Background RADICAL PC-2 (RAndomizeD Intervention for CArdiovascular and Lifestyle Risk Factors in Prostate Cancer Patients) was a pragmatic randomized controlled trial that tested whether routine referral to a cardiologist or an internist for cardiovascular (CV) risk-factor and lifestyle modification improves outcomes in patients with prostate cancer or receiving androgen-deprivation therapy. The intervention group had more favorable outcomes overall, driven by improved cholesterol control, with no differences in rates of CV death, myocardial infarction (MI), stroke, or heart failure (HF). Objectives The authors aim to identify patient subgroups more likely to benefit from routine CV care referral. Methods Prespecified subgroup analyses were used to assess whether patients at higher CV risk derived greater benefit from specialist referral, with treatment-effect heterogeneity assessed using interaction tests. The first primary outcome was a hierarchical composite of CV death, MI, stroke, HF, suboptimal cholesterol, and systolic blood pressure (SBP) control, evaluated using the win ratio. The second primary outcome was time to CV death, MI, stroke, or HF. Results Among 2487 participants, treatment effect differed by baseline total cholesterol ≤4 mmol/L vs >4 mmol/L (interaction P = 0.016), with respective win ratios of 1.21 (95% CI: 0.89-1.64) and 1.75 (95% CI: 1.51-2.03), and by baseline BP status (SBP ≥130 mm Hg or diastolic BP ≥80 mm Hg vs BP <130/80 mm Hg; interaction P = 0.003), with respective subdistribution HRs (sHRs) for CV death, MI, stroke, or HF of 0.86 (95% CI: 0.61-1.21) and 4.85 (95% CI: 1.65-14.26). The interaction for diabetes did not reach statistical significance (interaction P = 0.054) although the intervention effect estimates suggested a potential difference by diabetes status, with sHRs of 0.53 (95% CI: 0.24-1.15) among participants with diabetes and 1.25 (95% CI: 0.88-1.78) among participants without diabetes. The win ratio was higher among participants with total cholesterol >4 mmol/L, and sHRs were numerically lower among those with SBP ≥130 mm Hg or diastolic BP ≥80 mm Hg and diabetes. Conclusions Uncontrolled modifiable CV risk factors may identify patients with prostate cancer who are more likely to benefit from routine CV care referral.
Anthracyclines such as doxorubicin remain central to cancer therapy, but their clinical utility is constrained by dose-limiting cardiotoxicity and long-term cardiovascular sequelae. Although traditionally attributed to cardiomyocyte-intrinsic mechanisms, including mitochondrial dysfunction, oxidative stress, and DNA damage, emerging evidence demonstrates that these initial injuries rapidly activate the immune system, transforming doxorubicin-induced cardiotoxicity (DIC) into a multicellular inflammatory process. Release of mitochondrial and nuclear danger signals triggers innate immune pathways and recruitment of neutrophils, monocytes, and lymphocytes, whose sustained activation promotes maladaptive remodeling, fibrosis, and chronic dysfunction. Conversely, specific immune subsets exert context-dependent cardioprotective effects, underscoring the dual role of immune responses in disease progression. This review frames DIC within a cardioimmunology paradigm, highlighting the intersection of mitochondrial stress, sterile inflammation, and adaptive immunity across acute and chronic phases of injury. We discuss emerging therapeutic strategies that extend beyond cardiomyocyte protection, including immune recalibration rather than broad immunosuppression, immune-targeted interventions, and biomarker-guided monitoring, to enable mechanism-based, individualized cardioprotection without compromising anticancer efficacy.
BACKGROUND:Immune checkpoint inhibitor (ICI) myocarditis typically develops soon after treatment initiation (<90 days) but may also occur as a delayed complication after discontinuation of ICI therapy. The clinical and histopathologic differences between early- and late-manifestation ICI myocarditis remain unclear. OBJECTIVES:This study sought to compare the clinical features and myocardial histopathology of early- versus late-manifestation ICI myocarditis. METHODS:We conducted a retrospective national cohort study of patients diagnosed with myocarditis after ICI initiation who underwent endomyocardial biopsy. Biopsy samples were analyzed for inflammatory cell infiltration, severity of myocardial inflammation, and collagen volume fraction. RESULTS:Among 35 patients (mean age: 66 ± 13 years; 71.4% male), 26 (74.3%) developed early-manifestation myocarditis (<90 days), whereas 9 (25.7%) had late-manifestation myocarditis (≥90 days). Early-manifestation cases showed significantly more severe myocardial inflammation; higher levels (median [Q1-Q3]) of CD3+ T cells (432 [173-1,381] vs 121 [43-400] cells/mm2; P = 0.036), CD8+ T cells (289 [73-994] vs 86 [21-168] cells/mm2; P = 0.019), and CD 68+ macrophages (307 [116-841] vs 57 [36-200] cells/mm2; P = 0.008); and higher CD4+ T-cell levels that did not reach statistical significance (P = 0.054). There were no significant differences in regulatory T cells or collagen volume. Clinically, early-manifestation myocarditis was characterized by higher cardiac biomarker levels and older age, whereas left ventricular ejection fraction was similar between groups. Mortality due to myocarditis occurred in 2 early-manifestation cases and in no late-manifestation cases. Conversely, cancer-related mortality was more frequent in the late-manifestation group (n = 3) than in the early-manifestation group (n = 2). ICI therapy was reinitiated in only 2 patients overall. CONCLUSIONS:Late-manifestation ICI myocarditis may represent a temporally distinct or partially attenuated inflammatory phase. Despite a milder inflammatory profile, higher cancer-related mortality was observed, suggesting that cautious ICI reinitiation may warrant consideration in selected patients within this subgroup.
