Radiation-Induced Cardiovascular Disease: Mechanisms, Prevention, and Treatment.

PURPOSE OF REVIEW: Despite the advancements of modern radiotherapy, radiation-induced cardiovascular disease (RICVD) remains a common cause of morbidity and mortality among cancer survivors. RECENT FINDINGS: Proposed pathogenetic mechanisms of RICVD include endothelial cell damage with accelerated atherosclerosis, pro-thrombotic alterations in the coagulation pathway as well as inflammation and fibrosis of the myocardial, pericardial, valvular, and conduction tissues. Prevention of RICVD can be achieved by minimizing the exposure of the cardiovascular system to radiation, by treatment of underlying cardiovascular risk factors and cardiovascular disease, and possibly by prophylactic pharmacotherapy post exposure. Herein we summarize current knowledge on the mechanisms underlying the pathogenesis of RICVD and propose prevention and treatment strategies.

Myocardial Dysfunction in Patients with Cancer.

Myocardial dysfunction in patients with cancer is a major cause of morbidity and mortality. Cancer therapy-related cardiotoxicities are an important contributor to the development of cardiomyopathy in this patient population. Furthermore, cardiac AL amyloidosis, cardiac malignancies/metastases, accelerated atherosclerosis, stress cardiomyopathy, systemic and pulmonary hypertension are also linked to the development of myocardial dysfunction. Herein, we summarize current knowledge on the mechanisms of myocardial dysfunction in the setting of cancer and cancer-related therapies. Additionally, we briefly outline key recommendations on the surveillance and management of cancer therapy-related myocardial dysfunction based on the consensus of experts in the field of cardio-oncology.

Modern Radiotherapy and Risk of Cardiotoxicity.

Despite the advancements of modern radiotherapy, radiation-induced heart disease remains a common cause of morbidity and mortality amongst cancer survivors. This review outlines the basic mechanism, clinical presentation, risk stratification, early detection, possible mitigation, and treatment of this condition.

Cardiovascular manifestations of Erdheim-Chester disease.

INTRODUCTION: Erdheim-Chester disease is a rare, multisystem hematologic disease. Cardiovascular involvement is seen in patients with Erdheim-Chester disease and can lead to increased morbidity and mortality. In this series, we report various cardiovascular manifestations of patients with Erdheim-Chester disease. METHODS: This study includes patients with Erdheim-Chester disease who were referred to our institution from 12/3/2009 through 12/13/2017. All patients had biopsy-proven Erdheim-Chester disease. Clinical data, multimodality imaging, and cardiac tests were reviewed. RESULTS: Cardiovascular findings in 24 patients with Erdheim-Chester disease were included in the study. We reviewed available transthoracic echocardiograms, whole body PET/CT scans, and CMR studies. Most patients were male and mean age at the time of diagnosis was 58 years. Pericardial involvement (13%), myocardial infiltration (25%), endocardial involvement (4%), valvular disease (17%), aortic/vascular disease (17%), conduction system infiltration (8%), and coronary artery disease (25%) were present. At a median follow-up of 5.5 years, mortality was 17%. CONCLUSIONS: Erdheim-Chester disease can involve various cardiovascular structures and is frequently diagnosed on an imaging modality. Some patients had asymptomatic involvement, but others presented with ischemic heart disease, heart failure, valvular disease, and conduction system abnormalities. Early recognition of cardiovascular involvement of Erdheim-Chester disease is needed because of high morbidity and mortality.

Carcinoid Heart Disease: a Comprehensive Review.

PURPOSE OF REVIEW: Carcinoid heart disease is a rare disorder that is associated with significant morbidity and mortality. In this review of the literature, we will present current concepts in diagnosis and management of carcinoid heart disease. RECENT FINDINGS: Recent expert consensus guidelines highlight the role of echocardiography and screening with NT-proBNP for the evaluation of carcinoid heart disease. Advances in medical therapy along with better surgical outcomes highlight the experience and expertise that has been gained in the treatment of carcinoid heart disease. Carcinoid heart disease occurs in patients with neuroendocrine tumors who have carcinoid syndrome. Serotonin appears to play a central role in the development of carcinoid heart disease. Cardiac biomarkers and multimodality imaging can be used to aid in screening and diagnosis. The mainstay of treatment of carcinoid heart disease is surgery.

Chemotherapeutic Agents and the Risk of Ischemia and Arterial Thrombosis.

PURPOSE OF REVIEW: Numerous chemotherapeutic agents have been associated with the development of ischemia and arterial thrombosis. As newer therapies have been developed to treat cancer, some of these chemotherapy drugs have been implicated in the development of vascular disease. In this review, we will summarize the most common chemotherapeutic drug classes that may play a role in the development of ischemic heart disease. RECENT FINDINGS: Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors have a number of cardiovascular toxicities. The possible mechanisms of action of these drugs leading to ischemic complications are varied but include endothelial dysfunction, platelet aggregation, reduced levels of nitrous oxide (NO), and elevated levels of reactive oxygen species (ROS), and vasospasm. While some drugs act through multiple pathways that result in the development of ischemic heart disease, others such as the antimetabolites and antimicrotubules appear to primarily cause vasospasm. Furthermore, while aromatase inhibitors increase the risk of heart disease in comparison to tamoxifen in large studies, this finding likely occurs because of a protective role of tamoxifen on cardiovascular risk factors rather than a direct effect of aromatase inhibitors. Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors can lead to ischemic complications in patients with cancer. Many of these drugs have proven to be effective in improving cancer prognosis, but their possible cardiovascular effects have to be carefully monitored and treated. Treatment of ischemic complications in the setting of cancer therapy should focus on the optimal medical management of known cardiovascular risk factors and follow an evidence-based approach.

Evolution of echocardiography in subclinical detection of cancer therapy-related cardiac dysfunction.

Cancer therapies have resulted in increased survivorship in oncological patients. However, the benefits have been marred by the development of premature cardiovascular disease. The current definition outlines measurement of ejection fraction as a mean to diagnose cancer therapeutic-related cardiac dysfunction (CTRCD); however, up to 58% of the patients do not regain their cardiac function after the CTRCD diagnosis, despite therapeutic interventions. Therefore, there has been a growing interest in the markers for early myocardial changes (ie, changes with normal left ventricular ejection fraction [LVEF]) that may predict the development of subsequent left ventricular ejection fraction reduction or progression to heart failure. This review will highlight the use of diastolic parameters, tissue Doppler imaging (TDI), and speckle tracking echocardiogram (STE) as emerging technologies which can potentially detect cardiac dysfunction thereby stratifying patients for cardioprotective therapies. The goal of this manuscript was to highlight the concepts and discuss the current controversies surrounding these echocardiographic imaging modalities.

"Bringing on the light" in a complex clinical scenario: Optical coherence tomography-guided discontinuation of antiplatelet therapy in cancer patients with coronary artery disease (PROTECT-OCT registry).

BACKGROUND: Cancer patients with recently placed drug-eluting stents (DESs) often require premature dual antiplatelet therapy (DAPT) discontinuation for cancer-related procedures. Optical coherence tomography (OCT) can identify risk factors for stent thrombosis such as stent malapposition, incomplete strut coverage and in-stent restenosis and may help guide discontinuation of DAPT. METHODS: We conducted a single-center prospective study in cancer patients with recently placed (1-12 months) DES who required premature DAPT discontinuation. Patients were evaluated with diagnostic coronary angiogram and OCT. Individuals with appropriate stent strut coverage, expansion, apposition, and absence of in-stent restenosis or intraluminal masses were considered low risk and transiently discontinued DAPT to allow optimal cancer therapy. Patients who did not meet all these criteria were considered high risk and underwent further endovascular treatment when appropriate and bridging with low-molecular weight heparin. The incidence of adverse cardiovascular events was assessed after the procedure and at 12 months. RESULTS: A total of 40 patients were included. Twenty-seven patients (68%) were considered low risk by OCT criteria and DAPT was transiently discontinued. Thirteen patients (32%) were considered high risk with one or more OCT findings: uncovered stent struts (4 patients, 10%); stent underexpansion (3 patients, 8%); malapposition (8 patients, 20%); in-stent restenosis (2 patients, 5%). The high-risk patients with uncovered stent struts and malapposition underwent additional stent dilatation. There were no cardiovascular events in the low-risk group. One myocardial infarction occurred in the high-risk group. Fourteen non-cardiac deaths were registered before 12 months due to cancer progression or cancer therapy. CONCLUSION: OCT imaging allows identification of low-risk cancer patients with DES placed who may safely discontinue DAPT and proceed with cancer-related surgery or procedures.

Radiation-Induced Cardiovascular Disease.

PURPOSE OF REVIEW: Thoracic radiation therapy is an effective treatment for several malignancies, such as Hodgkin's lymphoma and breast cancer. Over the years, however, the incidence of cardiovascular events has increased in these patients, notably in younger survivors who do not have traditional risk factors. This review summarizes the pathology, incidence, clinical presentation, and management of cardiac events after radiation therapy. RECENT FINDINGS: Mediastinal radiation therapy accelerates the atherosclerosis process, resulting in early onset coronary artery disease. Valvular disease due to radiation therapy typically affects the left-sided valves, with aortic regurgitation being the most common. Rarely, it may lead to aortic stenosis requiring surgical interventions. Pericardial involvement includes acute and chronic pericardial disease and pericardial effusion. New studies are investigating the prevalence and pathogenesis of autonomic dysfunction in cancer survivors who have undergone mediastinal and neck radiation. Radiation therapy itself causes vascular endothelial dysfunction, resulting in clinical cardiovascular events, manifesting many years after completion of therapy. There remains little guidance regarding screening and therapies to prevent cardiovascular events in this population.

Predictors of left ventricular systolic function recovery in the setting of sinus tachycardia in patients with cancer.

OBJECTIVES: To identify unique echocardiographic features that could be used to reliably predict LVEF recovery upon resolution of sinus tachycardia in patients with cancer. BACKGROUND: Sinus tachycardia may be a manifestation of underlying cardiomyopathy or can lead to a reversible form of dilated cardiomyopathy known as tachycardia-mediated cardiomyopathy. While distinguishing the two can be challenging, predicting recovery regardless of cause can be of significant clinical importance in the cancer population. METHODS: Results of echocardiograms performed were collected. Patients with a repeat echocardiogram within 6 months of the initial echocardiogram were included. Patients with structural heart disease, acute coronary syndrome, sepsis, and pericardial disease were excluded. A comparison between baseline echocardiogram and subsequent echocardiogram was made to determine whether specific echocardiographic parameters predicted LVEF recovery. Two groups of patients were defined at the outset of the study. The recovered group was comprised of patients with reduced LVEF in the setting of sinus tachycardia and normal LVEF with resolution of tachycardia to normal sinus rhythm (NSR). The unrecovered group was comprised of subjects with low LVEF in the setting of both sinus tachycardia and NSR. RESULTS: A total of 40 patients were included in the study. LVEF in the recovered group (n=18) was 42.8% with sinus tachycardia and increased to 58.3% with NSR. Average LVEF in the unrecovered group (n=22) was 35.1% with tachycardia and improved to 38.5% with NSR. Medial TDI (E') was significantly greater in the recovered group with both tachycardia (7.95 cm/s versus 4.56 cm/s, P<.001) and NSR (8.11 cm/s versus 5.13 cm/s, P<.001). Similarly, lateral TDI (E') was significantly greater in the recovered group than in the unrecovered group during tachycardia (8.97 cm/s versus 5.13 cm/s, P<.001) and NSR (9.05 cm/s versus 5.13 cm/s, P<.001). Multivariable logistic regression analysis showed that medial TDI >6.5 cm/s (OR=30.9, P=.001) and lateral TDI >7.8 cm/s (OR=52.5, P=.002) are positively associated with the probability of LVEF recovery. CONCLUSIONS: In conclusion, TDI (medial E'>6.5 cm/s; lateral E'>7.8 cm/s) appears to predict LVEF recovery in patients with sinus tachycardia upon resolution of the tachycardia in patients with cancer.

Depression and Oropharynx Cancer Outcome.

BACKGROUND: Studies have shown a modest relationship between depression and mortality in patients with cancer. Our study addressed methodological weaknesses in the literature by restricting the sample to patients with one cancer type, adjusting for factors known to affect outcome, and following up patients for a sufficient period. METHODS: We prospectively followed patients newly diagnosed with squamous cell oropharyngeal cancer from the start of radiation therapy until death or until date of last clinical visit. All patients were optimally treated with radiation and sometimes chemotherapy. After adjusting for tumor stage, treatment, comorbidities, smoking, excessive alcohol use, and demographic factors, we assessed the effects of baseline self-reported depression on overall survival and recurrence. RESULTS: One hundred thirty participants were followed for a median of 5 years. The average age was 56 years, and 83% were male. Eighteen participants died during the study and 15 experienced disease recurrence. Self-reported depression was associated with decreased overall survival duration (hazard ratio = 3.6, 95% confidence interval = 1.2-10.8) and disease recurrence (hazard ratio = 3.8, 95% confidence interval = 1.2-12.2) in multivariate analysis. In addition, smoking was associated with disease recurrence. CONCLUSIONS: Patients with oropharyngeal cancer may benefit from depression screening and evidence-based treatments, if appropriate. Future studies are needed to determine whether depression is an independent prognostic factor of outcome and to elucidate biobehavioral mechanisms involved in patients with oropharyngeal cancer.

Radiation-related heart and vascular disease.

Improvement in cancer therapy has led to increasing number of cancer survivors, some of whom have previously been treated with mediastinal radiation. Cardiac complication may manifest years after completion of radiation therapy. Hence long-term follow-up is essential in these patients. In this paper, we have discussed the short- and long-term cardiovascular side effects of radiation therapy.

Elevated IL-6 and Tumor Necrosis Factor-α in Immune Checkpoint Inhibitor Myocarditis.

INTRODUCTION: The impact of peripheral cytokine levels on the prognosis and treatment of immune checkpoint inhibitor (ICI) myocarditis has not been well studied. OBJECTIVES: This study aimed to identify cytokines that can prognosticate and direct the treatment of ICI myocarditis. METHODS: This was a single-center, retrospective cohort study of patients with ICI myocarditis who had available peripheral cytokine levels between January 2011 and May 2022. Major adverse cardiovascular events (MACEs) were defined as a composite of heart failure with/without cardiogenic shock, arterial thrombosis, life-threatening arrhythmias, pulmonary embolism, and sudden cardiac death. RESULTS: In total, 65 patients with ICI myocarditis had cytokine data available. Patients were mostly males (70%), with a mean age of 67.8 ± 12.7 years. Interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) were the most common cytokines to be elevated with 48/65 (74%) of patients having a peak IL-6 above normal limits (>5 pg/mL) and 44/65 (68%) of patients with peak TNF-α above normal limits (>22 pg/mL). Patients with elevated peak IL-6 had similar 90-day mortality and MACE outcomes compared to those without (10.4% vs. 11.8%, p = 0.878 and 8.8% vs. 17.7%, p = 0.366, respectively). Similarly, those with elevated peak TNF-α had similar 90-day mortality and MACEs compared to those without (29.6% vs. 14.3%, p = 0.182 and 13.6% vs. 4.8%, p = 0.413, respectively). Kaplan-Meier survival analysis also showed that there was not a significant difference between MACE-free survival when comparing elevated and normal IL-6 and TNF-α levels (p = 0.182 and p = 0.118, respectively). MACEs and overall survival outcomes were similar between those who received infliximab and those who did not among all patients and those with elevated TNF-α (p-value 0.70 and 0.83, respectively). CONCLUSION: Peripheral blood levels of IL-6 and TNF-α are the most commonly elevated cytokines in patients with ICI myocarditis. However, their role in the prognostication and guidance of immunomodulatory treatment is currently limited.

Premature senescence and cardiovascular disease following cancer treatments: mechanistic insights.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality, especially among the aging population. The "response-to-injury" model proposed by Dr. Russell Ross in 1999 emphasizes inflammation as a critical factor in atherosclerosis development, with atherosclerotic plaques forming due to endothelial cell (EC) injury, followed by myeloid cell adhesion and invasion into the blood vessel walls. Recent evidence indicates that cancer and its treatments can lead to long-term complications, including CVD. Cellular senescence, a hallmark of aging, is implicated in CVD pathogenesis, particularly in cancer survivors. However, the precise mechanisms linking premature senescence to CVD in cancer survivors remain poorly understood. This article aims to provide mechanistic insights into this association and propose future directions to better comprehend this complex interplay.

Predictors of Recurrence and Survival in Cancer Patients With Pericardial Effusion Requiring Pericardiocentesis.

Aim: This study investigated the factors predicting survival and the recurrence of pericardial effusion (PE) requiring pericardiocentesis (PCC) in patients with cancer. Materials and Methods: We analyzed the data of patients who underwent PCC for large PEs from 2010 to 2020 at The University of Texas MD Anderson Cancer Center. The time to the first recurrent PE requiring PCC was the interval from the index PCC with pericardial drain placement to first recurrent PE requiring drainage (either repeated PCC or a pericardial window). Univariate and multivariate Fine-Gray models accounting for the competing risk of death were used to identify predictors of recurrent PE requiring drainage. Cox regression models were used to identify predictors of death. Results: The study cohort included 418 patients with index PCC and pericardial drain placement, of whom 65 (16%) had recurrent PEs requiring drainage. The cumulative incidences of recurrent PE requiring drainage at 12 and 60 months were 15.0% and 15.6%, respectively. Younger age, anti-inflammatory medication use, and solid tumors were associated with an increased risk of recurrence of PE requiring drainage, and that echocardiographic evidence of tamponade at presentation and receipt of immunotherapy were associated with a decreased risk of recurrence. Factors predicting poor survival included older age, malignant effusion on cytology, non-use of anti-inflammatory agents, non-lymphoma cancers and primary lung cancer. Conclusion: Among cancer patients with large PEs requiring drainage, young patients with solid tumors were more likely to experience recurrence, while elderly patients and those with lung cancer, malignant PE cytology, and non-use of anti-inflammatory agents showed worse survival.

The Impact of Radiation Dose to Heart Substructures on Major Coronary Events and Patient Survival after Chemoradiation Therapy for Esophageal Cancer.

Background: There is a paucity of data regarding the association between radiation exposure of heart substructures and the incidence of major coronary events (MCEs) in patients with esophageal cancer (ESOC) undergoing chemoradiation therapy. We studied radiation dosimetric determinants of MCE risk and measured their impact on patient prognosis using a cohort of ESOC patients treated at a single institution. Methods: Between March 2005 and October 2015, 355 ESOC patients treated with concurrent chemoradiotherapy were identified from a prospectively maintained and institutional-regulatory-board-approved clinical database. Dose-distribution parameters of the whole heart, the atria, the ventricles, the left main coronary artery, and three main coronary arteries were extracted for analysis. Results: Within a median follow-up time of 67 months, 14 patients experienced MCEs at a median of 16 months. The incidence of MCEs was significantly associated with the left anterior descending coronary artery (LAD) receiving ≥30 Gy (V30Gy) (p = 0.048). Patients receiving LAD V30Gy ≥ 10% of volume experienced a higher incidence of MCEs versus the LAD V30Gy < 10% group (p = 0.044). The relative rate of death increased with the left main coronary artery (LMA) mean dose (Gy) (p = 0.002). Furthermore, a mutual promotion effect of hyperlipidemia and RT on MCEs was observed. Conclusion: Radiation dose to coronary substructures is associated with MCEs and overall survival in patients with ESOC. In this study, the doses to these substructures appeared to be better predictors of toxicity outcomes than mean heart dose (MHD) or whole-heart V30Gy. These findings have implications for reducing coronary events through radiation therapy planning.

Acute coronary syndrome in patients with cancer.

INTRODUCTION: Improvement in cancer survival has led to an increased focus on cardiovascular disease as the other major determinant of survivorship. As a result, there has been an increasing interest in managing cardiovascular disease during and post cancer treatment. AREAS COVERED: This article reviews the current literature on the pathogenesis, risk factors, presentation, treatment and clinical outcomes of acute coronary syndrome (ACS) in patients with cancer. EXPERT OPINION: There is growing evidence that both medical therapy and invasive management of ACS improve outcomes in patients with cancer. Appropriate patient selection, risk stratification and tailored therapy represents the cornerstone of management in these patients.

Evaluation of contemporary echocardiographic and histomorphology parameters in predicting mortality in patients with endomyocardial biopsy-proven cardiac AL amyloidosis.

Introduction: This study examined the role of echocardiographic and cardiac histomorphology parameters in predicting mortality in patients with cardiac AL amyloidosis. Methods: Patients with endomyocardial biopsy-proven cardiac AL amyloidosis treated at MD Anderson Cancer Center between 6/2011 and 6/2020 were identified. Stored echocardiographic images and endomyocardial biopsy samples were processed for myocardial strain analysis and a detailed histomorphology characterization. Results: Of 43 patients; 44% were women and 63% white. Median age was 65 years; 51% underwent stem cell transplantation (SCT). Thirty patients (70%) died during follow up (median follow up: 4.1 years). Lower LA strain (<13.5%) and absence of SCT as a time-varying covariate were significantly associated with increased risk of death in the multivariate cox regression analysis. Higher LV mass and lower RV tricuspid annular plane systolic excursion were associated with increased odds of having ≥5% interstitial amyloid deposition on biopsy in the multivariate logistic regression analysis. Conclusion: Lower LA strain independently predicted mortality in our cohort, and its performance in the routine assessment of AL amyloidosis may be beneficial. Furthermore, SCT for cardiac AL amyloidosis was associated with improved OS. These findings need to be confirmed by larger studies in the era of contemporary systemic therapies.

Artificial intelligence-augmented analysis of contemporary procedural, mortality, and cost trends in carcinoid heart disease in a large national cohort with a focus on the "forgotten pulmonic valve".

Background: Carcinoid heart disease is increasingly recognized and challenging to manage due to limited outcomes data. This is the largest known cohort study of valvular pathology, treatment (including pulmonary and tricuspid valve replacements [PVR and TVR]), dispairties, mortality, and cost in patients with malignant carcinoid tumor (MCT). Methods: Machine learning-augmented propensity score-adjusted multivariable regression was conducted for clincal outcomes in the 2016-2018 U.S. National Inpatient Sample (NIS). Regression models were weighted by the complex survey design and adjusted for known confounders and the likelihood of undergoing valvular procedures. Results: Among 101,521,656 hospitalizations, 55,910 (0.06%) had MCT. Patients with MCT vs. those without had significantly higher inpatient mortality (2.93 vs. 2.04%, p = 0.002), longer mean length of stay (12.20 vs. 4.62, p < 0.001), and increased mean total cost of stay ($70,252.18 vs. 51,092.01, p < 0.001). There was a step-wise increased rate of TVR and PVR with each subsequent year, with significantly more TV (0.16% vs. 0.01, p < 0.001) and PV (0.03 vs. 0.00, p = 0.040) diagnosed with vs. without MCT for 2016, with comparable trends in 2017 and 2018. There were no significant procedural disparities among patients with MCT for sex, race, income, urban density, or geographic region, except in 2017, when the highest prevalence of PV procedures were performed in the Western North at 50.00% (p = 0.034). In machine learning and propensity score augmented multivariable regression, MCT did not significantly increase the likelihood of TVR or PVR. In sub-group analysis restricted to MCT, neither TVR nor PVR significantly increased mortality, though it did increase cost (respectively, $141,082.30, p = 0.015; $355,356.40, p = 0.012). Conclusion: This analysis reflects a favorable trend in recognizing the need for TVR and PVR in patients with MCT, with associated increased cost but not mortality. Our study also suggests that pulmonic valve pathology is increasingly recognized in MCT as reflected by the upward trend in PVRs. Further research and updated societal guidelines may need to focus on the "forgotten pulmonic valve" to improve outcomes and disparities in this understudied patient population.

Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications.

Numerous studies have revealed the critical role of premature senescence induced by various cancer treatment modalities in the pathogenesis of aging-related diseases. Senescence-associated secretory phenotype (SASP) can be induced by telomere dysfunction. Telomeric DNA damage response induced by some cancer treatments can persist for months, possibly accounting for long-term sequelae of cancer treatments. Telomeric DNA damage-induced mitochondrial dysfunction and increased reactive oxygen species production are hallmarks of premature senescence. Recently, we reported that the nucleus-mitochondria positive feedback loop formed by p90 ribosomal S6 kinase (p90RSK) and phosphorylation of S496 on ERK5 (a unique member of the mitogen-activated protein kinase family that is not only a kinase but also a transcriptional co-activator) were vital signaling events that played crucial roles in linking mitochondrial dysfunction, nuclear telomere dysfunction, persistent SASP induction, and atherosclerosis. In this review, we will discuss the role of NAD+ depletion in instigating SASP and its downstream signaling and regulatory mechanisms that lead to the premature onset of atherosclerotic cardiovascular diseases in cancer survivors.