analysis of the HF-ACTION Randomized Trial

PURPOSE To investigate the efficacy and safety of aerobic training (AT) in patients with cancer with medically stable heart failure (HF). PATIENTS AND METHODS A retrospective analysis of 90 patients with cancer who have HF and who were randomly assigned to AT (n = 47) or guideline-based usual care (UC; n = 43) was performed. AT consisted of three supervised sessions per week at 20 to 45 minutes per session at 60% to 70% of heart rate reserve for 12 weeks followed by home-based sessions for 4 to 12 months. The primary end point was all-cause mortality and hospitalization. Secondary end points were other clinical events, safety, and change in exercise capacity (VO(2peak)) and health-related quality of life (HRQOL). RESULTS Median follow-up was 35 months. In intention-to-treat (ITT) analyses, all-cause mortality or hospitalization at 2 years was 74% in the AT group compared with 67% in the UC group (adjusted hazard ratio [HR], 1.11; 95% CI, 0.69 to 1.77; P = .676). The incidence of cardiovascular mortality or cardiovascular hospitalization was significantly higher in the AT group compared with the UC group (41% v 67%; adjusted HR, 1.94; 95% CI, 1.12 to 3.16; P = .017). There were no differences in any VO(2peak) or HRQOL end points. In post hoc analyses based on adherence to AT, all-cause mortality and hospitalization was 66% in adherent patients (≥ 90 minutes per week) compared with 84% in nonadherent patients (< 90 minutes per week). CONCLUSION In ITT analyses, AT did not improve clinical outcomes in patients with cancer who had HF. Post hoc analyses suggested that patients not capable of adhering to the planned AT prescription may be at increased risk of clinical events.

Relationship Between Cancer and Cardiovascular Outcomes Following Percutaneous Coronary Intervention

Background Cardiovascular disease and cancer increasingly coexist, yet relationships between cancer and long-term cardiovascular outcomes post–percutaneous coronary intervention (PCI) are not well studied. Methods and Results We examined stented PCI patients at Duke (1996–2010) using linked data from the Duke Information Systems for Cardiovascular Care and the Duke Tumor Registry (a cancer treatment registry). Our primary outcome was cardiovascular mortality. Secondary outcomes included composite cardiovascular mortality, myocardial infarction, or repeat revascularization and all-cause mortality. We used adjusted cause-specific hazard models to examine outcomes among cancer patients (cancer treatment pre-PCI) versus controls (no cancer treatment pre-PCI). Cardiovascular mortality was explored in a cancer subgroup with recent (within 1 year pre-PCI) cancer and in post-PCI cancer patients using post-PCI cancer as a time-dependent variable. Among 15 008 patients, 3.3% (n=496) were cancer patients. Observed rates of 14-year cardiovascular mortality (31.4% versus 27.7%, P=0.31) and composite cardiovascular death, myocardial infarction, or revascularization (51.1% versus 55.8%, P=0.37) were similar for cancer versus control groups; all-cause mortality rates were higher (79.7% versus 49.3%, P<0.01). Adjusted risk of cardiovascular mortality was similar for cancer patients versus controls (hazard ratio 0.95; 95% CI 0.76 to 1.20) and for patients with versus without recent cancer (hazard ratio 1.46; 95% CI 0.92 to 2.33). Post-PCI cancer, present in 4.3% (n=647) of patients, was associated with cardiovascular mortality (adjusted hazard ratio 1.51; 95% CI 1.11 to 2.03). Conclusions Cancer history was present in a minority of PCI patients but was not associated with worse long-term cardiovascular outcomes. Further investigation into PCI outcomes in this population is warranted.