Patient phenotype profiling using echocardiography and natriuretic peptides to personalise heart failure therapy.

Heart failure (HF) is a progressive condition with a clinical picture resulting from reduced cardiac output (CO) and/or elevated left ventricular (LV) filling pressures (LVFP). The original Diamond-Forrester classification, based on haemodynamic data reflecting CO and pulmonary congestion, was introduced to grade severity, manage, and risk stratify advanced HF patients, providing evidence that survival progressively worsened for those classified as warm/dry, cold/dry, warm/wet, and cold/wet. Invasive haemodynamic evaluation in critically ill patients has been replaced by non-invasive haemodynamic phenotype profiling using echocardiography. Decreased CO is not infrequent among ambulatory HF patients with reduced ejection fraction, ranging from 23 to 45%. The Diamond-Forrester classification may be used in combination with the evaluation of natriuretic peptides (NPs) in ambulatory HF patients to pursue the goal of early identification of those at high risk of adverse events and personalise therapy to antagonise neurohormonal systems, reduce congestion, and preserve tissue/renal perfusion. The most benefit of the Guideline-directed medical treatment is to be expected in stable patients with the warm/dry profile, who more often respond with LV reverse remodelling, while more selective individualised treatments guided by echocardiography and NPs are necessary for patients with persisting congestion and/or tissue/renal hypoperfusion (cold/dry, warm/wet, and cold/wet phenotypes) to achieve stabilization and to avoid further neurohormonal activation, as a result of inappropriate use of vasodilating or negative chronotropic drugs, thus pursuing the therapeutic objectives. Therefore, tracking the haemodynamic status over time by clinical, imaging, and laboratory indicators helps implement therapy by individualising drug regimens and interventions according to patients' phenotypes even in an ambulatory setting.

Prognostic impact of diabetes in chronic and acute heart failure.

A strong, bidirectional relationship exists between diabetes mellitus (DM) and heart failure (HF) and DM is responsible of the activation of several molecular and pathophysiological mechanisms that may, on the long term, damage the heart. However, the prognostic role of DM in the context of chronic and acute HF is still not yet defined and there are several gaps of evidence in the literature on this topic. These gaps are related to the wide phenotypic heterogeneity of patients with chronic and acute HF and to the concept that not all diabetic patients are the same, but there is the necessity to better characterize the disease and each single patient, also considering the role of other possible comorbidities. The aim of the present review is to summarize the pathophysiological mechanisms subtending the negative effect of DM in HF and analyze the available data exploring the prognostic impact of such comorbidity in both chronic and acute HF.

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.

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.

The paradox of pulmonary arterial hypertension in Italy in the COVID-19 era: is risk of disease progression around the corner?

OBJECTIVE: The coronavirus disease 2019 (COVID-19) outbreak has led to significant restrictions on routine medical care. We conducted a multicentre nationwide survey of patients with pulmonary arterial hypertension (PAH) to determine the consequences of governance measures on PAH management and risk of poor outcome in patients with COVID-19. MATERIALS AND METHODS: The present study, which included 25 Italian centres, considered demographic data, the number of in-person visits, 6-min walk and echocardiographic test results, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide test results, World Health Organization functional class assessment, presence of elective and non-elective hospitalisation, need for treatment escalation/initiation, newly diagnosed PAH, incidence of COVID-19 and mortality rates. Data were collected, double-checked and tracked by institutional records between March 1 and May 1, 2020, to coincide with the first peak of COVID-19 and compared with the same time period in 2019. RESULTS: Among 1922 PAH patients, the incidences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 were 1.0% and 0.46%, respectively, with the latter comparable to that in the overall Italian population (0.34%) but associated with 100% mortality. Less systematic activities were converted into more effective remote interfacing between clinicians and PAH patients, resulting in lower rates of hospitalisation (1.2% versus 1.9%) and related death (0.3% versus 0.5%) compared with 2019 (p<0.001). A high level of attention is needed to avoid the potential risk of disease progression related to less aggressive escalation of treatment and the reduction in new PAH diagnoses compared with 2019. CONCLUSION: A cohesive partnership between healthcare providers and regional public health officials is needed to prioritise PAH patients for remote monitoring by dedicated tools.

Risk Reduction and Hemodynamics with Initial Combination Therapy in Pulmonary Arterial Hypertension.

Rationale: An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known.Objectives: To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs.Methods: The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist + phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores.Measurements and Main Results: Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR <25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status.Conclusions: A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.

Cardiovascular safety of the tyrosine kinase inhibitor nintedanib.

The intracellular tyrosine kinase inhibitor nintedanib has shown great efficacy for the treatment of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases. However, the incidence rate of myocardial infarction (MI) among participants in landmark IPF trials was remarkable, peaking at 3/100 patient-years. Although subjects with IPF often have a high cardiovascular (CV) risk profile, the occurrence of MI in nintedanib-treated patients may not be fully explained by clustering of CV risk factors. Nintedanib inhibits the vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor pathways, which play important roles in the biology of the atherosclerotic plaque and in the response of the heart to ischaemia. Hence, unwanted CV effects may partly account for nintedanib-related MI. We review the evidence supporting this hypothesis and discuss possible actions for a safe implementation of nintedanib in clinical practice, building on the experience with tyrosine kinase inhibitors acquired in cardio-oncology.

Cardiovascular Toxicity of Immune Checkpoint Inhibitors: Clinical Risk Factors.

PURPOSE OF REVIEW: Immune checkpoint inhibitors, such as monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1, have improved the outcome of many malignancies, but serious immune-related cardiovascular adverse events have been observed. Patients' risk factors for these toxicities are currently being investigated. RECENT FINDINGS: Interfering with the CTLA-4 and PD-1 axes can bring to several immune-related adverse events, including cardiotoxic events such as autoimmune myocarditis, pericarditis, and vasculitis, suggesting that these molecules play an important role in preventing autoimmunity. Risk factors (such as pre-existing cardiovascular conditions, previous and concomitant cardiotoxic treatments, underlying autoimmune diseases, tumor-related factors, simultaneous immune-related toxic effects, and genetic factors) should be always recognized for the correct management of these toxicities.

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.

Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis.

AIMS: Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented. METHODS AND RESULTS: From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE. CONCLUSION: These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.

A comprehensive echocardiographic method for risk stratification in pulmonary arterial hypertension.

QUESTION ADDRESSED: Echocardiography is not currently considered as providing sufficient prognostic information to serve as an integral part of treatment goals in pulmonary arterial hypertension (PAH). We tested the hypothesis that incorporation of multiple parameters reflecting right heart function would improve the prognostic value of this imaging modality. METHODS AND MAIN RESULTS: We pooled individual patient data from a total of 517 patients (mean age 52±15 years, 64.8% females) included in seven observational studies conducted at five European and United States academic centres. Patients were subdivided into three groups representing progressive degrees of right ventricular dysfunction based on a combination of echocardiographic measurements, as follows. Group 1 (low risk): normal tricuspid annular plane systolic excursion (TAPSE) and nonsignificant tricuspid regurgitation (TR) (n=129); group 2 (intermediate risk): normal TAPSE and significant TR or impaired TAPSE and nondilated inferior vena cava (IVC) (n=256); group 3 (high risk): impaired TAPSE and dilated IVC (n=132). The 5-year cumulative survival rate was 82% in group 1, 63% in group 2 and 43% in group 3. Low-risk patients had better survival rates than intermediate-risk patients (log-rank Chi-squared 12.25; p<0.001) and intermediate-risk patients had better survival rates than high-risk patients (log-rank Chi-squared 26.25; p<0.001). Inclusion of other parameters such as right atrial area and pericardial effusion did not provide added prognostic value. ANSWER TO THE QUESTION: The proposed echocardiographic approach integrating the evaluation of TAPSE, TR grade and IVC is effective in stratifying the risk for all-cause mortality in PAH patients, outperforming the prognostic parameters suggested by current guidelines.

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.

Progress in Understanding, Diagnosing, and Managing Cardiac Complications of Systemic Sclerosis.

PURPOSE OF THE REVIEW: Systemic sclerosis (scleroderma) is a complex autoimmune disease that commonly involves the cardiovascular system. Even if often subclinical, cardiac involvement is considered a poor prognostic factor as it is a leading cause of death in scleroderma patients. We review the cardiac manifestations of scleroderma, the diagnostic methods useful in detection, and current advances in therapeutic management. RECENT FINDINGS: Beside the routine exams for the assessment of cardiac status (including EKG, standard echocardiography, provocative tests) novel techniques such as myocardial strain imaging on echocardiography, cardiac magnetic resonance imaging, invasive hemodynamic assessment, and endomyocardial biopsy have been demonstrated to be useful in understanding the cardiac alterations that typically affect scleroderma patients. Recent application of novel cardiac detection strategies is providing increased insight into the breadth and pathogenesis of cardiac complications of scleroderma. Further studies coupling exercise provocation, invasive and imaging assessment, and mechanistic studies in scleroderma cardiac tissue are needed to develop the optimal approach to early detection of cardiac disease in scleroderma and targeted therapies.

Efficacy of a nutraceutical combination on lipid metabolism in patients with metabolic syndrome: a multicenter, double blind, randomized, placebo controlled trial.

BACKGROUND: Nutraceuticals represent a new therapeutic frontier in the treatment of metabolic syndrom (MetS) and related cardiovascular risk factors. The aim of this study was to evaluate the potential beneficial effects of Armolipid Plus (AP) (berberine 500 mg, red yest rice, monacolin K 3 mg and policosanol 10 mg) on insulin resistance, lipid profile, particularly on small and dense LDL cholesterol (sdLDL-C), representing the most atherogenic components, as well as its effects on high sensitivity C-reactive protein, a notable marker of cardiovascular risk, blood pressure and cardiac remodeling in subjects affected by MetS, with left ventricular hypertrophy. METHODS: The study was a prospective, multi-center, randomized, double blind, placebo-controlled trial. One hundred and fifty eight patients, aged between 28 and 76 years old, were enrolled and randomized to receive either one tablet of AP or placebo (PL) once daily for 24 weeks. Anthropometric and vital parameters, total cholesterol (tot-C), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglyceridemia (TG), non-HDL cholesterol (NHDL-C) and sdLDL-C were evaluated. RESULTS: After 24 weeks of treatment, the analysis performed on 141 subjects (71 in AP arm and 70 in PL arm), showed a significant improvement of lipid profile in the AP group, with reduction in tot-C (- 13.2 mg/dl), LDL-C (- 13.9 mg/dl) and NHDL-C (- 15.3 mg/dl) and increase in HDL-C (+ 2.0 mg/dl). These changes were equally significant compared with placebo (tot-C: AP - 13.2 mg/dL vs PL + 2.7 mg/dL, p < 0.01; LDL-C: AP -13.9 mg/dl vs PL + 1.5 mg/dl, p < 0.01; NHDL-C: AP -15.3 mg/dl vs PL + 2.8 mg/dl, p < 0.01), Although no significant difference was observed between the two arms in the reduction of HDL-C nevertheless it increased significantly in the AP group (AP + 2 mg/dL p < 0.05, PL 0.13 mg/dL). CONCLUSION: The results of this study, applicable to a specific local population show that, in a population of subjects affected by MetS, treatment with AP improves the lipid profile and the most atherogenic factors, thus suggesting a reduction in the risk of development and progression of atherosclerosis, particularly in subjects with high atherogenic risk, due to the presence of sdLDL-C.

Metabolomic Perspectives in Antiblastic Cardiotoxicity and Cardioprotection.

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.

Inflammatory, Serological and Vascular Determinants of Cardiovascular Disease in Systemic Lupus Erythematosus Patients.

BACKGROUND AND AIM: Systemic lupus erythematosus (SLE) is associated with increased risk of cardiovascular disease (CVD). Among many mechanisms, accelerated atherosclerosis, endothelial dysfunction, and hypercoagulability play a main role. Here, we investigate whether inflammatory, serological and clinical markers of SLE determine and correlate with arterial stiffness in SLE patients. MATERIALS AND METHODS: Routine blood samples, inflammatory mediators, specific antibodies, and 24 h proteinuria were measured in 43 SLE patients and 43 age and sex-matched controls using routine laboratory assays. We also assessed arterial stiffness by measuring radial artery applanation tonometry-derived augmentation index (AI), normalized AI (AIx@75), aortic pulse pressure, central systolic, diastolic and peripheral blood pressure. RESULTS: SLE patients showed a significantly greater arterial stiffness vs. controls, as demonstrated by the significantly higher AIx@75 and aortic pulse pressure. Interestingly, regression analysis showed that age, systolic pulse pressure, inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), daily dose of glucocorticoids, and cumulative organ damage positively correlated with arterial stiffness. CONCLUSIONS: SLE patients show increased arterial stiffness which correlates with markers of inflammation, that is involved in early alterations in arterial walls. Applanation tonometry can be used to screen SLE patients for subclinical vascular damage to implement prevention strategies for CVD.

Models of Heart Failure Based on the Cardiotoxicity of Anticancer Drugs.

Heart failure (HF) is a complication of oncological treatments that may have dramatic clinical impact. It may acutely worsen a patient's condition or it may present with delayed onset, even years after treatment, when cancer has been cured or is in stable remission. Several studies have addressed the mechanisms of cancer therapy-related HF and some have led to the definition of disease models that hold valid for other and more common types of HF. Here, we review these models of HF based on the cardiotoxicity of antineoplastic drugs and classify them in cardiomyocyte-intrinsic, paracrine, or potentially secondary to effects on cardiac progenitor cells. The first group includes HF resulting from the combination of oxidative stress, mitochondrial dysfunction, and activation of the DNA damage response, which is typically caused by anthracyclines, and HF resulting from deranged myocardial energetics, such as that triggered by anthracyclines and sunitinib. Blockade of the neuregulin-1/ErbB4/ErbB2, vascular endothelial growth factor/vascular endothelial growth factor receptor and platelet-derived growth factor /platelet-derived growth factor receptor pathways by trastuzumab, sorafenib and sunitinib is proposed as paradigm of cancer therapy-related HF associated with alterations of myocardial paracrine pathways. Finally, anthracyclines and trastuzumab are also presented as examples of antitumor agents that induce HF by affecting the cardiac progenitor cell population.

Novel metrics for risk stratification with nuclear cardiology.

Risk prediction through integration of clinical variables and imaging data into a prognostic model can identify those factors with a high impact on patient outcome. The development of a prognostic model traditionally includes the evaluation of the independent contribution of variables with consideration of covarying factors that may confound risk stratification. Several methods and metrics are available to assess the performance of a prediction model. Traditional measures for binary and survival outcomes include the concordance (C) statistic for discriminative ability, and goodness-of-fit statistics for calibration. Different prognostic approaches, including variants of the C statistic for survival data, reclassification tables, net reclassification improvement, and integrated discrimination improvement have been recently proposed to evaluate the contribution of new markers when they are added to a defined risk model and to evaluate how these variables are able to change the class of risk of the patient and the resulting diagnostic and therapeutic managements. Moreover, decision-analytic measures including decision curves analysis have been introduced to assess the net benefit obtained by making clinical decisions based on model predictions. This review provides an overview of various metrics available for risk stratification using nuclear cardiology procedures, underlying the need of choosing the appropriate prognostic model in order to justify the referral decision.