Atherosclerosis and the Bidirectional Relationship between Cancer and Cardiovascular Disease: From Bench to Bedside-Part 1.

Atherosclerosis, a complex metabolic-immune disease characterized by chronic inflammation driven by the buildup of lipid-rich plaques within arterial walls, has emerged as a pivotal factor in the intricate interplay between cancer and cardiovascular disease. This bidirectional relationship, marked by shared risk factors and pathophysiological mechanisms, underscores the need for a comprehensive understanding of how these two formidable health challenges intersect and influence each other. Cancer and its treatments can contribute to the progression of atherosclerosis, while atherosclerosis, with its inflammatory microenvironment, can exert profound effects on cancer development and outcomes. Both cancer and cardiovascular disease involve intricate interactions between general and personal exposomes. In this review, we aim to summarize the state of the art of translational data and try to show how oncologic studies on cardiotoxicity can broaden our knowledge of crucial pathways in cardiovascular biology and exert a positive impact on precision cardiology and cardio-oncology.

Corrigendum: Cancer survivorship at heart: a multidisciplinary cardio-oncology roadmap for healthcare professionals.

[This corrects the article DOI: 10.3389/fcvm.2023.1223660.].

Cancer survivorship at heart: a multidisciplinary cardio-oncology roadmap for healthcare professionals.

In cancer, a patient is considered a survivor from the time of initial diagnosis until the end of life. With improvements in early diagnosis and treatment, the number of cancer survivors (CS) has grown considerably and includes: (1) Patients cured and free from cancer who may be at risk of late-onset cancer therapy-related cardiovascular toxicity (CTR-CVT); (2) Patients with long-term control of not-curable cancers in whom CTR-CVT may need to be addressed. This paper highlights the importance of the cancer care continuum, of a patient-centered approach and of a prevention-oriented policy. The ultimate goal is a personalized care of CS, achievable only through a multidisciplinary-guided survivorship care plan, one that replaces the fragmented management of current healthcare systems. Collaboration between oncologists and cardiologists is the pillar of a framework in which primary care providers and other specialists must be engaged and in which familial, social and environmental factors are also taken into account.

[Hormone therapy, cardio-metabolic profile, and cardiotoxicity. Still a dark side of cardio-oncology - Part 2: Prostate cancer]. / Terapia ormonale, assetto cardio-metabolico e cardiotossicità. Il lato ancora oscuro della cardioncologia ­ Parte 2: Tumore della prostata.

Hormone therapies (HTs) with anti-androgenic properties are a cornerstone for the treatment of prostate cancer (PC) and have significantly improved the survival of patients, though exposing them to a higher risk of cardiovascular diseases (CVDs), which represent a major cause of morbidity and mortality. This occurs due to the high average age of patients undergoing HT for PC, an age group in which CVDs have a high prevalence and incidence, and due to the type and duration of HTs that are increasingly effective but at the same time more aggressive towards cardiovascular health. Recent evidence from the real world suggests, however, that the cardiometabolic risk is widely underestimated and undertreated with significant impact also on the oncological prognosis. In the light of the results of the PRONOUNCE study, in this review it is emphasized the need for a multidisciplinary management of patients with PC who are candidate for or treated with HT by implementing a personalized treatment program in accordance with the current European guidelines on CVD prevention.

Cardiovascular Effects of Immune Checkpoint Inhibitors: More Than Just Myocarditis.

PURPOSE OF REVIEW: Immune checkpoint inhibitors have reshaped the treatment of cancer, but they are characterized by peculiar toxicity consisting of immune-related adverse events that may potentially affect any organ or system. In this review, we summarize data on clinical presentation, diagnosis, pathogenesis, and management of the main immune-related cardiovascular toxicities of immune checkpoint inhibitors. RECENT FINDINGS: The most relevant immune-related cardiovascular toxicity is myocarditis, but other non-negligible reported events include non-inflammatory heart failure, conduction abnormalities, pericardial disease, and vasculitis. More recently, growing evidence suggests a role for immune checkpoint inhibitors in accelerating atherosclerosis and promoting plaque inflammation, thus leading to myocardial infarction. Immune checkpoint inhibitors are associated with several forms of cardiovascular toxicity; thus, an accurate cardiovascular baseline evaluation and periodical monitoring are required. Furthermore, the optimization of cardiovascular risk factors before, during, and after treatment may contribute to mitigating both short-term and long-term cardiovascular toxicity of these drugs.

Corrigendum: Cardio-oncology in the COVID Era (Co & Co): The never-ending story.

[This corrects the article DOI: 10.3389/fcvm.2022.821193.].

Prognostic Stratification of Clinically Stable Patients with Heart Failure by Echocardiographic Pressure/Volume Loop Model.

BACKGROUND: Pressure/volume (P/V) loops provide useful information on left ventricular performance and prognosis in patients with heart failure (HF) but do not lend themselves to routine clinical practice. The authors developed a noninvasive method to compute individualized P/V loops to predict adverse clinical outcomes in patients with stable HF, which the authors believe can be used clinically. METHODS: A derivation cohort (n = 443 patients) was used to develop an echocardiography P/V loop model, using brachial arterial pressure and trans-thoracic two-dimensional Doppler echocardiographic data. Each patient's P/V loop was depicted as an irregular pentagon, and a centroid was derived for each loop. The centroid distance (CD) from a reference centroid (derived from 101 healthy control subjects) was computed. This model was prospectively applied to 435 patients who constituted the validation cohort. The study end point was a composite of cardiac death or hospitalization for HF among study patients. RESULTS: In the derivation cohort, CD was threefold greater among patients who experienced adverse events than those who did not. During a follow-up period of 30 months (15-45 months), event rates were 35% (72 of 206 patients) and 12% (29 of 237 patients P < .001), respectively, among patients with CD > 33 mL/mm Hg and those with CD ≤33 mL/mm Hg (prognostic cutoff derived by receiver operating characteristic analysis). Multivariate Cox analysis identified CD as an independent predictor of adverse outcome (hazard ratio, 1.61; 95% CI, 1.03-2.50) independently of left ventricular end-diastolic volume, pulmonary capillary wedge pressure, and left ventricular ejection fraction. These conclusions were confirmed in the validation cohort. CONCLUSIONS: The authors propose a method to create a noninvasive P/V loop and its centroid. These data provide useful pathophysiologic and prognostic information in patients with HF.

Trends in Incidence and Mortality of Kidney Cancer in a Northern Italian Province: An Update to 2020.

The aim of this study was to examine the incidence and mortality trends for tumors and cardiovascular disease (CVD) in a province of northern Italy. The study included kidney cancers recorded in the period 1996−2020, divided by sex, age, year of incidence and years from diagnosis. The standardized incidence rate was calculated using the European population, and the Annual Percent Change (APC) was reported. In total, 2331 patients with kidney cancers were identified, mainly males (1504 cases) aged 60−79 years (1240 cases). There were 1257 deaths; there were no differences according sex but there were differences according to age (12.1% among younger adults and 80.4% among 80+). The incidence rate increased in males between 1996 and 2011 (APC = 2.3), while the mortality rate decreased in both males (APC = −3.3%) and females (APC = −4.5%). Comparing the same periods, kidney cancer-specific mortality decreased from 81.8% to 43.7%, while in the same period there was an increasing trend for CVD mortality. Moreover, the risk of CVD mortality increased as we moved away from the diagnosis (from 6.2% to 27.5%, p < 0.01). The same trend was observed for other causes of death (from 12.6% to 32.1%, p < 0.01). Thus, a multidisciplinary approach seems necessary during the follow-up and treatments of patients with kidney cancer.

Corrigendum: Cardio-Oncology in the COVID Era (Co & Co): The Never Ending Story.

[This corrects the article DOI: 10.3389/fcvm.2022.821193.].

Corrigendum: Portrait of Italian Cardio-Oncology: Results of a Nationwide Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) Survey.

[This corrects the article DOI: 10.3389/fcvm.2021.677544.].

[Hormone therapy, cardio-metabolic profile and cardiotoxicity. Still a dark side of cardio-oncology. Part 1: Breast cancer]. / Terapia ormonale, assetto cardio-metabolico e cardiotossicità. Il lato ancora oscuro della cardioncologia ­ Parte 1: Cancro della mammella.

Hormone therapy with anti-estrogenic purposes is a cornerstone in breast cancer therapy that expresses estrogen receptors, the most frequent immunohistotype among invasive breast cancer. Hormone therapy is administered for a long time and affects the cardio-metabolic profile with possible interactions with the woman's intrinsic cardiovascular risk and the cardiotoxic effects of other treatments (chemotherapy, radiotherapy, target therapy). In this review, we analyze the pathophysiological implications and cardiovascular effects of hormone therapy providing useful elements for the creation of a personalized management program based on the "stepwise approach" as recommended by the 2021 cardiovascular disease prevention guidelines of the European Society of Cardiology and on the possible use of new antidiabetic drugs potentially useful for the management of the metabolic syndrome.

Cardio-Oncology in the COVID Era (Co & Co): The Never Ending Story.

The pathophysiology of some non-communicable diseases (NCDs) such as hypertension, cardiovascular disease (CVD), diabetes, and cancer includes an alteration of the endothelial function. COVID-19 is a pulmonary and vascular disease with a negative impact on patients whose damaged endothelium is particularly vulnerable. The peculiar SARS-CoV-2-induced "endothelitis" triggers an intriguing immune-thrombosis that affects both the venous and arterial vascular beds. An increased liability for infection and an increased likelihood of a worse outcome have been observed during the pandemic in patients with active cancer and in cancer survivors. "Overlapping commonalities" between COVID-19 and Cardio-Oncology have been described that include shared phenotypes of cardiovascular toxicities such as left ventricular dysfunction, ischemic syndromes, conduction disturbances, myocarditis, pericarditis and right ventricular failure; shared pathophysiologic mechanisms such as inflammation, release of cytokines, the renin-angiotensin-aldosterone-pathway, coagulation abnormalities, microthrombosis and endothelial dysfunction. For these features and for the catalyst role of NCDs (mainly CVD and cancer), we should refer to COVID-19 as a "syndemic." Another challenging issue is the persistence of the symptoms, the so-called "long COVID" whose pathogenesis is still uncertain: it may be due to persistent multi-organ viral attacks or to an abnormal immune response. An intensive vaccination campaign is the most successful pharmacological weapon against SARS-CoV-2, but the increasing number of variants has reduced the efficacy of the vaccines in controlling SARS-CoV-2 infections. After a year of vaccinations we have also learned more about efficacy and side-effects of COVID-19 vaccines. An important byproduct of the COVID-19 pandemic has been the rapid expansion of telemedicine platforms across different care settings; this new modality of monitoring cancer patients may be useful even in a post pandemic era. In this paper we analyze the problems that the cardio-oncologists are facing in a pandemic scenario modified by the extensive vaccination campaign and add actionable recommendations derived from the ongoing studies and from the syndemic nature of the infection.

A Population-Based Study of Cardiovascular Disease Mortality in Italian Cancer Patients.

The present research describes 25 years of cardiovascular mortality in a cohort of patients in Northern Italy. The study included patients with malignant cancer enrolled in the period of 1996-2019, and describes cardiovascular and cancer mortality in relation to sex, age, year of diagnosis, months of survivorship, tumor site, and standardized mortality ratio (SMR). Out of 67,173 patients, 38,272 deaths (57.7%) were recorded: 4466 from cardiovascular disease (CVD) (6.6%), and 28,579 (42.6%) from cancer. The proportion of CVD death increased from 4.5% in the first two years after diagnosis, to 7.3% after more than 10 years, while the proportion of deaths from cancer decreased from 70.5% to 9.4%. The CVD SMR comparing cancer patients with the general population was 0.87 (95% CI: 0.82-0.92) in 1996-1999, rising to 0.95 (95% CI: 0.84-1.08) in 2015-2019, without differences in terms of sex or age. The risk of dying from CVD was higher compared with the general population (SMR 1.31; 95% CI: 1.24-1.39) only in the first two years after diagnosis. The trend over time underscored that CVD deaths increased in patients with breast, bladder, prostate, and colorectal cancers, and, in the more recent period, for kidney cancer and melanoma patients. Our data confirmed that cardiovascular mortality is an important issue in the modern management of cancer patients, suggesting the need for an extensive interdisciplinary approach.

[ANMCO Position paper: Cardio-oncology in the COVID-19 era]. / Position paper ANMCO: Cardio-oncologia in era COVID-19.

The COVID-19 pandemic and its impact on patients with cancer and cardiovascular disease have confirmed the particular vulnerability of this population. Indeed, not only a higher risk of contracting the infection has been reported, but also an increased occurrence of a more severe course and unfavorable outcome. Beyond the direct consequences of COVID-19, the pandemic has an enormous impact on global health systems. Screening programs and non-urgent tests have been postponed; clinical trials have suffered a setback. Similarly, in the area of cardiology care, a significant decline in ST-elevation myocardial infarction accesses and an increase in cases of late presenting heart attacks with increased mortality and complication rates have been reported. Health care systems must therefore get ready to tackle the "rebound effect" that will likely show a relative increase in the short and medium term incidence of diseases such as heart failure, myocardial infarction, arrhythmias and cardio- and cerebrovascular complications. Scientific societies are taking action to provide general guidance and recommendations aimed at mitigating the unfavorable outcomes of this pandemic emergency. Cardio-oncology, as an emerging discipline, is more flexible in modulating care pathways and represents a beacon of innovation in the development of multi-specialty patient management. In the era of the COVID-19 pandemic, cardio-oncology has rapidly modified its clinical care pathways and implemented flexible monitoring protocols that include targeted use of cardiac imaging, increased use of biomarkers, and telemedicine systems. The goal of these strategic adjustments is to minimize the risk of infection for providers and patients while maintaining standards of care for the treatment of oncologic and cardiovascular diseases. The aim of this position paper is to evaluate the impact of the COVID-19 pandemic on the management of cardio-oncologic patients with the-state-of-the-art knowledge about SARS-CoV-2 and COVID-19 in order to optimize medical strategies during and after the pandemic.

ANMCO POSITION PAPER: cardio-oncology in the COVID era (CO and CO).

The COVID-19 pandemic and its impact on patients with cancer and cardiovascular disease have confirmed the particular vulnerability of these populations. Indeed, not only a higher risk of contracting the infection has been reported but also an increased occurrence of a more severe course and unfavourable outcome. Beyond the direct consequences of COVID-19 infection, the pandemic has an enormous impact on global health systems. Screening programmes and non-urgent tests have been postponed; clinical trials have suffered a setback. Similarly, in the area of cardiology care, a significant decline in STEMI accesses and an increase in cases of late presenting heart attacks with increased mortality and complication rates have been reported. Health care systems must therefore get ready to tackle the 'rebound effect' that will likely show a relative increase in the short- and medium-term incidence of diseases such as heart failure, myocardial infarction, arrhythmias, and cardio- and cerebrovascular complications. Scientific societies are taking action to provide general guidance and recommendations aimed at mitigating the unfavourable outcomes of this pandemic emergency. Cardio-oncology, as an emerging discipline, is more flexible in modulating care pathways and represents a beacon of innovation in the development of multi-specialty patient management. In the era of the COVID-19 pandemic, cardio-oncology has rapidly modified its clinical care pathways and implemented flexible monitoring protocols that include targeted use of cardiac imaging, increased use of biomarkers, and telemedicine systems. The goal of these strategic adjustments is to minimize the risk of infection for providers and patients while maintaining standards of care for the treatment of oncologic and cardiovascular diseases. The aim of this document is to evaluate the impact of the pandemic on the management of cardio-oncologic patients with the-state-of-the-art knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease (COVID-19) in order to optimize medical strategies during and after the pandemic.

Portrait of Italian Cardio-Oncology: Results of a Nationwide Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) Survey.

Aims: Cardio-oncology has achieved a pivotal role in science, but real world data on its clinical impact are still limited. Methods: A questionnaire was sent out to all cardio-oncology services across Italy (n = 120). The questionnaire was made up of 28 questions divided into four blocks: (A) general information on hospitals and service, (B) the inner organization of cardio-oncology and its relationships with out-of-hospital cardiologists and general practitioners, (C) educational needs and referral guidelines, and (D) activities/specific workload. Results: Ninety-six out of 120 (80%) completed the questionnaire; 9.4% were cancer centers while 90.6% were general hospitals. A cardio-oncology team was present in 56% of the cancer centers and in 20% only of general hospitals, and a cardio-oncology pathway was active in 55% of cancer centers and in just 14% of the general hospitals. Relationships with out-of-hospital cardiologists and general practitioners were lacking. The guidelines of reference were ESC and ANMCO/AIOM. Patients receiving anthracycline chemotherapy underwent scheduled monitoring by means of echocardiography in 58% of cases. Routine use of cardiac damage biomarkers was overall low, ranging from 22 to 33% while the use of global longitudinal strain reached 44%. Conclusions: Italian cardio-oncology showed a growing influence on clinical practice but still has room for improvement. Cardio-oncology teams are still scarce, and the application of dedicated paths is poor. The need for specific training has been highlighted.

Adjuvant Hormonotherapy and Cardiovascular Risk in Post-Menopausal Women with Breast Cancer: A Large Population-Based Cohort Study.

BACKGROUND: Whether aromatase inhibitors (AIs) increase the risk of cardiovascular (CV) events, compared to tamoxifen, in women with breast cancer is still debated. We evaluated the association between AI and CV outcomes in a large population-based cohort of breast cancer women. METHODS: By using healthcare utilization databases of Lombardy (Italy), we identified women ≥50 years, with new diagnosis of breast cancer between 2009 and 2015, who started adjuvant therapy with either AI or tamoxifen. We estimated the association between exposure to AI and CV outcomes (including myocardial infarction, ischemic stroke, heart failure or any CV event) by a Cox proportional hazard model with inverse probability of treatment and censoring weighting. RESULTS: The study cohort included 26,009 women starting treatment with AI and 7937 with tamoxifen. Over a median follow-up of 5.8 years, a positive association was found between AI and heart failure (Hazard Ratio = 1.20, 95% CI: 1.02 to 1.42) and any CV event (1.14, 1.00 to 1.29). The CV risk increased in women with previous CV risk factors, including hypertension, diabetes and dyslipidemia. CONCLUSIONS: Adjuvant therapy with AI in breast cancer women aged more than 50 years is associated with increased risk of heart failure and combined CV events.

The troubling liaison between cancer and metabolic syndrome in chronic inflammatory rheumatic diseases.

BACKGROUND: Several studies on community populations found that metabolic syndrome (MetS) is associated with higher risk for total incident cancer with a predisposition for specific types of cancer. These findings have never been analyzed in patients with chronic inflammatory rheumatic and musculoskeletal diseases (RMD). We assessed prevalence/incidence and factors related to the development of cancer in a large cohort of these patients and evaluate whether MetS and its components were associated with cancer independent of traditional markers of inflammation. METHODS: Between March 2014 and April 2016, 474 patients with RMD involved in a cardiovascular primary prevention program were consecutively recruited into this ambispective (combination of retrospective/prospective) study. They underwent clinical, laboratory, and echocardiographic evaluations. MetS was diagnosed according to the ATPIII criteria. RESULTS: Duration of follow-up was 42 [18-60] months. Patients with a diagnosis of cancer (made before recruitment or during follow-up) were 46 (9.7%). Cancer was diagnosed in 22/76 patients (29%) with MetS and in 24/398 patients (6%, p < 0.001) without MetS; nearly two thirds of malignancies belonged to those traditionally related to MetS. MetS was the strongest cancer risk factor. Cancer was positively associated with the number of MetS components identified in each patient. Beyond MetS, cancer was associated to older age and increased inflammatory disease activity; this information allowed to build a simple performance indicator highly sensitive for cancer development. CONCLUSION: In light of our results, an increasingly accurate assessment of MetS would be required in patients with RMD as potential measure of clinical outcomes including the risk of cancer.

Cancer in adult patients with inflammatory arthritis is associated with high ascending aortic stiffness and left ventricular hypertrophy and diastolic dysfunction.

Inflammatory arthritis, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), are associated with both cancer and cardiovascular (CV) adverse events. Cancer and CV abnormalities have coincident etiologic and pathophysiologic pathways in RA/PsA/AS patients. However, a comprehensive evaluation of CV system has never been performed in these patients in relation to the presence of cancer. This study was designed to assess the possible relationships between CV abnormalities and cancer among RA/PsA/AS patients. Between March 2014 and March 2015, 414 patients (214 RA, 125 PsA, and 75 SA) in sinus rhythm without known cardiac disease underwent clinical and color Doppler echocardiographic evaluation and were prospectively followed up. Patients had a mean age of 58 ± 12 years, 64% women. Forty-two patients (10.1%) had a diagnosis of cancer (made before enrollment in 24 cases and in 18 cases during the 36 months of follow-up). Skin cancer was the most frequent malignancy found, followed by thyroid, colon, pancreas, and breast cancer. Patients who had cancer were older with higher systolic blood pressure, more frequent hypertension and moderate/high disease activity, left ventricular (LV) hypertrophy, diastolic dysfunction, and higher ascending aortic stiffness index (AOSI) than those who had not. At multivariate logistic regression analysis, LV diastolic dysfunction and abnormally high AOSI emerged as conditions associated with cancer together with older age and hypertension. Cancer in RA/PsA/AS adults without history of CV disease is closely associated with specific asymptomatic CV abnormalities, such as LV diastolic dysfunction and reduced vascular elasticity, which are independent of age and hypertension.

Clinical profile and outcome of patients with chronic inflammatory arthritis and metabolic syndrome.

Systemic chronic inflammation may favor the onset of metabolic syndrome (MetS) which represents a risk factor for CV events. Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are disorders with high prevalence of MetS. We assessed the factors associated with MetS and its prognostic role in non-selected RA/AS/PsA patients. Between March 2014 and April 2016, 458 patients (228 RA, 134 PsA, 96 AS) selected for a primary prevention program for cardiovascular diseases were analyzed. Primary and co-primary end points were a composite of all-cause death/all-cause hospitalization and CV death/CV hospitalization, respectively. MetS was diagnosed according to the IDF Task Force on Epidemiology and Prevention. Patients were divided into MetS + (73 = 16%) and MetS - (385 = 84%). At multivariate logistic analysis, cancer, moderate/high disease activity, higher LV mass (LVM) and degree of LV diastolic dysfunction were independently associated with MetS. At 36-month follow-up, the event rate for primary/co-primary end point was 52/15% in MetS + vs 23/7% in MetS - (both p < 0.001). At multivariate Cox regression analysis, MetS was related to primary end point (HR 1.52 [CI 1.01-2.47], p = 0.04) together with higher LVM, disease duration and higher prevalence of biologic DMARDs refractoriness, and to co-primary end point (HR 2.05 [CI 1.16-3.60], p = 0.01) together with older age and higher LVM. The RA/AS/PsA phenotype MetS + is a subject with moderate/high disease activity, LV structural and functional abnormalities at increased risk for cancer. MetS + identifies RA/AS/PsA patients at higher risk for CV and non-CV events, independently of traditional CV risk factors analyzed individually and traditional indexes of inflammation.