Inclisiran: A New Pharmacological Approach for Hypercholesterolemia.

Therapeutic approaches based on gene silencing technologies represent a new opportunity to manage hypercholesterolemia. Inclisiran is a small interfering RNA that targets proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA. Clinical studies have demonstrated that inclisiran is effective, safe, and well-tolerated in reducing low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia, atherosclerotic cardiovascular disease, and atherosclerotic cardiovascular disease risk equivalents. A meta-analysis of phase 3 trials demonstrated a 51% reduction in LDL-C levels at 18 months as compared with placebo. Adverse event incidence was found to be comparable in individuals treated with inclisiran and those receiving placebo, though the reactions at the site of injection were more common in patients receiving inclisiran as compared with those receiving placebo. The recommended inclisiran dose is 284 mg administered as a subcutaneous injection to be repeated after three months with a subsequent 6-month maintenance regimen. Overall, since the pharmacological efficacy of inclisiran in LDL-C reduction is comparable to that of monoclonal antibodies against PCSK9, the longer effect duration and the favorable safety profile may favor this newer approach for hypercholesterolemia management.

Aortic Regurgitation in Bicuspid Aortic Valve: The Role of Multimodality Imaging.

The evaluation of aortic regurgitation (AR) in bicuspid valve (BAV) is still a challenge because of the eccentricity of the jet, which may under/overestimate the regurgitation. The commonly used echocardiography parameters (such as vena contracta, pressure half-time, etc.) may not be useful in this kind of patient. A multimodality approach combining echocardiography, cardiac MRI, cardiac CT, and advanced technologies applied to non-invasive cardiac imaging (e.g., 4D flow and strain imaging) may be useful to better quantify regurgitation and to select patients suitable for valve replacement. This review provides an overview of the most recent insights about cardiovascular imaging tools and their utility in BAV evaluation, focusing on chronic regurgitation. We describe the role of multimodality imaging in both diagnosis and risk assessment of this disease, pointing out the advantages and disadvantages of the imaging techniques, aiming to provide a guide to clinicians and cardiovascular imaging specialists in choosing the best imaging tools to use.

Comprehensive diagnostic workup in patients with suspected heart failure and preserved ejection fraction.

Diagnosis of heart failure with preserved ejection fraction (HFpEF) can be challenging and it could require different tests, some of which are affected by limited availability. Nowadays, considering that new therapies are available for HFpEF and related conditions, a prompt and correct diagnosis is relevant. However, the diagnostic role of biomarker level, imaging tools, score-based algorithms and invasive evaluation, should be based on the strengths and weaknesses of each test. The aim of this review is to help the clinician in diagnosing HFpEF, overcoming the diagnostic uncertainty and disentangling among the different underlying causes, in order to properly treat this kind of patient.

Cardiovascular magnetic resonance parametric techniques to characterize myocardial effects of anthracycline therapy in adults with normal left ventricular ejection fraction: a systematic review and meta-analysis.

BACKGROUND: The cardiotoxic effects of anthracyclines therapy are well recognized, both in the short and long term. Echocardiography allows monitoring of cancer patients treated with this class of drugs by serial assessment of left ventricle ejection fraction (LVEF) as a surrogate of systolic function. However, changes in myocardial function may occur late in the process when cardiac damage is already established. Novel cardiac magnetic resonance (CMR) parametric techniques, like native T1 mapping and extra-cellular volume (ECV), may detect subclinical myocardial damage in these patients, recognizing early signs of cardiotoxicity before development of overt cancer therapy-related cardiac dysfunction (CTRCD) and prompting tailored therapeutic and follow-up strategies to improve outcome. METHODS AND RESULTS: We conducted a systematic review and a meta-analysis to investigate the difference in CMR derived native T1 relaxation time and ECV values, respectively, in anthracyclines-treated cancer patients with preserved EF versus healthy controls. PubMed, Embase, Web of Science and Cochrane Central were searched for relevant studies. A total of 6 studies were retrieved from 1057 publications, of which, four studies with 547 patients were included in the systematic review on T1 mapping and five studies with 481 patients were included in the meta-analysis on ECV. Three out of the four included studies in the systematic review showed higher T1 mapping values in anthracyclines treated patients compared to healthy controls. The meta-analysis demonstrated no statistically significant difference in ECV values between the two groups in the main analysis (Hedges´s g =3.20, 95% CI -0.72-7.12, p =0.11, I2 =99%), while ECV was significantly higher in the anthracyclines-treated group when sensitivity analysis was performed. CONCLUSIONS: Higher T1 mapping and ECV values in patients exposed to anthracyclines could represent early biomarkers of CTRCD, able to detect subclinical myocardial changes present before the development of overt myocardial dysfunction. Our results highlight the need for further studies to investigate the correlation between anthracyclines-based chemotherapy and changes in CMR mapping parameters that may guide future tailored follow-up strategies in this group of patients.

Sex differences in patients presenting with acute coronary syndrome: a state-of-the-art review.

Cardiovascular conditions in the spectrum of acute coronary syndromes are characterized by sex differences with regard to pathophysiology, risk factors, clinical presentation, invasive and pharmacologic treatment, and outcomes. This review delves into these differences, including specific subsets like myocardial infarction with non-obstructed coronary arteries or Spontaneous Coronary Artery Dissection, and alternative diagnoses like Takotsubo cardiomyopathy or myocarditis. Moreover, practical considerations are enclosed, on how a sex-specific approach should be integrated in clinical practice: in fact, personal history should focus on female-specific risk factors, and hormonal status and hormonal therapy should be assessed. Moreover, physical and psychological stressors should be investigated, particularly in the event of Spontaneous Coronary Artery Dissection or Takotsubo cardiomyopathy.

[Substance abuse and cardiovascular risk: energy drinks]. / Sostanze d'abuso e rischio cardiovascolare: gli energy drinks.

The consumption of energy drinks (ED) has become a growing public health issue, since potentially ED-related serious adverse cardiovascular events, including arrhythmias, myocardial infarction, cardiomyopathies, and sudden cardiac death, have been reported in recent years. The substances contained in ED include caffeine, taurine, sugars, B group vitamins and phyto-derivatives, which, especially if taken in large quantities and in a short amount of time, could cause serious side effects through various mechanisms of action, such as increased blood pressure and QT interval prolongation. Although there are still many open questions on ED that require further specific investigations, there is an urgent need for information and educational plans to the population, as well as for regulatory actions, particularly regarding transparency of substances and possible adverse effects.

How to tackle therapeutic inertia in heart failure with reduced ejection fraction. A scientific statement of the Heart Failure Association of the ESC.

Guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF) reduces morbidity and mortality, but its implementation is often poor in daily clinical practice. Barriers to implementation include clinical and organizational factors that might contribute to clinical inertia, i.e. avoidance/delay of recommended treatment initiation/optimization. The spectrum of strategies that might be applied to foster GDMT implementation is wide, and involves the organizational set-up of heart failure care pathways, tailored drug initiation/optimization strategies increasing the chance of successful implementation, digital tools/telehealth interventions, educational activities and strategies targeting patient/physician awareness, and use of quality registries. This scientific statement by the Heart Failure Association of the ESC provides an overview of the current state of GDMT implementation in HFrEF, clinical and organizational barriers to implementation, and aims at suggesting a comprehensive framework on how to overcome clinical inertia and ultimately improve implementation of GDMT in HFrEF based on up-to-date evidence.

Haemodynamics, exercise capacity and clinical events in pulmonary arterial hypertension.

The purpose of this study was to clarify whether changes in cardiopulmonary haemodynamics induced by pharmacological therapy correlate with exercise capacity and clinical events in patients with pulmonary arterial hypertension. 16 randomised trials including 2353 patients, followed up for 16.4±10.6 weeks, measuring cardiopulmonary haemodynamics by right heart catheterisation and reporting clinical events were included. Meta-analysis and meta-regression analysis were performed to assess the effects of treatments on clinical events and the relationship between haemodynamic changes (pulmonary artery pressure, pulmonary vascular resistance, cardiac index and right atrial pressure) and clinical events. Treatments significantly reduced all-cause death (OR 0.5, 95% CI 0.3-0.7; p<0.01), hospitalisation for pulmonary arterial hypertension (OR 0.4, 95% CI 0.2-0.7; p<0.01), initiation of rescue therapy (OR 0.3, 95% CI 0.2-0.6; p<0.01) and the composite outcome (OR 0.3, 95% CI 0.3-0.5; p<0.01). No relationship was found between changes of haemodynamic parameters and clinical events, whereas changes of cardiac index and pulmonary vascular resistance significantly correlated with changes in the 6-min walking distance (r = 0.64, p = 0.03; r = -0.55, p = 0.04, respectively). In patients with pulmonary arterial hypertension, improvements of cardiopulmonary haemodynamics observed in randomised clinical trials correlate with exercise capacity changes but do not predict clinical events in a short-term follow-up.

Takotsubo cardiomyopathy: overview.

Takotsubo cardiomyopathy (TTC) is a unique acute syndrome characterized by transient left ventricular systolic dysfunction in the absence of significant coronary artery disease, occurring mostly in postmenopausal women after emotional and/or physical stress. Given the nonspecific symptoms and signs, a high clinical index of suspicion is necessary to detect the disease in different clinical settings and scenarios. Noninvasive multimodality imaging may be useful to distinguish this cardiomyopathy from other acute cardiac and thoracic diseases. Coronary angiography remains, however, mandatory to differentiate TTC from acute coronary syndromes. This article reviews the clinical features and management of TTC and some new insights.

Patient profiles in heart failure with reduced ejection fraction: Prevalence, characteristics, treatments and outcomes in a real-world heart failure population.

AIMS: The Heart Failure Association of the European Society of Cardiology has recently proposed to optimize guideline-directed medical treatments according to patient's profiles. The aim of this analysis was to investigate prevalence/characteristics/treatments/outcomes for individual profiles. METHODS AND RESULTS: Patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in the Swedish Heart Failure Registry (SwedeHF) between 2013 and 2021 were considered. Among 108 profiles generated by combining different strata of renal function (by estimated glomerular filtration rate [eGFR]), systolic blood pressure (sBP), heart rate, atrial fibrillation (AF) status and presence of hyperkalaemia, 93 were identified in our cohort. Event rates for a composite of cardiovascular (CV) mortality or first HF hospitalization were calculated for each profile. The nine most frequent profiles accounting for 70.5% of the population had eGFR 30-60 or ≥60 ml/min/1.73 m2 , sBP 90-140 mmHg and no hyperkalaemia. Heart rate and AF were evenly distributed. The highest risk of CV mortality/first HF hospitalization was observed in those with concomitant eGFR 30-60 ml/min/1.73 m2 and AF. We also identified nine profiles with the highest event rates, representing only 5% of the study population, characterized by no hyperkalaemia, even distribution among the sBP strata, predominance of eGFR <30 ml/min/1.73 m2 and AF. The three profiles with eGFR 30-60 ml/min/1.73 m2 also showed sBP <90 mmHg. CONCLUSIONS: In a real-world cohort, most patients fit in a few easily identifiable profiles; the nine profiles at highest risk of mortality/morbidity accounted for only 5% of the population. Our data might contribute to identifying profile-tailored approaches to guide drug implementation and follow-up.

Safety of continuing mineralocorticoid receptor antagonist treatment in patients with heart failure with reduced ejection fraction and severe kidney disease: Data from Swedish Heart Failure Registry.

AIMS: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in heart failure with reduced ejection fraction (HFrEF) but remain underused and are often discontinued especially in patients with chronic kidney disease (CKD) due to concerns on renal safety. Therefore, in a real-world HFrEF population we investigated the safety of MRA use, in terms of risk of renal events, any mortality and any hospitalization, across the estimated glomerular filtration rate (eGFR) spectrum including severe CKD. METHODS AND RESULTS: We analysed patients with HFrEF (ejection fraction <40%), not on dialysis, from the Swedish Heart Failure Registry. We performed multivariable logistic regression models to investigate patient characteristics independently associated with MRA use, and univariable and multivariable Cox regression models to assess the associations between MRA use and outcomes. Of 33 942 patients, 17 489 (51%) received MRA, 32%, 45%, 54%, 54% with eGFR <30, 30-44, 45-59 or ≥60 ml/min/1.73 m2 , respectively. An eGFR ≥60 ml/min/1.73 m2 and patient characteristics linked with more severe HF were independently associated with more likely MRA use. In multivariable analyses, MRA use was consistently not associated with a higher risk of renal events (i.e. composite of dialysis/renal death/hospitalization for renal failure or hyperkalaemia) (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.98-1.10), all-cause death (HR 1.02, 95% CI 0.97-1.08) as well as of all-cause hospitalization (HR 0.99, 95% CI 0.95-1.02) across the eGFR spectrum including also severe CKD. CONCLUSIONS: The use of MRAs in patients with HFrEF decreased with worse renal function; however their safety profile was demonstrated to be consistent across the entire eGFR spectrum.

Management of temporary mechanical circulatory support devices in cath-lab and cardiac intensive care unit.

Different temporary mechanical circulatory support (tMCS) devices are available and can be used to maintain end-organ perfusion while reducing cardiac work and myocardial oxygen demand. tMCS can provide support to the right ventricle, left ventricle, or both, and its use can be considered in emergency situations such as cardiogenic shock or in elective procedures such as high-risk percutaneous coronary intervention to prevent haemodynamic deterioration. Invasive and, most importantly, non-invasive haemodynamic parameters should be taken into account when choosing the type of tMCS device and its initiation and weaning timing, determining the need for a device upgrade, and screening for complications. In this context, ultrasound tools, specifically echocardiography, can provide important data. This review aims to provide a description of the different tMCS devices, the invasive and non-invasive tools and parameters to guide their management, and their advantages and drawbacks.

Comprehensive Phenotypic Characterization of Late Gadolinium Enhancement Predicts Sudden Cardiac Death in Coronary Artery Disease.

BACKGROUND: Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) offers the potential to noninvasively characterize the phenotypic substrate for sudden cardiac death (SCD). OBJECTIVES: The authors assessed the utility of infarct characterization by CMR, including scar microstructure analysis, to predict SCD in patients with coronary artery disease (CAD). METHODS: Patients with stable CAD were prospectively recruited into a CMR registry. LGE quantification of core infarction and the peri-infarct zone (PIZ) was performed alongside computational image analysis to extract morphologic and texture scar microstructure features. The primary outcome was SCD or aborted SCD. RESULTS: Of 437 patients (mean age: 64 years; mean left ventricular ejection fraction [LVEF]: 47%) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. On multivariable analysis, PIZ mass and core infarct mass were independently associated with the primary outcome (per gram: HR: 1.07 [95% CI: 1.02-1.12]; P = 0.002 and HR: 1.03 [95% CI: 1.01-1.05]; P = 0.01, respectively), and the addition of both parameters improved discrimination of the model (Harrell's C-statistic: 0.64-0.79). PIZ mass, however, did not provide incremental prognostic value over core infarct mass based on Harrell's C-statistic or risk reclassification analysis. Severely reduced LVEF did not predict the primary endpoint after adjustment for scar mass. On scar microstructure analysis, the number of LGE islands in addition to scar transmurality, radiality, interface area, and entropy were all associated with the primary outcome after adjustment for severely reduced LVEF and New York Heart Association functional class of >1. No scar microstructure feature remained associated with the primary endpoint when PIZ mass and core infarct mass were added to the regression models. CONCLUSIONS: Comprehensive LGE characterization independently predicted SCD risk beyond conventional predictors used in implantable cardioverter-defibrillator (ICD) insertion guidelines. These results signify the potential for a more personalized approach to determining ICD candidacy in CAD.

N-terminal pro-b-type natriuretic peptide and left atrial function in patients with congestive heart failure and severely reduced ejection fraction.

AIMS: Amino-terminal portion of pro-B-type natriuretic peptide (NT-pro-BNP) is a valuable diagnostic and prognostic marker in congestive heart failure (CHF). In CHF patients, elevation of natriuretic peptide levels correlate with decreased left ventricular (LV) ejection fraction (EF) and increased left atrial (LA) volumes, but a correlation with LA function that is a determinant of haemodynamic and clinical status in CHF with independent prognostic value has never been investigated. Aim of this study was to evaluate the relationship between cardiac neurohormonal activation and LA function in patients with CHF due to dilated cardiomyopathy. METHODS AND RESULTS: One hundred and one patients (86% males; mean age, 64 ± 11 years) with dilated ischaemic or non-ischaemic cardiomyopathy, LV EF ≤45% (mean LV EF, 33 ± 8%), and New York Heart Association class II-IV underwent transthoracic echocardiography to evaluate LA fractional active and total emptying from M- and B-Mode images, and, on the same day, venous blood sample collection to dose NT-pro-BNP. By univariate analyses, NT-pro-BNP significantly correlated to age, LA dimensions, LA function indexes, EF, and functional class. At multivariate analysis, LV EF and M- or B-Mode indexes of LA function were the only independent predictors of NT-pro-BNP values. A NT-pro-BNP cut-off of 1480 pg/mL identified LA dysfunction with 89% specificity and 54% sensitivity. CONCLUSION: In CHF patients with severely impaired systolic function, NT-pro-BNP levels reflect LA and LV dysfunction. These data should prompt studies to investigate the relationship between changes of LA function and NT-pro-BNP levels and their clinical value as prognostic and therapeutic targets in CHF.

[Coronary computed tomography: current role and future perspectives for cardiovascular risk stratification]. / L'impiego della TC coronarica per la stratificazione del rischio cardiovascolare: evidenze e prospettive dopo lo studio CONFIRM.

Atherosclerotic coronary artery disease (CAD) is a major cause of morbidity and mortality. The majority of cardiovascular events, more than 50% of CAD deaths, occur in previously asymptomatic individuals at intermediate cardiovascular risk, highlighting the relevance of accurate individual risk assessment to decrease cardiovascular events through more appropriate targeting of preventive measures. In the last decades, the development of non-invasive imaging techniques have prompted interest in imaging of atherosclerosis. Coronary computed tomography provides the opportunity to assess the deposition of calcium in the coronary tree and to non-invasively image coronary vessels. Both information are useful for risk stratification of asymptomatic subjects or of subjects with suspected CAD.

[From myocardium to the atherosclerotic plaque: new perspectives in cardiologic imaging]. / Dal miocardio alla placca aterosclerotica: le nuove prospettive dell'imaging in cardiologia.

Molecular imaging is an innovative and promising approach in cardiology for functional characterization of atherosclerosis. Nuclear, ultrasound and magnetic resonance imaging have been used for assessment of atherosclerosis of large and small arteries in several clinical and experimental studies. Positron Emission Tomography with fluorodeoxyglucose can measure metabolic activity and vulnerability of atherosclerotic plaques, identifying individuals at risk of future cardiovascular events. Magnetic resonance imaging can quantify carotid artery inflammation using iron oxide nanoparticles as contrast agent. In addition, macrophage accumulation of iron particles in atherosclerotic plaques may allow monitoring of inflammation during drug therapy, whereas contrast-enhanced ultrasound imaging may detect plaque neovascularization. Currently, technical factors, including cardiac and diaphragmatic motion and small size of coronary vessels, limit routine application of these techniques for coronary imaging. Purpose of this review is to describe state of the art and potential areas of clinical applications of molecular imaging of atherosclerosis.

[Clinical and therapeutic value of carotid intima-media thickness]. / Il valore clinico e terapeutico dello Spessore Medio-Intimale Carotideo.

Carotid Intima Media Thickness (IMT) has been widely used to predict cardiovascular events in primary and secondary prevention studies. Yet, the power of IMT to reclassify risk level on top of conventional risk assessment based on classical risk factors remains unsettled. In fact, recent data indicate that the prognostic power of IMT is lower than that provided by the identification of carotid plaques. The role of IMT as surrogate endpoint to assess the efficacy of cardiovascular protective therapies is also still debated. In fact, no studies have ever been designed and powered to show a relationship between changes in carotid IMT during follow-up and cardiovascular events. Recently, two meta-analysis of trials using IMT as surrogate endpoint failed to demonstrate an association between IMT regression and cardiovascular events. The reasons for the lack of predictive role for changes in IMT are uncertain. It has been shown that IMT is not a pure atherosclerotic index, being substantially affected by age and hemodynamic factors including blood pressure and vessel wall shear stress. In addition, the status of carotid vessels does not strictly reflect that of coronary arteries. Finally, intra and inter-observer variability of measurements may further limit the association between IMT changes in individual patients and cardiovascular risk. Thus, IMT represents a valuable risk marker in population studies but its role for tailoring cardiovascular therapy in clinical practice remains currently uncertain.

Association of individual aortic leaflet calcification on paravalvular regurgitation and conduction abnormalities with self-expanding trans-catheter aortic valve insertion.

BACKGROUND: Complication rates of paravalvular aortic regurgitation (PVR) and permanent pacemaker insertion remain high in patients undergoing trans-catheter aortic valve insertion for severe aortic stenosis. The spatial distribution of calcium between individual aortic valve leaflets, and its potential role in these complications is gaining interest. We aimed to assess the accuracy of individual aortic valve leaflet calcium quantification, and to determine its effect on the frequency of these complications. METHODS: This was a retrospective study of 251 patients who underwent trans-catheter aortic valve insertion using the Evolut RTM valve. The off-line Terarecon software platform was used for Agatston scoring the short axis views. RESULTS: There was a correlation between the sum of the individual leaflet and the total aortic valve calcium score. There was a univariate association between an increase [per 100 Agatston unit (AU)] in both right coronary leaflet (RCL) and left coronary leaflet (LCL) calcium with the risk of PVR. There was an association between an increase in LCL calcium score (per 100 AU) and need for post-implantation balloon aortic valvuloplasty (BAV). There was no association between individual leaflet calcification on the risk of permanent pacemaker insertion. CONCLUSIONS: This study supports the idea that a quantifiable and reproducible method of individual valve leaflet calcification score may serve as an independent risk factor for paravalvular regurgitation, beyond visual assessment of asymmetry. However, the same may not be true of spatial calcium distribution and permanent pacemaker implantation (PPI).