Search

Cardiovascular disease and cancer are the two leading causes of morbidity and mortality in the world. The emerging field of cardio-oncology described several shared risk factors that predispose patients to both cardiovascular disease and cancer. Post-acute COVID-19 syndrome is a chronic condition that occurs in many patients who have experienced a SARS-CoV-2 infection, mainly based on chronic fatigue, sedentary lifestyle, cramps, breathing difficulties, and reduced lung performance. Post-acute COVID-19 exposes patients to increased visceral adiposity, insulin resistance, myosteatosis, and white adipose tissue content (surrounded by M1 macrophages and characterized by a Th1/Th17 phenotype), which increases the risk of cardiovascular mortality and cancer recurrence. In this review, the main metabolic affections of post-acute COVID-19 syndrome in cancer patients at low and high risk of cardiomyopathies will be summarized. Furthermore, several non-pharmacological strategies aimed at reducing atherosclerotic and cardiac risk will be provided, especially through anti-inflammatory nutrition with a low insulin and glycemic index, appropriate physical activity, and immune-modulating bioactivities able to reduce visceral obesity and myosteatosis, improving insulin-related signaling and myocardial metabolism.

Congestion is the main therapeutic target of acute heart failure (HF) treatment, and loop diuretics (LDs) are widely used drugs for this purpose. Despite their extensive use, these agents remain largely understudied in terms of modality administration, treatment duration, and escalation dose for subjects responding poorly to therapy. LDs were initially investigated in several edematous statuses such as cirrhosis, nephrotic syndrome, and congestive HF and initially approved for the treatment of cardiogenic congestion in 1966. Despite the long history and the undoubted role in congestion management, the use of LDs in the acute phase is mostly based on the physician’s experience, the oral amount chronically administered, and clinical decongestion response. Recent literature suggests monitoring diuretic activity by the evaluation of daily diuresis, weight loss, and sample urinary sodium assessment after early intravenous LD administration. More recently, the measurement of urinary sodium integrated with urinary and blood creatinine values and fluid status has been suggested as optimal marker to predict whole diuretic efficiency and to target the optimal dose. However, this method is not easily available in the chronic setting or in patients with recurrent hospitalization taking a high loop diuretic amount. Since high loop diuretic dose is related to diuretic resistance (DR) and poorer outcome, additional diuretics acting in different nephron sites are often required. Current sequential nephron blockade can stimulate diuresis by synergic mechanisms. This strategy is attempted in patients with poor response, revealing good results in the early period, but the effects of neuro-endocrine stimulation and electrolyte balance across long-term follow-up are still questioned. This paper reviews the historical course of loop diuretics and highlights the need for a universal approach based on clinical conditions, cardio–renal interactions, and HF phenotypes.

Serum biomarkers represent a reproducible, sensitive, minimally invasive and inexpensive method to explore possible adverse cardiovascular effects of antineoplastic treatments. They are useful tools in risk stratification, the early detection of cardiotoxicity and the follow-up and prognostic assessment of cancer patients. In this literature review, we aim at describing the current state of knowledge on the meaning and the usefulness of cardiovascular biomarkers in patients with cancer; analyzing the intricate relationship between cancer and cardiovascular disease (especially HF) and how this affects cardiovascular and tumor biomarkers; exploring the role of cardiovascular biomarkers in the risk stratification and in the identification of chemotherapy-induced cardiotoxicity; and providing a summary of the novel potential biomarkers in this clinical setting.

Heart failure (HF) is a significant disease affecting 1–2% of the general population. Despite its general aspects, HF, like other cardiovascular diseases, presents various gender-specific aspects in terms of etiology, hemodynamics, clinical characteristics, therapy, and outcomes. As is well known, HF with preserved ejection fraction more frequently affects females, with diabetes and arterial hypertension representing the most critical determinants of HF. On the other hand, women are traditionally underrepresented in clinical trials and are often considered undertreated. However, it is not clear whether such differences reflect cultural behaviors and clinical inertia or if they indicate different clinical profiles and the impact of sex on hard clinical outcomes. We aimed to review the sex-related differences in patients affected by HF.

Left ventricular global longitudinal strain (GLS) has an important role in the diagnosis of cancer therapy-related cardiac dysfunction (CTRCD). Little is known about the role of atrial function in diagnosing CTRCD. The aim of our study was to assess the impact of anti-cancer drugs on atrial function measured by speckle-tracking echocardiography in breast cancer women. A prospective multicenter study was conducted enrolling 169 breast cancer women treated with anthracyclines. A cardiological evaluation including an electrocardiogram and echocardiogram with an analysis of GLS, left atrial (LA) strain, and LA stiffness (LASi) was performed at baseline (T0), 3 (T1), and 6 months (T2) after starting chemotherapy. The patients were divided into two groups: patients with asymptomatic mild cardiotoxicity at T1 (with a relative reduction in GLS > 15%; Group 1) and those without (Group 2). We did not find a significant change in left ventricular ejection fraction (LVEF) at T1 and T2; we found a significant change in GLS (p-value < 0.0001) in the peak atrial longitudinal strain (PALS) and in LASi (p-value < 0.0001). Impairment of atrial function was greater in Group 1 compared to Group 2. A PALS variation > 20.8% identified patients who were most likely to develop asymptomatic mild cardiotoxicity [AUC 0.62; CI (0.51–0.73) p = 0.06, sensitivity 45%, specificity 69.5%]. Conclusions: PALS and LASi significantly change during chemotherapy in association with GLS. Atrial strain is an additional parameter that could be measured together with GLS to detect cardiotoxicity early.

Cardiovascular diseases (CVDs), particularly ischemic heart disease (IHD) and stroke, present epidemiologically in a different way among sexes. The reasons of these sex-based differences should be delved into sex-specific cardiovascular (CV) risk factors and different mechanisms of atherosclerotic progression. Imaging techniques of both carotid and coronary atherosclerotic plaques represent a tool to demonstrate sex-related features which might be used to further and better assess CV risk of male and female population. The aim of this review is to evaluate current knowledge on sex-specific qualitative and quantitative plaque features of coronary and carotid atherosclerosis. We also discuss the clinical implication of a sex-based plaque phenotype, evaluated with non-invasive imaging techniques, such as CT-angiography and MRI-angiography, to stratify CV risk.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease, and several studies have suggested possible early RV involvement. Aim of the study was to evaluate the 3D echo parameters of the right ventricle (RV) and the metabolomic profile to correlate both with SLE severity. Forty SLE patients, free of cardiovascular disease, were enrolled and the following 3D parameters were evaluated: the RV ejection fraction (RV-EF), longitudinal strain of the interventricular septum (Septal LS), longitudinal strain of the free wall (Free-LS) and the fractional area change (FAC). In addition, a metabolomic analysis was performed. Direct correlations were observed between TAPSE values and the RV 3D parameters. Then, when splitting the population according to the SDI value, it was found that patients with higher cumulative damage (≥3) had significantly lower FAC, RV-EF, Septal LS, and Free-LS values; the latter three parameters showed a significant correlation with the metabolic profile of the patients. Furthermore, the division based on SDI values identified different metabolic profiles related to the degree of RV dysfunction. The RV dysfunction induced by the chronic inflammatory state present in SLE can be identified early by 3D echocardiography. Its severity seems to be related to systemic organ damage and the results associated with a specific metabolic fingerprint constituted by 2,4-dihydroxybutyric acid, 3,4-dihydroxybutyric acid, citric acid, glucose, glutamine, glycine, linoleic acid, oleic acid, phosphate, urea, and valine.

Metabolic syndrome (Mets) is a clinical condition characterized by a cluster of major risk factors for cardiovascular disease (CVD) and type 2 diabetes: proatherogenic dyslipidemia, elevated blood pressure, dysglycemia, and abdominal obesity. Each risk factor has an independent effect, but, when aggregated, they become synergistic, doubling the risk of developing cardiovascular diseases and causing a 1.5-fold increase in all-cause mortality. We will highlight gender differences in the epidemiology, etiology, pathophysiology, and clinical expression of the aforementioned Mets components. Moreover, we will discuss gender differences in new biochemical markers of metabolic syndrome and cardiovascular risk.

Antiblastic drugs-induced cardiomyopathy remains a relevant cause of morbidity and mortality, during and after chemotherapy, despite the progression in protective therapy against cardiovascular diseases and myocardial function. In the last few decades, many groups of researchers have focused their attention on studying the metabolic profile, first in animals, and, subsequently, in humans, looking for profiles which could be able to predict drug-induced cardiotoxicity and cardiovascular damage. In clinical practice, patients identified as being at risk of developing cardiotoxicity undergo a close follow-up and more tailored therapies. Injury to the heart can be a consequence of both new targeted therapies, such as tyrosine kinase inhibitors, and conventional chemotherapeutic agents, such as anthracyclines. This review aims to describe all of the studies carried on this topic of growing interest.

A multicenter, cross-sectional observational study (Italian GENder Differences in Awareness of Cardiovascular risk, IGENDA study) was carried out to evaluate the perception and knowledge of cardiovascular risk among Italian women. An anonymous questionnaire was completed by 4454 women (44.3 ± 14.1 years). The 70% of respondents correctly identified cardiovascular disease (CVD) as the leading cause of death. More than half of respondents quoted cancer as the greatest current and future health problem of women of same age. Sixty percent of interviewed women considered CVD as an almost exclusively male condition. Although respondents showed a good knowledge of the major cardiovascular risk factors, the presence of cardiovascular risk factors was not associated with higher odds of identifying CVD as the biggest cause of death. Less than 10% of respondents perceived themselves as being at high CVD risk, and the increased CVD risk perception was associated with ageing, higher frequency of cardiovascular risk factors and disease, and a poorer self-rated health status. The findings of this study highlight the low perception of cardiovascular risk in Italian women and suggest an urgent need to enhance knowledge and perception of CVD risk in women as a real health problem and not just as a as a life-threatening threat.

Traditional cardiovascular (CV) risk factors (RFs) and coronary artery disease (CAD) do not always show a direct correlation. We investigated the metabolic differences in a cohort of patients with a high CV risk profile who developed, or did not develop, among those enrolled in the Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation (CAPIRE) study. We studied 112 subjects with a high CV risk profile, subdividing them according to the presence (CAD/High-RFs) or absence of CAD (No-CAD/High-RFs), assessed by computed tomography angiography. The metabolic differences between the two groups were identified by gas chromatography-mass spectrometry. Characteristic patterns and specific metabolites emerged for each of the two phenotypic groups: high concentrations of pyruvic acid, pipecolic acid, p-cresol, 3-aminoisobutyric acid, isoleucine, glyceric acid, lactic acid, sucrose, phosphoric acid, trimethylamine-N-oxide, 3-hydroxy-3-methylglutaric acid, erythritol, 3-hydroxybutyric acid, glucose, leucine, and glutamic acid; and low concentrations of cholesterol, hypoxanthine, glycerol-3-P, and cysteine in the CAD/High-RFs group vs the No-CAD/High-RFs group. Our results show the existence of different metabolic profiles between patients who develop CAD and those who do not, despite comparable high CV risk profiles. A specific cluster of metabolites, rather than a single marker, appears to be able to identify novel predisposing or protective mechanisms towards CAD beyond classic CVRFs.

The purpose of this study was to assess whether metabolomics, associated with echocardiography, was able to highlight pathophysiological differences between obstructive (OHCM) or non-obstructive (NOHCM) hypertrophic cardiomyopathy. Thirty-one HCM patients underwent standard and advanced echocardiography; a plasma sample was collected for metabolomic analysis. Results. Patients with OHCM compared with subjects with NOHCM had higher values of 2DLVEF (66.5 ± 3.3% vs. 60.6 ± 1.8%, p < 0.01), S wave (7.6 ± 1.1 vs. 6.3 ± 0.7 cm/s, p < 0.01) and 3D global longitudinal strain (17.2 ± 4.2%, vs. 13.4 ± 1.3%, p < 0.05). A 2-group PLS-Discriminant Analysis was performed to verify whether the two HCM groups differed also based on the metabolic fingerprint. A clear clustering was shown (ANOVA p = 0.014). The most discriminating metabolites resulted as follows: in the NOHCM Group, there were higher levels of threitol, aminomalonic acid, and sucrose, while the OHCM Group presented higher levels of amino acids, in particular those branched chains, of intermediates of glycolysis (lactate) and the Krebs cycle (fumarate, succinate, citrate), of fatty acids (arachidonic acid, palmitoleic acid), of ketone bodies (2-OH-butyrate). Our data point out a different systolic function related to a specific metabolic activity in the two HCM phenotypic forms, with specific metabolites associated with better contractility in OHCM.

Abstract Background The endothelium is a key variable in the pathogenesis of atherosclerosis and its complications, particularly coronary artery disease (CAD). Current evidence suggests that the endothelial status can be regarded as an integrated index of individual atherogenic and anti-atherogenic properties, and that the interaction between circulating factors and the arterial wall might be critical for atherogenesis. In organism-level investigations, a functional view is provided by metabolomics, the study of the metabolic profile of small molecules. We sought to verify whether metabolomic analysis can reveal the presence of coronary microenvironment peculiarities associated with distinct manifestations of CAD. Methods Thirty-two coronary blood samples were analyzed using 1H-NMR-based metabolomics. Samples collected from patients with evidence of myocardial ischemia formed the case group, and were further divided into the stenotic-disease (SD) group (N = 13) and absence of stenosis (microvascular disease; “Micro”) group (N = 8); specimens of patients presenting no evidence of ischemic heart disease (dilated cardiomyopathy, valvular diseases) constituted the control group (N = 11). Results Application of an orthogonal partial least squares discriminant analysis (OPLS-DA) model to the entire dataset clearly separated the samples into 3 groups, indicating 3 distinct metabolic fingerprints. Relative to control-group members, Micro patients showed a higher content of 2-hydroxybutirate, alanine, leucine, isoleucine, and N-acetyl groups and lower levels of creatine/phosphocreatine, creatinine, and glucose, whereas SD patients showed higher levels of 3-hydroxybutirate and acetate and a lower content of 2-hydroxybutirate. Moreover, relative to SD patients, Micro patients showed higher levels of 2-hydroxybutirate, alanine, leucine, and N-acetyl groups and lower levels of 3-hydroxybutirate and acetate. Conclusions Specific coronary microenvironments are likely associated with distinct development and pathological expression of CAD.

Metabolic syndrome (MetS) is a well established risk factor for cardiovascular (CV) diseases. In addition, several studies indicate that MetS correlates with the increased risk of cancer in adults. The mechanisms linking MetS and cancer are not fully understood. Several risk factors involved in MetS are also cancer risk factors, such as the consumption of high calorie-food or high fat intake, low fibre intake, and sedentary lifestyle. Other common aspects of both cancer and MetS are oxidative stress and inflammation. In addition, some anticancer treatments can induce cardiotoxicity, including, for instance, left ventricular (LV) dysfunction and heart failure (HF), endothelial dysfunction and hypertension. In this review, we analyse several aspects of MetS, cancer and cardiotoxicity from anticancer drugs. In particular, we focus on oxidative stress in ageing, cancer and CV diseases, and we analyse the connections among CV risk factors, cancer and cardiotoxicity from anticancer drugs.

Background: Cardiovascular adverse events (CV-AEs) are considered critical complications in chronic myeloid leukemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (TKIs). The aim of our study was to assess the correlation between metabolic profiles and CV-AEs in CML patients treated with TKIs. Methods: We investigated 39 adult CML patients in chronic-phase (mean age 49 years, range 24–70 years), with no comorbidities evidenced at baseline, who were consecutively identified with CML and treated with imatinib, nilotinib, dasatinib, and ponatinib. All patients performed Gas-Chromatography-Mass-Spectrometry-based metabolomic analysis and were divided into two groups (with and without CV-AEs). Results: Ten CV-AEs were documented. Seven CV-AEs were rated as 3 according to the Common Toxicity Criteria, and one patient died of a dissecting aneurysm of the aorta. The patients’ samples were clearly separated into two groups after analysis and the main discriminant metabolites were tyrosine, lysine, glutamic acid, ornithine, 2-piperdinecarboxylic acid, citric acid, proline, phenylalanine, threonine, mannitol, leucine, serine, creatine, alanine, and 4-hydroxyproline, which were more abundant in the CV-AE group. Conversely, myristic acid, oxalic acid, arabitol, 4-deoxy rithronic acid, ribose, and elaidic acid were less represented in the CV-AE group. Conclusions: CML patients with CV-AEs show a different metabolic profile, suggesting probable mechanisms of endothelial damage.

Ponatinib, a third-generation tyrosine kinase inhibitor (TKI), is the only approved TKI that is effective against T315I mutations in patients with chronic myeloid leukemia (CML). Specific activation of Notch signaling in CML cells by ponatinib can be considered as the “on-target effect” on the tumor and represents a therapeutic approach for CML. Nevertheless, ponatinib-induced vascular toxicity remains a serious concern, with underlying mechanisms being poorly understood. We aimed to determine the mechanisms of ponatinib-induced vascular toxicity, defining associated signaling pathways and identifying potential rescue strategies. We exposed human umbilical endothelial cells (HUVECs) to ponatinib or vehicle in the presence or absence of the neutralizing factor anti-Notch-1 antibody for exposure times of 0−72 h. Label-free proteomics and network analysis showed that protein cargo of HUVECs treated with ponatinib triggered apoptosis and inhibited vasculature development. We validated the proteomic data showing the inhibition of matrigel tube formation, an up-regulation of cleaved caspase-3 and a downregulation of phosphorylated AKT and phosphorylated eNOS. We delineated the signaling of ponatinib-induced vascular toxicity, demonstrating that ponatinib inhibits endothelial survival, reduces angiogenesis and induces endothelial senescence and apoptosis via the Notch-1 pathway. Ponatinib induced endothelial toxicity in vitro. Hyperactivation of Notch-1 in the vessels can lead to abnormal vascular development and vascular dysfunction. By hyperactivating Notch-1 in the vessels, ponatinib exerts an “on-target off tumor effect”, which leads to deleterious effects and may explain the drug’s vasculotoxicity. Selective blockade of Notch-1 prevented ponatinib-induced vascular toxicity.

Despite advances in supportive and protective therapy for myocardial function, cardiovascular diseases due to antineoplastic therapy—primarily cardiomyopathy associated with contractile dysfunction—remain a major cause of morbidity and mortality. Because of the limitations associated with current therapies, investigators are searching for alternative strategies that can timely recognise cardiovascular damage—thus permitting a quick therapeutic approach—or prevent the development of the disease. Damage to the heart can result from both traditional chemotherapeutic agents, such as anthracyclines, and new targeted therapies, such as tyrosine kinase inhibitors. In recent years, metabolomics has proved to be a practical tool to highlight fundamental changes in the metabolic state in several pathological conditions. In this article, we present the state-of-the-art technology with regard to the metabolic mechanisms underlying cardiotoxicity and cardioprotection.

Metabolomics, also referred to as metabonomics, is one of the most recent innovative technologies in medicine. It offers a direct functional read-out of phenotypes by the detection, identification, and quantification of a large number of metabolites within a biological sample such as urine and blood. Metabolites (

Antineoplastic drugs can be associated with several side effects, including cardiovascular toxicity (CTX). Biochemical studies have identified multiple mechanisms of CTX. Chemoterapeutic agents can alter redox homeostasis by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species RNS. Cellular sources of ROS/RNS are cardiomyocytes, endothelial cells, stromal and inflammatory cells in the heart. Mitochondria, peroxisomes and other subcellular components are central hubs that control redox homeostasis. Mitochondria are central targets for antineoplastic drug-induced CTX. Understanding the mechanisms of CTX is fundamental for effective cardioprotection, without compromising the efficacy of anticancer treatments. Type 1 CTX is associated with irreversible cardiac cell injury and is typically caused by anthracyclines and conventional chemotherapeutic agents. Type 2 CTX, associated with reversible myocardial dysfunction, is generally caused by biologicals and targeted drugs. Although oxidative/nitrosative reactions play a central role in CTX caused by different antineoplastic drugs, additional mechanisms involving directly and indirectly cardiomyocytes and inflammatory cells play a role in cardiovascular toxicities. Identification of cardiologic risk factors and an integrated approach using molecular, imaging, and clinical data may allow the selection of patients at risk of developing chemotherapy-related CTX. Although the last decade has witnessed intense research related to the molecular and biochemical mechanisms of CTX of antineoplastic drugs, experimental and clinical studies are urgently needed to balance safety and efficacy of novel cancer therapies.

A 48-year-old woman was scheduled by our lab to perform a standard dobutamine/atropine stress echocardiogram. During the test, the patient referred to a slight chest discomfort and developed a progressive left ventricle akinesia of all midbasal LV segments, thus mimicking a midbasal ballooning. ECG persisted without significant abnormalities and with no raise of Troponin I. Coronary angiography showed normal coronary arteries and ventriculography a severe EF reduction and apical hypercontractility. Echocardiography showed a progressive improvement with a complete recovery 48 hours later. This is a rare case of inverted takotsubo syndrome induced by dobutamine stress echocardiography that occurred with atypical presentation.