Clinical application of CMR in cardiomyopathies: evolving concepts and techniques : A position paper of myocardial and pericardial diseases and cardiac magnetic resonance working groups of Italian society of cardiology.

Cardiac magnetic resonance (CMR) has become an essential tool for the evaluation of patients affected or at risk of developing cardiomyopathies (CMPs). In fact, CMR not only provides precise data on cardiac volumes, wall thickness, mass and systolic function but it also a non-invasive characterization of myocardial tissue, thus helping the early diagnosis and the precise phenotyping of the different CMPs, which is essential for early and individualized treatment of patients. Furthermore, several CMR characteristics, such as the presence of extensive LGE or abnormal mapping values, are emerging as prognostic markers, therefore helping to define patients' risk. Lastly new experimental CMR techniques are under investigation and might contribute to widen our knowledge in the field of CMPs. In this perspective, CMR appears an essential tool to be systematically applied in the diagnostic and prognostic work-up of CMPs in clinical practice. This review provides a deep overview of clinical applicability of standard and emerging CMR techniques in the management of CMPs.

Effects of sacubitril/valsartan on exercise capacity: a prognostic improvement that starts during uptitration.

PURPOSE: Sacubitril/valsartan is a mainstay of the treatment of heart failure with reduced ejection fraction (HFrEF); however, its effects on exercise performance yielded conflicting results. Aim of our study was to evaluate the impact of sacubitril/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses. METHODS: We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril/valsartan was introduced at 24/26 mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97/103 mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6 months after reaching the maximum tolerated dose. RESULTS: Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6 ± 4.5 to 16.5 ± 4.9 mL/min/kg; p trend = 0.001), while minute ventilation/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril/valsartan induced positive left ventricle reverse remodeling (EF from 31 ± 5 to 37 ± 8%; p trend < 0.001), while NT-proBNP reduced from 1179 [610-2757] to 780 [372-1344] pg/ml (p trend < 0.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42-7.71] to 2.35% [1.24-4.96], p = 0.003. CONCLUSIONS: A holistic and progressive HF improvement was observed with sacubitril/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.

Direct oral anticoagulants across the heart failure spectrum: the precision medicine era.

Heart failure (HF) is characterized by a pro-thrombotic state, which might aggravate its morbidity and, consequently, mortality. Several and commonly observed comorbidities, such as coronary artery disease, atrial fibrillation (AF), renal dysfunction, and diabetes often complicate HF, increasing the thromboembolic risk. In the past decade, direct oral anticoagulants (DOACs) have been approved for the treatment and prevention of stroke and embolic events in patients with nonvalvular AF. Due to their lower bleeding risk, these drugs are frequently used instead of warfarin; however, some controversies exist on their use in HF patients with or without comorbidities. Indeed, the management of anticoagulation in HF patients with underlying conditions is poorly investigated since these patients are underrepresented or excluded from randomized controlled trials. The aim of this research is to review current evidence on the use of DOACs in HF patients, also discussing their specific use in different clinical scenarios. Graphical abstract.

Progressive right ventricular dysfunction and exercise impairment in patients with heart failure and diabetes mellitus: insights from the T.O.S.CA. Registry.

BACKGROUND: Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance-IR or diabetes mellitus-T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. METHODS: Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. RESULTS: Compared with EU and IR, T2D was associated with increased filling pressures (E/e'ratio: 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p < 0.01) and worse right ventricular(RV)-arterial uncoupling (RVAUC) (TAPSE/PASP ratio 0.52 ± 0.2, 0.6 ± 0.3, and 0.6 ± 0.3 in T2D, EU and IR, respectively, p < 0.05). Likewise, impairment in peak oxygen consumption (peak VO2) in TD2 vs EU and IR patients was recorded (respectively, 15.8 ± 3.8 ml/Kg/min, 18.4 ± 4.3 ml/Kg/min and 16.5 ± 4.3 ml/Kg/min, p < 0.003). Longitudinal data demonstrated higher deterioration of RVAUC, RV dimension, and peak VO2 in the T2D group (+ 13% increase in RV dimension, - 21% decline in TAPSE/PAPS ratio and - 20% decrease in peak VO2). CONCLUSION: The higher risk of death and CV hospitalizations exhibited by HF-T2D patients in the T.O.S.CA. Registry is associated with progressive RV ventricular dysfunction and exercise impairment when compared to euglycemic CHF patients, supporting the pivotal importance of hyperglycaemia and right chambers in HF prognosis. Trial registration ClinicalTrials.gov identifier: NCT023358017.

Cardiorenal syndrome: Pathophysiology as a key to the therapeutic approach in an under-diagnosed disease.

Cardiorenal syndrome is a clinical condition that impacts both the heart and the kidneys. One organ's chronic or acute impairment can lead to the other's chronic or acute dysregulation. The cardiorenal syndrome has been grouped into five subcategories that describe the etiology, pathophysiology, duration, and pattern of cardiac and renal dysfunction. This classification reflects the large spectrum of interrelated dysfunctions and underlines the bidirectional nature of heart-kidney interactions. However, more evidence is needed to apply these early findings in medical practice. Understanding the relationship between these two organs during each organ's impairment has significant clinical implications that are relevant for therapy in both chronic and acute conditions. The epidemiology, definition, classification, pathophysiology, therapy, and outcome of each form of cardiorenal syndrome are all examined in this review.

Renal function and cardiac adrenergic impairment in patients affected by heart failure.

Although in heart failure (HF) there is a strict correlation between heart and kidney, no data are available on the potential relationship in HF between renal dysfunction (RD) and the impaired sympathetic innervation. Aim of the present study was to assess the relationship between RD and cardiac sympathetic innervation in HF patients with reduced ejection fraction. Two hundred and sixty-three patients with mild-to-severe HF underwent iodine-123 meta-iodobenzylguanidine myocardial scintigraphy to assess sympathetic innervation, evaluating early and late heart-to-mediastinum (H/M) ratios and washout rate. In all patients, glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was assessed. A direct association was found between EPI-eGFR and late H/M (r = .215; P < .001). Dividing the population into moderate-to-severe eGFR reduction and normal-to-mildly reduced eGFR (cutoff ≤ 60 mL·min-1·1.73 m-2), a statistically significant reduction of late H/M value was found in patients with RD compared to patients with preserved eGFR (P = .030). By multivariable linear regression analysis, eGFR resulted in the prediction of impaired late H/M in patients with RD (P = .005). Patients with RD and HF show more impaired cardiac sympathetic activity than HF patients with preserved renal function, and reduced eGFR is a predictor of reduced late H/M.

Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era.

AIMS: To evaluate the impact of the COVID-19 pandemic on patient admissions to Italian cardiac care units (CCUs). METHODS AND RESULTS: We conducted a multicentre, observational, nationwide survey to collect data on admissions for acute myocardial infarction (AMI) at Italian CCUs throughout a 1 week period during the COVID-19 outbreak, compared with the equivalent week in 2019. We observed a 48.4% reduction in admissions for AMI compared with the equivalent week in 2019 (P < 0.001). The reduction was significant for both ST-segment elevation myocardial infarction [STEMI; 26.5%, 95% confidence interval (CI) 21.7-32.3; P = 0.009] and non-STEMI (NSTEMI; 65.1%, 95% CI 60.3-70.3; P < 0.001). Among STEMIs, the reduction was higher for women (41.2%; P = 0.011) than men (17.8%; P = 0.191). A similar reduction in AMI admissions was registered in North Italy (52.1%), Central Italy (59.3%), and South Italy (52.1%). The STEMI case fatality rate during the pandemic was substantially increased compared with 2019 [risk ratio (RR) = 3.3, 95% CI 1.7-6.6; P < 0.001]. A parallel increase in complications was also registered (RR = 1.8, 95% CI 1.1-2.8; P = 0.009). CONCLUSION: Admissions for AMI were significantly reduced during the COVID-19 pandemic across Italy, with a parallel increase in fatality and complication rates. This constitutes a serious social issue, demanding attention by the scientific and healthcare communities and public regulatory agencies.

Impact of body mass index on cardiac adrenergic derangement in heart failure patients: a 123I-mIBG imaging study.

PURPOSE: To assess the impact of body mass index (BMI) on cardiac adrenergic derangement, measured by iodine-123 meta-iodobenzylguanidine (123I-mIBG) imaging in heart failure (HF) patients. Overweight and obesity represent relevant health issues, and augmented sympathetic tone has been described in patients with increased BMI. An extensive literature supports that HF-dependent cardiac denervation, measured through mIBG parameters, is an independent predictor of cardiovascular outcomes and mortality. However, the influence of BMI on cardiac mIBG uptake has not been largely investigated. METHODS: We prospectively enrolled patients with systolic HF, collecting demographic, clinical, echocardiographic data, and mIBG imaging parameters. In order to detect the factors associated with mIBG parameters, a model building strategy, based on the Multivariable Fractional Polynomial algorithm, has been employed. RESULTS: We studied 249 patients with systolic HF, mean age of 66.4 ± 10.6 years, and mean left ventricular ejection fraction (LVEF) of 30.7% ± 6.4, undergoing cardiac 123I-mIBG imaging to assess HF severity and prognosis. Seventy-eight patients (31.3%) presented a BMI ≥ 30 kg/m2 and obese patients showed a significant reduction in early heart to mediastinum (H/M) ratio (1.66 ± 0.19 vs. 1.75 ± 0.26; p = 0.008) and a trend to reduction in washout rate (33.6 ± 18.3 vs. 38.1 ± 20.1; p = 0.092) compared with patients with BMI < 30 kg/m2. Multiple regression analysis revealed that BMI, age, and LVEF were significantly correlated with early and late H/M ratios. CONCLUSIONS: Results of the present study indicate that BMI, together with LVEF and age, is independently correlated with cardiac mIBG uptake in HF patients.

Prognostic Value of Lymphocyte G Protein-Coupled Receptor Kinase-2 Protein Levels in Patients With Heart Failure.

RATIONALE: Sympathetic nervous system hyperactivity is associated with poor prognosis in patients with heart failure (HF), yet routine assessment of sympathetic nervous system activation is not recommended for clinical practice. Myocardial G protein-coupled receptor kinase-2 (GRK2) is upregulated in HF patients, causing dysfunctional ß-adrenergic receptor signaling. Importantly, myocardial GRK2 levels correlate with levels found in peripheral lymphocytes of HF patients. OBJECTIVE: The independent prognostic value of blood GRK2 measurements in HF patients has never been investigated; thus, the purpose of this study was to evaluate whether lymphocyte GRK2 levels predict clinical outcome in HF patients. METHODS AND RESULTS: We prospectively studied 257 HF patients with mean left ventricular ejection fraction of 31.4±8.5%. At the time of enrollment, plasma norepinephrine, serum NT-proBNP, and lymphocyte GRK2 levels, as well as clinical and instrumental variables were measured. The prognostic value of GRK2 to predict cardiovascular (CV) death and all-cause mortality was assessed using the Cox proportional hazard model including demographic, clinical, instrumental, and laboratory data. Over a mean follow-up period of 37.5±20.2 months (range, 3-60 months), there were 102 CV deaths. Age, left ventricular ejection fraction, New York Heart Association class, chronic obstructive pulmonary disease, chronic kidney disease, N-terminal-pro brain natriuretic peptide, and lymphocyte GRK2 protein levels were independent predictors of CV mortality in HF patients. GRK2 levels showed an additional prognostic and clinical value over demographic and clinical variables. The independent prognostic value of lymphocyte GRK2 levels was also confirmed for all-cause mortality. CONCLUSIONS: Lymphocyte GRK2 protein levels can independently predict prognosis in patients with HF.

Impact of aging on cardiac sympathetic innervation measured by 123I-mIBG imaging in patients with systolic heart failure.

PURPOSE: Sympathetic nervous system (SNS) hyperactivity is a salient characteristic of chronic heart failure (HF) and contributes to the progression of the disease. Iodine-123 meta-iodobenzylguanidine (123I-mIBG) imaging has been successfully used to assess cardiac SNS activity in HF patients and to predict prognosis. Importantly, SNS hyperactivity characterizes also physiological ageing, and there is conflicting evidence on cardiac 123I-mIBG uptake in healthy elderly subjects compared to adults. However, little data are available on the impact of ageing on cardiac sympathetic nerve activity assessed by 123I-mIBG scintigraphy, in patients with HF. METHODS AND RESULTS: We studied 180 HF patients (age = 66.1 ± 10.5 years [yrs]), left ventricular ejection fraction (LVEF = 30.6 ± 6.3 %) undergoing cardiac 123I-mIBG imaging. Early and late heart to mediastinum (H/M) ratios and washout rate were calculated in all patients. Demographic, clinical, and echocardiographic data were also collected. Our study population consisted of 53 patients aged >75 years (age = 77.7 ± 4.0 year), 67 patients aged 62-72 years (age = 67.9 ± 3.2 years) and 60 patients aged ≤61 year (age = 53.9 ± 5.6 years). In elderly patients, both early and late H/M ratios were significantly lower compared to younger patients (p < 0.05). By multivariate analysis, H/M ratios (both early and late) and washout rate were significantly correlated with LVEF and age. CONCLUSIONS: Our data indicate that, in a population of HF patients, there is an independent age-related effect on cardiac SNS innervation assessed by 123I-mIBG imaging. This finding suggests that cardiac 123I-mIBG uptake in patients with HF might be affected by patient age.

Current practice in identifying and treating cardiovascular risk, with a focus on residual risk associated with atherogenic dyslipidaemia.

A panel of European experts on lipids and cardiovascular disease discussed clinical approaches to managing cardiovascular risk in clinical practice, including residual cardiovascular risk associated with lipid abnormalities, such as atherogenic dyslipidaemia (AD). A simplified definition of AD was proposed to enhance understanding of this condition, its prevalence, and its impact on cardiovascular risk. Atherogenic dyslipidaemia can be defined by high fasting triglyceride levels (≥2.3 mmol/L) and low high-density lipoprotein cholesterol (HDL-c) levels (≤1.0 and ≤1.3 mmol/L in men and women, respectively) in statin-treated patients at high cardiovascular risk. The use of a single marker for the diagnosis and treatment of AD, such as non-HDL-c, was advocated. Interventions including lifestyle optimization and low-density lipoprotein (LDL)-lowering therapy with statins (±ezetimibe) are implemented by all experts. Treatment of residual AD can be performed with the addition of fenofibrate, since it can improve the complete lipoprotein profile and reduce the risk of cardiovascular events in patients with AD. Specific clinical scenarios in which fenofibrate may be prescribed are discussed, and include patients with very high triglycerides (≥5.6 mmol/L), patients who are intolerant or resistant to statins, and patients with AD and at high cardiovascular risk. The fenofibrate-statin combination was considered by the experts to benefit from a favourable benefit-risk profile. Cardiovascular experts adopt a multifaceted approach to the prevention of atherosclerotic cardiovascular disease, with lifestyle optimization, LDL-lowering therapy, and treatment of AD with fenofibrate routinely used to help reduce a patient's overall cardiovascular risk.

Alterations of left ventricular deformation and cardiac sympathetic derangement in patients with systolic heart failure: a 3D speckle tracking echocardiography and cardiac ¹²³I-MIBG study.

PURPOSE: Myocardial contractile function is under the control of cardiac sympathetic activity. Three-dimensional speckle tracking echocardiography (3D-STE) and cardiac imaging with (123)I-metaiodobenzylguanidine ((123)I-MIBG) are two sophisticated techniques for the assessment of left ventricular (LV) deformation and sympathetic innervation, respectively, which offer important prognostic information in patients with heart failure (HF). The purpose of this investigation was to explore, in patients with systolic HF, the relationship between LV deformation assessed by 3D-STE and cardiac sympathetic derangement evaluated by (123)I-MIBG imaging. METHODS: We prospectively studied 75 patients with systolic HF. All patients underwent a 3D-STE study (longitudinal, circumferential, area and radial) and (123)I-MIBG planar and SPECT cardiac imaging. RESULTS: 3D-STE longitudinal, circumferential and area strain values were correlated with (123)I-MIBG late heart to mediastinum (H/M) ratio and late SPECT total defect score. After stratification of the patients according to ischaemic or nonischaemic HF aetiology, we observed a good correlation of all 3D-STE measurements with late H/M ratio and SPECT data in the ischaemic group, but in patients with HF of nonischaemic aetiology, no correlation was found between LV deformation and cardiac sympathetic activity. At the regional level, the strongest correlation between LV deformation and adrenergic innervation was found for the left anterior descending coronary artery distribution territory for all four 3D-STE values. In multivariate linear regression analyses, including age, gender, LV ejection fraction, NYHA class, body mass index, heart rate and HF aetiology, only 3D-STE area and radial strain values significantly predicted cardiac sympathetic derangement on (123)I-MIBG late SPECT. CONCLUSION: This study indicated that 3D-STE measurements are correlated with (123)I-MIBG planar and SPECT data. Furthermore, 3D-STE area and radial strain values, but not LVEF, predict cardiac sympathetic derangement in human postischaemic HF.

Sharing the multidisciplinary clinical approach to peri- and postmenopausal women: A Delphi consensus among Italian gynecologists, endocrinologists, and cardiologists for an integrated and optimal approach to clinical practice.

OBJECTIVE: The critical phase of perimenopausal period is marked by a reduction in estrogen levels, leading to various clinical issues (vasomotor and neurodegenerative symptoms, increased osteoporosis risk and cardiovascular risk). These complex clinical scenarios pose challenges to clinicians in providing the right support for diagnosis and treatment. A group of Italian cardiologists, endocrinologists, and gynecologists conducted a survey among expert colleagues to assess consensus on controversial issues and best practices for screening and treating peri- and postmenopausal women. METHODS: The Delphi methodology was used to analyze responses from a qualitative expert panel comprising 25 cardiologists, 25 endocrinologists, and 25 gynecologists, selected nationwide. Two consecutive questionnaires were proposed between February and May 2023. Agreement among experts was assessed following the Delphi method as developed by the RAND Corporation. RESULTS: The results of this Delphi Consensus have been shared by the leading scientific societies: Italian Society of Cardiology, Italian Society of Endocrinology, Italian Society of Gynecology and Obstetrics, and Italian Hospital Obstetricians Gynecologists Association. CONCLUSIONS: The experts highlighted comorbidities and hormone deprivation as crucial clinical problems to be evaluated in perimenopausal women, requiring investigation from cardiovascular and endocrinologic perspectives to assess cardiovascular risk, involving the use of BMI, standard blood samples, endocrine-metabolic tests, and lifestyle assessment, particularly in women with higher cardiovascular and metabolic risks candidates for hormone replacement therapy (HRT). The experts also agreed on the benefits of HRT in improving lipid metabolism and reducing insulin resistance, thereby mitigating the metabolic risks associated with menopause. However, this therapy should be tailored considering individual women's comorbidities and thrombotic risk.

Right ventricular dysfunction in chronic heart failure: clinical laboratory and echocardiographic characteristics. (the RIVED-CHF registry).

BACKGROUND: Right ventricular dysfunction (RVD) and pulmonary hypertension have been recognized as two important prognostic features in patients with left side heart failure. Current literature does not distinguish between right heart failure (RHF) and RVD, and the two terms are used indiscriminately to describe pulmonary hypertension and RVD as well as clinical sign of RHF. Therefore, the right ventricle (RV) adaptation across the whole spectrum of left ventricular ejection fraction (LVEF) values has been poorly investigated. METHODS: This is a multicenter observational prospective study endorsed by the Italian Society of Cardiology aiming to analyze the concordance between the signs and symptoms of RHF and echocardiographic features of RVD. The protocol will assess patients affected by chronic heart failure in stable condition regardless of the LVEF threshold by clinical, laboratory, and detailed echocardiographic study. During the follow-up period, patients will be observed by direct check-up visit and/or virtual visits every 6 months for a mean period of 3 years. All clinical laboratory and echocardiographic data will be recorded in a web platform system accessible for all centers included in the study. RESULTS: The main study goals are: to investigate the concordance and discordance between clinical signs of RHF and RVD measured by ultrasonographic examination; to evaluate prognostic impact (in terms of cardiovascular mortality and heart failure hospitalization) of RVD and RHF during a mean follow-up period of 3 years; to investigate the prevalence of different right ventricular maladaptation (isolated right ventricular dilatation, isolated pulmonary hypertension, combined pattern) and the related prognostic impact. CONCLUSIONS: With this protocol, we would investigate the three main RVD patterns according to heart failure types and stages; we would clarify different RVD and pulmonary hypertension severity according to the heart failure types. Additionally, by a serial multiparametric analysis of RV, we would provide a better definition of RVD stage and how much is it related with clinical signs of RHF (ClinicalTrials.gov Identifier: NCT06002321).

What about chronotropic incompetence in heart failure with mildly reduced ejection fraction? Clinical and prognostic implications from the Metabolic Exercise combined with Cardiac and Kidney Indexes score dataset.

AIMS: Chronotropic incompetence (CI) is a strong predictor of outcome in heart failure with reduced ejection fraction, however no data on its clinical and prognostic impacts in heart failure with mildly reduced ejection fraction (HFmrEF) are available. Therefore, the study aims to investigate, in a large multicentre HFmrEF cohort, the prevalence of CI as well as its relationship with exercise capacity and its prognostic role over the cardiopulmonary exercise testing (CPET) parameters. METHODS AND RESULTS: Within the Metabolic Exercise combined with Cardiac and Kidney Indexes (MECKI) database, we analysed data of 864 HFmrEF out of 1164 stable outpatients who performed a maximal CPET at the cycle ergometer and who had no significant rhythm disorders or comorbidities. The primary study endpoint was cardiovascular (CV) death. All-cause death was also explored. Chronotropic incompetence prevalence differed depending on the method (peak heart rate, pHR% vs. pHR reserve, pHRR%) and the cut-off adopted (pHR% from ≤75% to ≤60% and pHRR% ≤ 65% to ≤50%), ranging from 11% to 62%. A total of 84 (9.7%) CV deaths were collected, with 39 (4.5%) occurring within 5 years. At multivariate analysis, both pHR% [hazard ratio 0.97 (0.95-0.99), P < 0.05] and pHRR% [hazard ratio 0.977 (0.961-0.993), P < 0.01] were associated with the primary endpoint. A pHR% ≤ 75% and a pHRR% ≤ 50% represented the most accurate cut-off values in predicting the outcome. CONCLUSION: The study suggests an association between blunted exercise-HR response, functional capacity, and CV death risk among patients with HFmrEF. Whether the CI presence might be adopted in daily HFmrEF management needs to be addressed in larger prospective studies.

Chronotropic incompetence is an easy-to-obtain additive parameter for cardiovascular death risk stratification in heart failure with mildly reduced ejection fraction (HFmrEF). Peak heart rate and peak heart rate reserve are associated with exercise capacity in HFmrEF. Peak heart rate and peak heart rate reserve are associated with cardiovascular death in HFmrEF.

A matter of sex-persistent predictive value of MECKI score prognostic power in men and women with heart failure and reduced ejection fraction: a multicenter study.

Background: A sex-based evaluation of prognosis in heart failure (HF) is lacking. Methods and results: We analyzed the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score registry, which includes HF with reduced ejection fraction (HFrEF) patients. A cross-validation procedure was performed to estimate weights separately for men and women of all MECKI score parameters: left ventricular ejection fraction (LVEF), hemoglobin, kidney function assessed by Modification of Diet in Renal Disease, blood sodium level, ventilation vs. carbon dioxide production slope, and peak oxygen consumption (peakVO2). The primary outcomes were the composite of all-cause mortality, urgent heart transplant, and implant of a left ventricle assist device. The difference in predictive ability between the native and sex recalibrated MECKI (S-MECKI) was calculated using a receiver operating characteristic (ROC) curve at 2 years and a calibration plot. We retrospectively analyzed 7,900 HFrEF patients included in the MECKI score registry (mean age 61 ± 13 years, 6,456 men/1,444 women, mean LVEF 33% ± 10%, mean peakVO2 56.2% ± 17.6% of predicted) with a median follow-up of 4.05 years (range 1.72-7.47). Our results revealed an unadjusted risk of events that was doubled in men compared to women (9.7 vs. 4.1) and a significant difference in weight between the sexes of most of the parameters included in the MECKI score. S-MECKI showed improved risk classification and accuracy (area under the ROC curve: 0.7893 vs. 0.7799, p = 0.02) due to prognostication improvement in the high-risk settings in both sexes (MECKI score >10 in men and >5 in women). Conclusions: S-MECKI, i.e., the recalibrated MECKI according to sex-specific differences, constitutes a further step in the prognostic assessment of patients with severe HFrEF.

[New perspectives in cardiovascular risk reduction: focus on HDL]. / Nuove prospettive nella riduzione del rischio cardiovascolare: focus su HDL.

Cardiovascular diseases represent the leading cause of morbidity and mortality worldwide, mostly contributing to hospitalizations and health care costs. Dyslipidemias represent one of the major cardiovascular risk factor and its management, throughout life-style modifications and pharmacological interventions, has shown to reduce cardiac events. The risk of adverse cardiovascular events is related not only to elevated LDL blood levels, but also to decreased HDL concentrations, that exhibit protective effects in the development of atherosclerotic process. Aim of this review is to summarize current evidences about defensing effects of such lipoproteins and to show the most recent pharmacological strategies to reduce cardiovascular risk through the increase of their circulating levels.

[Endothelial function as a marker of pre-clinical atherosclerosis: assessment techniques and clinical implications]. / Funzione endoteliale quale marker di aterosclerosi subclinica: metodiche di valutazione ed applicazioni cliniche.

Endothelium plays a key role in maintenance of vascular homeostasis. Cardiovascular risk factors promote development of endothelial dysfunction, characterized by increased vasoconstriction and by procoagulant/pro-inflammatory endothelial activities. In coronary artery, endothelium-dependent dilation improves blood flow, while the occurrence of endothelial dysfunction reduces myocardial perfusion, so new methods have been developed for assessment of endothelial function in coronary and peripheral arteries. The quantitative angiography with intracoronary infusion of acetylcholine remains the "gold standard" to assess the endothelium-dependent vasodilatation. The use of this technique is restricted to patients who have a clinical indication for coronary angiography, so new imaging methods have been considered for noninvasive diagnosis of coronary microvascular disease, such as magnetic resonance imaging phase contrast and positron emission tomography. The advent of new techniques has facilitated testing of endothelial dysfunction in peripheral arteries with non-invasive methods. This review presents available in-vivo and ex-vivo methods for evaluating endothelial function with special focus on more recent ones. The diagnostic tools include local vasodilatation by venous occlusion plethysmography and assessment of flow-mediated dilatation, arterial pulse wave analysis and pulse amplitude tonometry, laser Doppler flowmetry. The possibility to detect endothelial dysfunction as an early marker of atherosclerosis makes these instruments useful for early stratification of patients at risk for cardiovascular events. Aim of this review is to summarize the characteristics of non-invasive assessment of endothelial function in order to optimize cardiovascular risk management.

How cardiologists can manage excess body weight and related cardiovascular risk. An expert opinion.

Obesity is an important independent cardiovascular (CV) risk factor and a chronic inflammatory disease related to the development of insulin resistance, type 2 diabetes, dyslipidaemia, coronary artery disease, hypertension, heart failure, atrial fibrillation and obstructive sleep apnoea. Body Mass Index (BMI) values >27 kg/m2 are associated with an exponential increase in the risk for Major Adverse Cardiac Events (MACE). On the other hand, weight reduction can significantly reduce metabolic, CV and oncological risk. Orlistat, bupropion/naltrexone, liraglutide and semaglutide, combined with lifestyle changes, have proven to be effective in weight loss; the last two have been tested in randomized clinical trials (RCTs) with CV outcomes only in diabetic patients, and not in obese patients. To fill a fundamental gap of knowledge, the SELECT trial on patients with obesity and CV disease treated with semaglutide is ongoing, aiming at MACE as the primary endpoint. The battle against the social and clinical stigma towards obesity must be counteracted by promoting an awareness that elevates obesity to a complex chronic disease. Several actions should be implemented to improve the management of obesity, and cardiologists have a key role for achieving a global approach to patients with excess weight also through the correct implementation of available treatment strategies.

Innovations in medical therapy of heart failure with reduced ejection fraction.

Heart failure with reduced ejection fraction (HFrEF) is a pathological condition still characterized by high rates of mortality and disease exacerbation frequently leading to hospitalization, thus there is a continuous need for pharmacological treatments impacting on disease stability and long-term prognosis. Moreover, the phenotype of heart failure patients is continuously changing over time, and the development of new heart failure drugs is crucial to promote a personalized and targeted approach. In recent years, several therapeutic innovations have emerged in the landscape of acute and chronic HFrEF, largely changing and improving our approach to the disease. Various studies on new drugs and experimental therapeutic approaches are ongoing. The present review discusses the latest data on both recently approved drugs and developing therapeutic targets, in order to provide a critical overview for an informed and optimal approach to such a complex disease.