Cardiovascular Biomarkers in Cardio-Oncology: Antineoplastic Drug Cardiotoxicity and Beyond.

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.

"Under the Bridge": Looking for Ischemia in a Patient with Intramyocardial Coronary Artery Course-The Role of the Cardiopulmonary Exercise Test.

Many variables obtained during cardiopulmonary exercise test (CPET), including O2 uptake (VO2) versus heart rate (HR, O2-pulse) and work rate (VO2/Watt), provide quantitative patterns of responses to exercise when left ventricular dysfunction is an effect of myocardial ischemia (MI). Therefore, CPET offers a unique approach to evaluate exercise-induced MI in the presence of fixed or dynamic coronary arteries stenosis. In this paper, we examined the case of a 74-year-old patient presenting with an ischemic CPET and a normal stress cardiac magnetic resonance (CMR) with dipyridamole. A coronary angiography demonstrated the presence of myocardial bridging (MB), a well-known congenital coronary anomaly that is able to generate MI during exercise (but not in provocative testing using coronary artery vasodilators, such as dipyridamole). Despite the good diagnostic accuracy of the imaging methods (i.e., stress CMR) in MI detection, this case shows that exercise should be the method of choice in elicit ischemia in specific cases, like MB.

Mildly Elevated Pulmonary Hypertension: Gray Zone or Already a Disease?

During the sixth World Symposium on Pulmonary Hypertension, the threshold of mean pulmonary arterial pressure (mPAP) for the definition of pulmonary hypertension (PH) has been lowered to a value of greater than 20 mmHg, measured by means of right heart catheterization at rest. In this review, we aim at describing the impact of the new definition of PH, analyzing the available data from the latest scientific literature concerning subjects with mPAP between 21 and 24 mmHg (defined as "mildly elevated PH"), discussing the impact of the new threshold for mPAP in the clinical practice, and highlighting the new perspectives in this field.

Right ventricular failure in left heart disease: from pathophysiology to clinical manifestations and prognosis.

Right heart failure (RHF) is a clinical syndrome in which symptoms and signs are caused by dysfunction and/or overload of the right heart structures, predominantly the right ventricle (RV), resulting in systemic venous hypertension, peripheral oedema and finally, the impaired ability of the right heart to provide tissue perfusion. Pathogenesis of RHF includes the incompetence of the right heart to maintain systemic venous pressure sufficiently low to guarantee an optimal venous return and to preserve renal function. Virtually, all myocardial diseases involving the left heart may be responsible for RHF. This may result from coronary artery disease, hypertension, valvular heart disease, cardiomyopathies and myocarditis. The most prominent clinical signs of RHF comprise swelling of the neck veins with an elevation of jugular venous pressure and ankle oedema. As the situation worsens, fluid accumulation becomes generalised with extensive oedema of the legs, congestive hepatomegaly and eventually ascites. Diagnosis of RHF requires the presence of signs of elevated right atrial and venous pressures, including dilation of neck veins, with at least one of the following criteria: (1) compromised RV function; (2) pulmonary hypertension; (3) peripheral oedema and congestive hepatomegaly. Early recognition of RHF and identifying the underlying aetiology as well as triggering factors are crucial to treating patients and possibly reversing the clinical manifestations effectively and improving prognosis.

Causes and outcomes of ICU hospitalisations in patients with pulmonary arterial hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a rare disease characterised by limited survival despite remarkable improvements in therapy. The causes, clinical burden and outcomes of patients admitted to the intensive care unit (ICU) remain poorly characterised. The aim of this study was to describe patient characteristics, causes of ICU hospitalisation, and risk factors for ICU and 1-year mortality. Methods: Data from patients enrolled in the Johns Hopkins Pulmonary Hypertension Registry were analysed for the period between January 2010 and December 2020. Clinical, functional, haemodynamic and laboratory data were collected. Measurements and main results: 102 adult patients with 155 consecutive ICU hospitalisations were included. The leading causes for admission were right heart failure (RHF, 53.3%), infection (17.4%) and arrhythmia (11.0%). ICU mortality was 27.1%. Mortality risk factors included Na <136 mEq·mL-1 (OR: 3.10, 95% CI: 1.41-6.82), elevated pro-B-type natriuretic peptide (proBNP) (OR: 1.75, 95% CI: 1.03-2.98), hyperbilirubinaemia (OR: 1.40, 95% CI: 1.09-1.80), hyperlactaemia (OR: 1.42, 95% CI: 1.05-1.93), and need for vasopressors/inotropes (OR: 5.29, 95% CI: 2.28-12.28), mechanical ventilation (OR: 3.76, 95% CI: 1.63-8.76) and renal replacement therapy (OR: 5.57, 95% CI: 1.25-24.76). Mortality rates at 3, 6 and 12 months were 17.5%, 27.6% and 39.0%, respectively. Connective tissue disease-associated PAH has lower 1-year survival compared to idiopathic PAH (51.4% versus 79.8%, log-rank test p=0.019). Conclusions: RHF is the most common cause for ICU admission. In-hospital and 1-year mortality remain exceedingly high despite improved ICU care. Recognising specific risk factors on admission can help identifying patients at risk for poor outcomes.

Janus, or the Inevitable Battle Between Too Much and Too Little Oxygen.

Significance: Oxygen levels are key regulators of virtually every living mammalian cell, under both physiological and pathological conditions. Starting from embryonic and fetal development, through the growth, onset, and progression of diseases, oxygen is a subtle, although pivotal, mediator of key processes such as differentiation, proliferation, autophagy, necrosis, and apoptosis. Hypoxia-driven modifications of cellular physiology are investigated in depth or for their clinical and translational relevance, especially in the ischemic scenario. Recent Advances: The mild or severe lack of oxygen is, undoubtedly, related to cell death, although abundant evidence points at oscillating oxygen levels, instead of permanent low pO2, as the most detrimental factor. Different cell types can consume oxygen at different rates and, most interestingly, some cells can shift from low to high consumption according to the metabolic demand. Hence, we can assume that, in the intracellular compartment, oxygen tension varies from low to high levels depending on both supply and consumption. Critical Issues: The positive balance between supply and consumption leads to a pro-oxidative environment, with some cell types facing hypoxia/hyperoxia cycles, whereas some others are under fairly constant oxygen tension. Future Directions: Within this frame, the alterations of oxygen levels (dysoxia) are critical in two paradigmatic organs, the heart and brain, under physiological and pathological conditions and the interactions of oxygen with other physiologically relevant gases, such as nitric oxide, can alternatively contribute to the worsening or protection of ischemic organs. Further, the effects of dysoxia are of pivotal importance for iron metabolism. Antioxid. Redox Signal. 37, 972-989.

New-Onset Cancer in the HF Population: Epidemiology, Pathophysiology, and Clinical Management.

PURPOSE OF REVIEW: Oncological treatments are known to induce cardiac toxicity, but the impact of new-onset cancer in patients with pre-existing HF remains unknown. This review focuses on the epidemiology, pathophysiological mechanisms, and clinical implications of HF patients who develop malignancies. RECENT FINDINGS: Novel findings suggest that HF and cancer, beside common risk factors, are deeply linked by shared pathophysiological mechanisms. In particular, HF itself may enhance carcinogenesis by producing pro-inflammatory cytokines, and it has been suggested that neurohormonal activation, commonly associated with the failing heart, might play a pivotal role in promoting neoplastic transformation. The risk of malignancies seems to be higher in HF patients compared to the general population, probably due to shared risk factors and common pathophysiological pathways. Additionally, management of these patients represents a challenge for clinicians, considering that the co-existence of these diseases significantly worsens patients' prognosis and negatively affects therapeutic options for both diseases.

Oxidative stress in anticancer therapies-related cardiac dysfunction.

Redox abnormalities are at the crossroad of cardiovascular diseases, cancer and cardiotoxicity from anticancer treatments. Indeed, disturbances of the redox equilibrium are common drivers of these conditions. Not only is an increase in oxidative stress a fundamental mechanism of action of anthracyclines (which have historically been the most studied anticancer treatments) but also this is at the basis of the toxic cardiovascular effects of antineoplastic targeted drugs and radiotherapy. Here we examine the oxidative mechanisms involved in the different cardiotoxicities induced by the main redox-based antineoplastic treatments, and discuss novel approaches for the treatment of such toxicities.

Cancer Risk in the Heart Failure Population: Epidemiology, Mechanisms, and Clinical Implications.

PURPOSE OF REVIEW: Along with population aging, the incidence of both heart failure (HF) and cancer is increasing. However, little is known about new-onset cancer in HF patients. This review aims at showing recent discoveries concerning this subset of patients. RECENT FINDINGS: Not only cancer and HF share similar risk factors but also HF itself can stimulate cancer development. Some cytokines produced by the failing heart induce mild inflammation promoting carcinogenesis, as it has been recently suggested by an experimental model of HF in mice. The incidence of new-onset cancer is higher in HF patients compared to the general population, and it significantly worsens their prognosis. Moreover, the management of HF patients developing new-onset cancer is challenging, especially due to the limited therapeutic options for patients affected by both cancer and HF and the higher risk of cardiotoxicity from anticancer drugs.

Pulmonary Hypertension Phenotypes in Systemic Sclerosis: The Right Diagnosis for the Right Treatment.

Systemic sclerosis is an auto-immune disease characterized by skin involvement that often affects multiple organ systems. Pulmonary hypertension is a common finding that can significantly impact prognosis. Molecular pathophysiological mechanisms underlying pulmonary hypertension in systemic sclerosis can be extremely heterogeneous, leading to distinct clinical phenotypes. In addition, different causes of pulmonary hypertension may overlap within the same patient. Since pulmonary hypertension treatment is very different for each phenotype, it is fundamental to perform an adequate diagnostic work-up to properly and promptly identify the prevalent mechanism underlying pulmonary hypertension in order to start the right therapies. When pulmonary hypertension is caused by a primary vasculopathy of the small pulmonary arteries, treatment with pulmonary vasodilators, often in an initial double-combination regimen, is indicated, aimed at reducing the mortality risk profile. In this review, we describe the different clinical phenotypes of pulmonary hypertension in the scleroderma population and discuss the utility of clinical tools to identify the presence of pulmonary vascular disease. Furthermore, we focus on systemic sclerosis-associated pulmonary arterial hypertension, highlighting the advances in the knowledge of right ventricular dysfunction in this setting and the latest updates in terms of treatment with pulmonary vasodilator drugs.

Heart Failure and Cancer: Mechanisms of Old and New Cardiotoxic Drugs in Cancer Patients.

Although there have been many improvements in prognosis for patients with cancer, anticancer therapies are burdened by the risk of cardiovascular toxicity. Heart failure is one of the most dramatic clinical expressions of cardiotoxicity, and it may occur acutely or appear years after treatment. This article reviews the main mechanisms and clinical presentations of left ventricular dysfunction induced by some old and new cardiotoxic drugs in cancer patients, referring to the most recent advances in the field. The authors describe the mechanisms of cardiotoxicity induced by anthracyclines, which can lead to cardiovascular problems in up to 48% of patients who take them. The authors also describe mechanisms of cardiotoxicity induced by biological drugs that produce left ventricular dysfunction through secondary mechanisms. They outline the recent advances in immunotherapies, which have revolutionised anticancer therapies.