Guideline-Directed Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Incident Cancer.

BACKGROUND: It has been postulated that cancer hampers the delivery of guideline-directed medical therapy (GDMT) for heart failure (HF). However, few data are available in this regard. METHODS: We performed a retrospective analysis from the HF Outpatient Clinic of the IRCCS Ospedale Policlinico San Martino in Genova, Italy. All HF patients evaluated between 2010 and 2019, with a left ventricular ejection fraction <50% and at least two visits ≥3 months apart with complete information about GDMT were included in the study. We assessed the prescription of GDMT-in particular, beta-blockers (BB), renin-angiotensin system inhibitors (RASi), and mineralocorticoid antagonists (MRA)-at the time of the last HF evaluation and compared it between patients with and without incidental cancer. For those with incidental cancer, we also evaluated modifications of GDMT comparing the HF evaluations before and after cancer diagnosis. RESULTS: Of 464 HF patients, 39 (8%) had incidental cancer. There were no statistical differences in GDMT between patients with and without incidental cancer at last evaluation. In the year following cancer diagnosis, of 33 patients with incidental cancer on BB, none stopped therapy, but two had a down-titration to a dosage <50%; of 27 patients on RASi, two patients stopped therapy and three had a down-titration to a dosage <50%; of 19 patients on MRA, four stopped therapy. CONCLUSIONS: Although HF patients with incidental cancer may need to have GDMT down-titrated at the time of cancer diagnosis, this does not appear to significantly hinder the delivery of HF therapies during follow-up.

Association between Immune Checkpoint Inhibitors and Atherosclerotic Cardiovascular Disease Risk: Another Brick in the Wall.

In recent years, immune checkpoint inhibitors have significantly changed the field of oncology, emerging as first-line treatment, either alone or in combination with other regimens, for numerous malignancies, improving overall survival and progression-free survival in these patients. However, immune checkpoint inhibitors might also cause severe or fatal immune-related adverse events, including adverse cardiovascular events. Initially, myocarditis was recognized as the main immune checkpoint inhibitor-related cardiac event, but our knowledge of other potential immune-related cardiovascular adverse events continues to broaden. Recently, preclinical and clinical data seem to support an association between immune checkpoint inhibitors and accelerated atherosclerosis as well as atherosclerotic cardiovascular events such as cardiac ischemic disease, stroke, and peripheral artery disease. In this review, by offering a comprehensive overview of the pivotal role of inflammation in atherosclerosis, we focus on the potential molecular pathways underlying the effects of immune checkpoint inhibitors on cardiovascular diseases. Moreover, we provide an overview of therapeutic strategies for cancer patients undergoing immunotherapy to prevent the development of cardiovascular diseases.

Atrial Fibrillation in Patients with Hypertrophic Cardiomyopathy and Cardiac Amyloidosis: From Clinical Management to Catheter Ablation Indication.

Atrial fibrillation (AF) is the most common arrhythmia in patients affected by cardiomyopathies. Reports estimate a prevalence of 27% in patients with hypertrophic cardiomyopathy (HCM) and 40% in patients with cardiac amyloidosis (CA). The presence of AF typically results in progressive functional decline, an increased frequency of hospitalizations for heart failure, and a higher thromboembolic risk. Medical management using mainly beta-blockers or amiodarone has produced variable outcomes and a high rate of recurrence. Catheter ablation reduces symptom burden and complications despite a moderate rate of recurrence. Recent evidence suggests that an early rhythm control strategy may lead to more favorable short- and long-term outcomes. In this review, we summarize contemporary data on the management of AF in patients with cardiomyopathy (HCM and CA) with particular reference to the timing and outcomes of ablation procedures.

Low Perception of Obesity as a Pathological Condition Among Italian Cardiologists.

INTRODUCTION: Obesity is not only an important modifiable cardiovascular risk factor but also a chronic disease with relevant consequences on morbidity and mortality in the general population. According to European guidelines, cardiologists must recognize and treat it properly. AIMS: To assess perception of obesity as a modifiable pathological condition and the importance to treat it in a real-world sample of cardiologists and residents in cardiology. METHODS: A nationwide, web-based, epidemiological survey on the perception of obesity as a disease and as a modifiable cardiovascular risk factors was conducted in 137 medical doctors (cardiologists and residents in cardiology). Participants filled with their answers a questionnaire of 31 questions about perception of obesity and strategies on cardiovascular disease prevention in clinical practice. RESULTS: Of 137 individuals enrolled in our survey only 5 (3.6%) reported to measure waist circumference in their clinical practice and only 3 (2.2%) reported to measure waist-to-hip ratio. One-hundred-twenty participants (87.6%) would not prescribe an anti-obesity drug to a patient with grade II obesity. Sixty-eight (49.6%) participants have never read or heard of a clinical trial on obesity. On the other hand, 134 (97.8%) routinely measured blood pressure in their clinical practice, 129 (94.2%) would prescribe a statin for a hypercholesterolemic patient and 132 (96.4%) subjects have read/heard a clinical trial on type 2 diabetes in their life. CONCLUSIONS: Although obesity is a chronic disease and an important modifiable cardiovascular risk factor such as arterial hypertension, hypercholesterolemia, cigarette smoke and diabetes, cardiologists and residents in cardiology substantially underestimate it ignoring that it should be treated as a proper disease.

Role of Arterial Hypertension and Hypertension-Mediated Organ Damage in Cardiotoxicity of Anticancer Therapies.

PURPOSE OF THE REVIEW: Arterial hypertension (AH) is the most common cardiovascular (CV) risk factor in the community and in oncologic patients. It also represents the most important CV condition predisposing to anticancer treatment-related cardiotoxicity. This risk is heightened in the presence of cardiac AH-mediated organ damage (HMOD). Influence of AH and HMOD on the development of cardiotoxicity will be reviewed, with a focus on specific scenarios and implications for management of oncologic patients. RECENT FINDINGS: Not adequately controlled AH before or during anticancer treatments and/or development of AH during or after completion of such therapies have detrimental effects on the clinical course of oncologic patients, particularly if HMOD is present. As overlooking CV health can jeopardize the success of anticancer treatments, the goal for clinicians caring for the oncologic patient should include the treatment of AH and HMOD.

A contemporary update on cancer and takotsubo syndrome.

Takotsubo syndrome (TTS) is characterized by a transient left ventricular systolic dysfunction, burdened by significant acute and long-term mortality and morbidity. The prognosis of TTS, especially in the long-term, is influenced by both non-cardiovascular (non-CV) and CV comorbidities, among which cancer is one of the most common. The presence of a malignancy is proven to be associated with higher mortality in TTS. Moreover, a number of anticancer treatments has been reported to possibly cause TTS as a form of cardiotoxicity, even though clearcut associations are lacking. The aim of this narrative review is to sum up contemporary knowledge on the association of cancer and TTS, addressing unmet needs and practical implications. The importance of a close collaboration between cardiologists and oncologists is herein highlighted, both to allow an adequate management of the acute TTS phase, and to actively and safely return to the oncologic management once the acute setting is resolved.

Exploring the influence of takotsubo syndrome on oncologic patients' mortality.

It has been reported that patients affected by takotsubo syndrome (TTS) with a concurrent diagnosis of cancer suffer from greater mortality as compared to their non-cancer counterpart. It remains unclear whether TTS worsens the prognosis of cancer patients as well. Aim of this study was to compare outcomes of cancer patients with and without TTS. We combined data from two independent cohorts: one consisted of a prospective multicentre TTS registry; the second cohort consisted of all oncologic patients from two Cardio-Oncology Outpatient Clinics, who did not have cardiovascular conditions at the time of the cardio-oncologic visit. From the TTS registry, we selected patients with cancer (cancer-TTS patients). Next, we matched these patients with those from the cardio-oncologic cohort (cancer non-TTS patients) in a 1:2 fashion by age, sex, and type and cancer staging. Study endpoint was all-cause mortality. Among 318 TTS patients, 42 (13%) had a concurrent diagnosis of cancer. Characteristics of cancer-TTS patients and of the 84 matched cancer non-TTS subjects were comparable with the exception of diabetes mellitus, which was more common in cancer non-TTS patients. All-cause mortality was similar between cancer-TTS and cancer non-TTS patients. At Cox regression analysis TTS was not associated with mortality (OR 1.4, 95% CI 0.6-3.3, p = 0.43). Our findings show that even in the presence of acute heart failure due to TTS, the prognosis of oncologic patients is driven by the malignancy itself. Our results may prove useful for integrated management of cardio-oncologic patients.

New Insights on the Toxicity on Heart and Vessels of Breast Cancer Therapies.

Cardiovascular diseases are largely represented in patients with cancer and appear to be important side effects of cancer treatments, heavily affecting quality of life and leading to premature morbidity and death among cancer survivors. In particular, treatments for breast cancer have been shown to potentially play serious detrimental effects on cardiovascular health. This review aims to explore the available literature on breast cancer therapy-induced side effects on heart and vessels, illustrating the molecular mechanisms of cardiotoxicity known so far. Moreover, principles of cardiovascular risk assessment and management of cardiotoxicity in clinical practice will also be elucidated. Chemotherapy (anthracycline, taxanes, cyclophosphamide and 5-fluorouracil), hormonal therapy (estrogen receptor modulator and gonadotropin or luteinizing releasing hormone agonists) and targeted therapy (epidermal growth factor receptor 2 and Cyclin-dependent kinases 4 and 6 inhibitors) adverse events include arterial and pulmonary hypertension, supraventricular and ventricular arrhythmias, systolic and diastolic cardiac dysfunction and coronary artery diseases due to different and still not well-dissected molecular pathways. Therefore, cardiovascular prevention programs and treatment of cardiotoxicity appear to be crucial to improve morbidity and mortality of cancer survivors.

Baseline cardio-oncologic risk assessment in breast cancer women and occurrence of cardiovascular events: The HFA/ICOS risk tool in real-world practice.

BACKGROUND: the European Society of Cardiology Heart Failure Association (HFA) together with the International Cardio-Oncology Society (ICOS) proposed charts for baseline CV risk assessment of cancer patients scheduled to receive anthracyclines and anti-human epidermal growth factor receptor-2 (HER2) agents. METHODS: We investigated HFA/ICOS risk stratification, prescriptions of cardioactive drugs, and occurrence of CV events in a multicentric breast cancer (BC) cohort from 3 Italian Outpatient Cardio-Oncology Clinics. RESULTS: 373 BC patients who underwent a baseline Cardio-Oncologic evaluation were included, of whom 202 scheduled to receive anthracyclines and 171 anti-HER2. Mean age was 60 ± 12 years and 49% of BC patients had ≥2 CV risk factors. In the anthracyclines group, 51% were at low-risk, 43% at medium-risk and 6% at high-risk; while in the anti-HER2 group, 27% patients were at low-risk, 58% at medium-risk and 15% at high-risk. In both groups, a medium-to-high risk was associated with use of cardioactive therapies (p < 0.0001). There were no LVD events in anthracycline recipients, and 16 LVD among anti-HER2 patients. A medium-to-high risk was not associated with LVD occurrence (p = 0.17). CONCLUSIONS: Patients with medium-to-high HFA/ICOS risk were more likely to receive cardioactive therapies, possibly explaining the lack of association of risk categories with LVD occurrence.

Antihypertensive drugs and the risks of cancer: More fakes than facts.

In the last century, the diffusion of medical news to the public has been profoundly changed by the progressive spread of more pervasive, but at the same time often unreliable, means of communication. The misinterpretation of scientific evidence or fallacious presentation through social media could play as a great drawback to the success in the management of many diseases. This may become particularly alarming when concerning chronic diseases widely affecting the population. Arterial hypertension is still today one of the major causes of mortality and morbidity in most countries, and its management generally requires chronic therapy lasting for decades. Therefore, a recent debate about the potential oncogenic effect of antihypertensive drugs has been made widely available to patients mostly through social media. Since this is a topic of great impact for millions of patients and of main relevance for the scientific community, it must not be contaminated by the spread of fake or twisted news. The objective of this article is to briefly discuss the almost complete lack of hard evidence about the potential oncogenic effect of the major classes of antihypertensive drugs as opposed to the exaggerated mediatic communication and impact of scattered and unconfirmed observations. We believe that it is of key importance to provide authoritative support for patients and clinicians from scientific societies and guidelines to balance an unopposed widespread penetration of twisted or even fake news.

Effect of direct renin inhibition on vascular function after long-term treatment with aliskiren in hypertensive and diabetic patients.

OBJECTIVE: We tested the hypothesis that chronic treatment with the direct renin inhibitor aliskiren improves vascular function in resistance and conduit arteries of type two diabetic and hypertensive patients. METHOD: Sixteen patients with mild essential hypertension and with a previous diagnosis of noninsulin-dependent diabetes mellitus were included in the study. Patients were then randomized to aliskiren (150 mg once daily, n = 9), or ramipril (5 mg once daily, n = 7). Each patient underwent a biopsy of the subcutaneous tissue and small arteries were dissected and mounted on a pressurized micromyograph to evaluate endothelium dependent vasorelaxation in response to acetylcholine ±â€ŠN omega-nitro-L-arginine methyl ester hydrochloride in vessels precontracted with norepinephrine. Endothelial function has been quantified also in large conduit arteries by flow-mediated dilation. RESULTS: A similar office blood pressure-lowering effect was observed with the two drugs, although changes in DBP were not statistically significant in the ramipril group. Aliskiren significantly improved endothelium-dependent relaxation in subcutaneous resistance arteries, as well as increased flow-mediated dilation in conduit arteries, whereas the effects induced by ramipril did not reach statistical significance. Only aliskiren significantly increased the expression of p1177-endothelial nitric oxide synthase in the endothelium. Both aliskiren and ramipril had a negligible effect on markers of oxidative stress. CONCLUSION: Aliskiren restored endothelial function and induced a more prompt peripheral vasodilation in hypertensive and diabetic patients possibly through the increased production of nitric oxide via the enhanced expression and function of the active phosphorylated form of endothelial nitric oxide synthase.

Mas Receptor Activation Contributes to the Improvement of Nitric Oxide Bioavailability and Vascular Remodeling During Chronic AT1R (Angiotensin Type-1 Receptor) Blockade in Experimental Hypertension.

Angiotensin (1-7) production increases during AT1R (angiotensin type-1 receptor) blockade. The contribution of Ang (1-7) (angiotensin [1-7]) and its receptor (MasR) to the favorable effect of angiotensin receptor blockers on remodeling and function of resistance arteries remains unclear. We sought to determine whether MasR contributes to the improvement of vascular structure and function during chronic AT1R blockade. Spontaneously hypertensive rats were treated with Ang (1-7) or olmesartan ± MasR antagonist A-779, or vehicle, for 14 days. Blood pressure was measured by tail cuff methodology. Mesenteric arteries were dissected and mounted on a pressurized micromyograph to evaluate media-to-lumen ratio (M/L) and endothelial function. Expression of MasR and eNOS (endothelial nitric oxide synthase) was evaluated by immunoblotting, plasma nitrate by colorimetric assay, and reactive oxygen species production by dihydroethidium staining. Independently of blood pressure, olmesartan significantly reduced M/L and improved NO bioavailability, A-779 prevented these effects. Likewise, Ang (1-7) significantly reduced M/L and NO bioavailability. MasR expression was significantly increased by Ang (1-7) as well as by olmesartan, and it was blunted in the presence of A-779. Both Ang (1-7) and olmesartan increased eNOS expression and plasma nitrite which were reduced by A-779. Superoxide generation was attenuated by olmesartan and Ang (1-7) and was blunted in the presence of A-779. These MasR-mediated actions were independent of AT2R activation since olmesartan and Ang (1-7) increased MasR expression and reduced M/L in Ang II (angiotensin II)-infused AT2R knockout mice, independently of blood pressure control. A-779 prevented these effects. Hence, MasR activation may contribute to the favorable effects of AT1R antagonism on NO bioavailability and microvascular remodeling, independently of AT2R activation and blood pressure control.

Antihypertensive drugs and the risk of cancer: a critical review of available evidence and perspective.

: The issue of a potential danger of antihypertensive drugs related to cancer susceptibility is currently generating a major debate in the scientific community, concerns in the public and emphasized interest from the media. The present article is a thorough review of what is known on the various classes of antihypertensive drugs concerning the risk of developing different neoplasms and about the suggested pathophysiological mechanisms, whenever available. The main limitations of evidence derived from studies currently available in this setting are also discussed, high-lightening the need for newly developed approaches to generate more accurate recommendations and informed advice for physicians.

Recent Warnings about Antihypertensive Drugs and Cancer Risk: Where Do They Come From?

The recent decrease in mortality related to cardiovascular diseases has largely been due to the more effective treatment of cardiovascular risk factors and secondary prevention therapies. More people than ever are now on long-term medications. Hypertension, which is one of the most common cardiovascular risk factors, requires life-long treatment. Recent evidence has focused attention on the risk of cancer that may be associated with the long-term use of antihypertensive therapy. This article summarises available evidence surrounding three recent events in this setting. Even though this is a crucial patient safety issue, there are no conclusive answers at this time and further studies are required.

ARNi: A Novel Approach to Counteract Cardiovascular Diseases.

Cardiovascular diseases (CVDs) still represent the greatest burden on healthcare systems worldwide. Despite the enormous efforts over the last twenty years to limit the spread of cardiovascular risk factors, their prevalence is growing and control is still suboptimal. Therefore, the availability of new therapeutic tools that may interfere with different pathophysiological pathways to slow the establishment of clinical CVDs is important. Previously, the inhibition of neurohormonal systems, namely the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, has proven to be useful in the treatment of many CVDs. Attempts have recently been made to target an additional hormonal system, that of the natriuretic peptides (NPs), which, when dysregulated, can also play a role in the development CVDs. Indeed, a new class of drug, the angiotensin receptor-neprilysin inhibitors (ARNi), has the ability to counteract the effects of angiotensin II as well as to increase the activity of NPs. ARNi have already been proven to be effective in the treatment of heart failure with reduced ejection fraction. New evidence has suggested that, in the next years, the field of ARNi application will widen to include other CVDs, such as heart failure, with preserved ejection fraction and hypertension.

Executive Summary of the 2018 Joint Consensus Document on Cardiovascular Disease Prevention in Italy.

Cardiovascular diseases (CVDs) are the leading cause of death, disability and hospitalization in Italy. Primary prevention strategies are able to prevent clinically evident CVDs, mostly by early identifying asymptomatic, otherwise healthy individuals at risk of developing CVDs. A more modern approach recommended for effective CVD prevention is based on "4P", that is: Predictive, Preventive, Personalized and Participative. This executive document reflects the key points of a consensus paper on CV prevention in Italy, realized though the contribution of different Italian Scientific Societies and the National Research Council, and coordinated by the Italian Society of Cardiovascular Prevention (SIPREC), published in 2018. The need for such document relies on the difficulty to apply "sic et simpliciter" European guidelines, to which this document is largely inspired, to national, regional and local realities, in this Mediterranean country, namely Italy. Indeed, our Country has specific features in terms of demography, socio-cultural habits, distribution and prevalence of risk factors, organization, policy and access to National Health Service compared to other European countries.

Achievement of multiple therapeutic targets for cardiovascular disease prevention: Retrospective analysis of real practice in Italy.

BACKGROUND: Pharmacological therapy in patients at high cardiovascular (CV) risk should be tailored to achieve recommended therapeutic targets. HYPOTHESIS: To evaluate individual global CV risk profile and to estimate the control rates of multiple therapeutic targets for in adult outpatients followed in real practice in Italy. METHODS: Data extracted from a cross-sectional, national medical database of adult outpatients in real practice in Italy were analyzed for global CV risk assessment and rates of control of major CV risk factors, including hypertension, dyslipidemia, diabetes, and obesity. CV risk characterization was based on the European SCORE equation and the study population stratified into 3 groups: low risk (<2%), intermediate risk (≥2%-<5%), and high to very high risk (≥5%). RESULTS: We analyzed data from 7158 adult outpatients (mean age, 57.7 ±5.3 years; BMI, 28.3 ±5.0 kg/m2 , BP, 136.0 ±14.3/82.2 ±8.3 mm Hg; total cholesterol, 212.7 ±40.7 mg/dL), among whom 2029 (45.2%) had low, 1730 (24.2%) intermediate, and 731 (16.3%) high to very high risk. Increased SCORE risk was an independent predictor of poor achievement of diastolic BP <90 mm Hg (OR: 0.852, 95% CI: 0.822-0.882), LDL-C < 130 mg/dL (OR: 0.892, 95% CI: 0.861-0.924), HDL-C > 40 (males)/>50 (females) mg/dL (OR: 0.926, 95% CI: 0.895-0.958), triglycerides <160 mg/dL (OR: 0.925, 95% CI: 0.895-0.957), and BMI <25 kg/m2 (OR: 0.888, 95% CI: 0.851-0.926), even after correction for diabetes, renal function, pharmacological therapy, and referring physicians (P < 0.001). CONCLUSIONS: Despite low prevalence and optimal medical therapy, individuals with high to very high SCORE risk did not achieve recommended therapeutic targets in a real-world practice.

Prevalence and clinical outcomes of white-coat and masked hypertension: Analysis of a large ambulatory blood pressure database.

The aim of this study was to analyze prevalence and clinical outcomes of the following clinical conditions: normotension (NT; clinic BP < 140/90 mm Hg; 24-hour BP < 130/80 mm Hg), white-coat hypertension (WCHT; clinic BP ≥ 140 and/or ≥90 mm Hg; 24-hour BP < 130/80 mm Hg), masked hypertension (MHT; clinic BP < 140/90 mm Hg; 24-hour BP ≥ 130 and/or ≥80 mm Hg), and sustained hypertension (SHT; clinic BP ≥ 140 and/or ≥90 mm Hg; 24-hour BP ≥ 130 and/or ≥80 mm Hg) in a large cohort of adult untreated individuals. Systematic research throughout the medical database of Regione Lazio (Italy) was performed to estimate incidence of myocardial infarction (MI), stroke, and hospitalizations for HT and heart failure (HF). Among a total study sample of 2209 outpatients, 377 (17.1%) had NT, 351 (15.9%) had WCHT, 149 (6.7%) had MHT, and 1332 had (60.3%) SHT. During an average follow-up of 120.1 ± 73.9 months, WCHT was associated with increased risk of hospitalization for HT (OR 95% CI: 1.927 [1.233-3.013]; P = .04) and HF (OR 95% CI: 3.449 [1.321-9.007]; P = .011). MHT was associated with an increased risk of MI (OR 95% CI: 5.062 [2.218-11.550]; P < .001), hospitalization for HT (OR 95% CI: 2.553 [1.446-4.508]; P = .001), and for HF (OR 95% CI: 4.214 [1.449-12.249]; P = .008). These effects remained statistically significant event after corrections for confounding factors including age, BMI, gender, smoking, dyslipidaemia, diabetes, and presence of antihypertensive therapies.

Aspirin and the Primary Prevention of Cardiovascular Diseases: An Approach Based on Individualized, Integrated Estimation of Risk.

While the use of aspirin in the secondary prevention of cardiovascular (CVD) is well established, aspirin in primary prevention is not systematically recommended because the absolute CV event reduction is similar to the absolute excess in major bleedings. Recently, emerging evidence suggests the possibility that the assumption of aspirin, may also be effective in the prevention of cancer. By adding to the CV prevention benefits the potential beneficial effect of aspirin in reducing the incidence of mortality and cancer could tip the balance between risks and benefits of aspirin therapy in the primary prevention in favour of the latter and broaden the indication for treatment with in populations at average risk. While prospective and randomized study are currently investigating the effect of aspirin in prevention of both cancer and CVD, clinical efforts at the individual level to promote the use of aspirin in global (or total) primary prevention could be already based on a balanced evaluation of the benefit/risk ratio.