Position Statement of the Italian Society of Cardiovascular Prevention (SIPREC) and Italian Heart Failure Association (ITAHFA) on Cardiac Rehabilitation and Protection Programs as a Cornerstone of Secondary Prevention after Myocardial Infarction or Revascularization.

Despite the remarkable and progressive advances made in the prevention and management of cardiovascular diseases, the recurrence of cardiovascular events remains unacceptably elevated with a notable size of the residual risk. Indeed, in patients who suffered from myocardial infarction or who underwent percutaneous or surgical myocardial revascularization, life-style changes and optimized pharmacological therapy with antiplatelet drugs, lipid lowering agents, beta-blockers, renin angiotensin system inhibitors and antidiabetic drugs, when appropriate, are systematically prescribed but they might be insufficient to protect from further events. In such a context, an increasing body of evidence supports the benefits of cardiac rehabilitation (CR) in the setting of secondary cardiovascular prevention, consisting in the reduction of myocardial oxygen demands, in the inhibition of atherosclerotic plaque progression and in an improvement of exercise performance, quality of life and survival. However, prescription and implementation of CR programs is still not sufficiently considered.The aim of this position paper of the Italian Society of Cardiovascular Prevention (SIPREC) and of the Italian Heart Failure Association (ITAHFA) is to examine the reasons of the insufficient use of this strategy in clinical practice and to propose some feasible solutions to overcome this clinical gap.

Advances in nucleic acid-targeted therapies for cardiovascular disease prevention.

Nucleic acid-based therapies are being rapidly developed for prevention and management of cardiovascular diseases (CVD). Remarkable advancements have been achieved in the delivery, safety, and effectiveness of these therapeutics in the past decade. These therapies can also modulate therapeutic targets that cannot be sufficiently addressed using traditional drugs or antibodies. Among the nucleic acid-targeted therapeutics under development for CVD prevention are RNA-targeted approaches, including antisense oligonucleotides (ASO), small interfering RNAs (siRNA), and novel genome editing techniques. Genetic studies have identified potential therapeutic targets that are suggested to play a causative role in development and progression of CVD. RNA- and DNA-targeted therapeutics can be particularly well delivered to the liver, where atherogenic lipoproteins and angiotensinogen are produced. Lipoproteins currently targeted include proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein A (Apo(a)), apolipoprotein C3 (APOC3), angiopoietin-like 3 (ANGPTL3). Several large-scale clinical development programs for nucleic acid-targeted therapies in cardiovascular prevention are under way, which may also be attractive from a therapy adherence point of view, given the long action of these therapeutics. In addition to genome editing, the concept of gene transfer is presently under assessment in preclinical and clinical investigations as a potential approach for addressing LDL-R deficiency. Furthermore, ongoing research is exploring the use of RNA-targeted therapies to treat arterial hypertension by reducing hepatic angiotensinogen (AGT) production. This review summarizes the rapid translation of siRNA and ASO therapeutics as well as gene editing into clinical studies to treat dyslipidemia and arterial hypertension for CVD prevention. It also outlines potential innovative therapeutic options that are likely relevant to the future of cardiovascular medicine.

Risk of Cardiovascular Events in Metabolically Healthy Overweight or Obese Adults: Role of LDL-Cholesterol in the Stratification of Risk.

The objective of this study was to investigate the longitudinal association of metabolically healthy overweight/obese adults with major adverse cardiovascular events (MACE) and the effect of LDL-cholesterol levels on this association. This study was conducted with 15,904 participants from the URRAH study grouped according to BMI and metabolic status. Healthy metabolic status was identified with and without including LDL-cholesterol. The risk of MACE during 11.8 years of follow-up was evaluated with multivariable Cox regressions. Among the participants aged <70 years, high BMI was associated with an increased risk of MACE, whereas among the older subjects it was associated with lower risk. Compared to the group with normal weight/healthy metabolic status, the metabolically healthy participants aged <70 years who were overweight/obese had an increased risk of MACE with an adjusted hazard ratio of 3.81 (95% CI, 1.34-10.85, p = 0.012). However, when LDL-cholesterol < 130 mg/dL was included in the definition of healthy metabolic status, no increase in risk was found in the overweight/obese adults compared to the normal weight individuals (hazard ratio 0.70 (0.07-6.71, p = 0.75). The present data show that the risk of MACE is increased in metabolically healthy overweight/obese individuals identified according to standard criteria. However, when LDL-cholesterol is included in the definition, metabolically healthy individuals who are overweight/obese have no increase in risk.

Asymptomatic hyperuricemia: to treat or not a threat? A clinical and evidence-based approach to the management of hyperuricemia in the context of cardiovascular diseases.

Asymptomatic hyperuricemia is defined by serum uric acid levels above 6.2 mg/dl in women and 7 mg/dl in men. In the presence of monosodium urate crystal formation and articular inflammation, hyperuricemia may become symptomatic (namely nephrolithiasis and gout). Uric acid results from purine catabolism and is at the centre of a complex metabolic interplay that involves oxidative stress, inflammation, renin-angiotensin-aldosterone system (RAAS) activation and insulin resistance. Uric acid levels present a continuous relation with conditions like hypertension and chronic kidney disease (CKD) and are reported to have an impact on risk of cardiovascular events. However, whether elevated uric acid is a causal agent and thus a possible therapeutic target is still uncertain and matter of further investigation. Treating symptomatic hyperuricemia involves lowering uric acid drugs and controlling inflammation. Urate-lowering agents are well tolerated but show minimal impact on cardiovascular events in patients with gout. Use of direct-acting urate-lowering agents in asymptomatic hyperuricemia associated with cardiovascular diseases does not warrant a clear benefit, whereas addressing cardiovascular issues with guideline-recommended therapies lowers uric acid and reduces the occurrence of cardiovascular events. Regular assessment of uric acid and clinical symptoms is advised before starting and renewing a urate-lowering treatment.

"The impact of the COVID-19 pandemic on research activities: A survey of the largest Italian academic community".

PURPOSE: The aim of the present work is to explore the impact of the COVID-19 pandemic on research activities in a vast multidisciplinary academic community to identify the most critical issues. METHOD: To this purpose we planned a survey addressed to the entire academic research staff at "Sapienza" University of Rome, which represents the largest Italian academic community. A questionnaire consisting of both open and closed-ended questions was delivered to 4118 individuals in April 2021. RESULTS: A total of 544 responses were collected. All academic roles were sufficiently represented in the study cohort. The median number of critical issues experienced by academic research staff was three. Among these, the three most frequently reported were related to: "Access to libraries / laboratories / research sites" (21.9%), "Limitation to stay abroad / study / research periods" (17.6%), "Progress of experimental work" (14.7%), with variable prevalence according to academic position and gender. Older subjects reported issues with "Projects' financial reporting" and "Expiration of acquired consumable material more frequently". The most common critical aspects reported in relation to the economic burden were: being "Unable to allocate funds" (31.4%), a "Reduction in clinical and scientific activity" (26.3%) and experiencing "Increased expenses (comprising private costs)" (21.2%) with no differences between genders. Researchers in Applied Sciences and Natural Sciences reported a higher frequency of problems in clinical and scientific activities, whereas increased expenses were reported also by researchers operating in the Humanities field. As a possible solution aimed at improving these issues, most subjects, especially those aged >45 years, indicated "Economic aid" (22.6%), "Reduction in bureaucracy" (19.9%) or "Enhancement of the scientific and clinical activities", whereas those aged ≤45 years felt that an increased duration and better access to PhD programs were to be prioritized. CONCLUSION: Our findings highlight the most critical issues related to research activities during the COVID-19 pandemic in a large academic community. The information achieved may be useful to identify researchers' needs and to design appropriate policies aimed at preparing research institutions for unexpected catastrophic events and limiting the negative impact on academic research activities.

Serum Uric Acid, Hypertriglyceridemia, and Carotid Plaques: A Sub-Analysis of the URic Acid Right for Heart Health (URRAH) Study.

High levels of serum uric acid (SUA) and triglycerides (TG) might promote high-cardiovascular-risk phenotypes, including subclinical atherosclerosis. An interaction between plaques xanthine oxidase (XO) expression, SUA, and HDL-C has been recently postulated. Subjects from the URic acid Right for heArt Health (URRAH) study with carotid ultrasound and without previous cardiovascular diseases (CVD) (n = 6209), followed over 20 years, were included in the analysis. Hypertriglyceridemia (hTG) was defined as TG ≥ 150 mg/dL. Higher levels of SUA (hSUA) were defined as ≥5.6 mg/dL in men and 5.1 mg/dL in women. A carotid plaque was identified in 1742 subjects (28%). SUA and TG predicted carotid plaque (HR 1.09 [1.04-1.27], p < 0.001 and HR 1.25 [1.09-1.45], p < 0.001) in the whole population, independently of age, sex, diabetes, systolic blood pressure, HDL and LDL cholesterol and treatment. Four different groups were identified (normal SUA and TG, hSUA and normal TG, normal SUA and hTG, hSUA and hTG). The prevalence of plaque was progressively greater in subjects with normal SUA and TG (23%), hSUA and normal TG (31%), normal SUA and hTG (34%), and hSUA and hTG (38%) (Chi-square, 0.0001). Logistic regression analysis showed that hSUA and normal TG [HR 1.159 (1.002 to 1.341); p = 0.001], normal SUA and hTG [HR 1.305 (1.057 to 1.611); p = 0.001], and the combination of hUA and hTG [HR 1.539 (1.274 to 1.859); p = 0.001] were associated with a higher risk of plaque. Our findings demonstrate that SUA is independently associated with the presence of carotid plaque and suggest that the combination of hyperuricemia and hypertriglyceridemia is a stronger determinant of carotid plaque than hSUA or hTG taken as single risk factors. The association between SUA and CVD events may be explained in part by a direct association of UA with carotid plaques.

May Measure Month 2022 in Italy: A Focus on Fixed-dose Combination, Therapeutic Adherence, and Medical Inertia in a Nationwide Survey.

INTRODUCTION: Hypertension is the main risk factor for cardiovascular diseases (CVD). Notably, only about half of hypertensive patients manage to achieve the recommended blood pressure (BP) control. Main reasons for the persistence of uncontrolled BP during treatment are lack of compliance on the patients' side, and therapeutic inertia on physicians' side. METHODS: During the global BP screening campaign "May Measure Month" (MMM) (May 1st to July 31st, 2022), a nationwide, cross-sectional, opportunistic study endorsed by the Italian Society of Hypertension was conducted on volunteer adults ≥ 18 years to raise awareness of the health issues surrounding high BP. A questionnaire on demographic/clinical features and questions on the use of fixed-dose single-pills for the treatment of hypertension was administered. BP was measured with standard procedures. RESULTS: A total of 1612 participants (mean age 60.0±15.41 years; 44.7% women) were enrolled. Their mean BP was 128.5±18.1/77.1±10.4 mmHg. About half of participants were sedentary, or overweight/obese, or hypertensive. 55.5% individuals with complete BP assessment had uncontrolled hypertension. Most were not on a fixed-dose combination of antihypertensive drugs and did not regularly measure BP at home. Self-reported adherence to BP medications was similar between individuals with controlled and uncontrolled BP (95% vs 95.5%). CONCLUSIONS: This survey identified a remarkable degree of therapeutic inertia and poor patients' involvement in the therapeutic process and its monitoring in the examined population, underlining the importance of prevention campaigns to identify areas of unsatisfactory management of hypertension, to increase risk factors' awareness in the population with the final purpose of reducing cardiovascular risk.

Prevalence, Clustering, and Current Management of Cardiovascular Risk Factors Upon First Referral to Hypertension Specialists: the APPROACH Study.

INTRODUCTION: Several observational studies have been conducted to assess the prevalence of cardiovascular risk factors in hypertensive patients; however, none has yet investigated prevalence, clustering, and current management of cardiovascular risk factors upon first referral to hypertension specialists, which is the aim of the present study. METHODS: Consecutive adult outpatients with essential/secondary hypertension were included at the time of their first referral to hypertension specialists at 13 Italian centers in the period April 2022-2023 if they had at least one additional major cardiovascular risk factor among LDL-hypercholesterolemia, type 2 diabetes, and cigarette smoking. Prevalence, degree of control, and current management strategies of cardiovascular risk factors were assessed. RESULTS: A total of 255 individuals were included, 40.2% women and 98.4% Caucasian. Mean age was 60.3±13.3 years and mean blood pressure [BP] was 140.3±17.9/84.8±12.3 mmHg). Most participants were smokers (55.3%), had a sedentary lifestyle (75.7%), suffered from overweight/obesity (51%) or high LDL-cholesterol (41.6%), had never adopted strategies to lose weight (55.7%), and were not on a low-salt diet (57.4%). Only a minority of patients reported receiving specialist counseling, and 27.9% had never received recommendations to correct unhealthy lifestyle habits. Nearly 90% of individuals with an estimated high/very high cardiovascular risk profile did not achieve recommended LDL-cholesterol targets. CONCLUSIONS: In patients with hypertension, both pharmacological and lifestyle therapeutic advice are yet to improve before referral to hypertension specialists. This should be considered in the primary care setting in order to optimize cardiovascular risk management strategies.

Systematic Review Article: New Drug Strategies for Treating Resistant Hypertension-the Importance of a Mechanistic, Personalized Approach.

Resistant hypertension (RHT) is characterized by persistently high blood pressure (BP) levels above the widely recommended therapeutic targets of less than 140/90 mmHg office BP, despite life-style measures and optimal medical therapies, including at least three antihypertensive drug classes at maximum tolerated dose (one should be a diuretic). This condition is strongly related to hypertension-mediated organ damage and, mostly, high risk of hospitalization due to hypertension emergencies or acute cardiovascular events. Hypertension guidelines proposed a triple combination therapy based on renin angiotensin system blocking agent, a thiazide or thiazide-like diuretic, and a dihydropyridinic calcium-channel blocker, to almost all patients with RHT, who should also receive either a beta-blocker or a mineralocorticoid receptor antagonist, or both, depending on concomitant conditions and contraindications. Several other drugs may be attempted, when elevated BP levels persist in these RHT patients, although their added efficacy in lowering BP levels on top of optimal medical therapy is uncertain. Also, renal denervation has demonstrated to be a valid therapeutic alternative in RHT patients. More recently, novel drug classes and molecules have been tested in phase 2 randomised controlled clinical trials in patients with RHT on top of optimal medical therapy with at least 2-3 antihypertensive drugs. These novel drugs, which are orally administered and are able to antagonize different pathophysiological pathways, are represented by non-steroid mineralocorticorticoid receptor antagonists, selective aldosterone synthase inhibitors, and dual endothelin receptor antagonists, all of which have proven to reduce seated office and 24-h ambulatory systolic/diastolic BP levels. The main findings of randomized clinical trials performed with these drugs  as well as their potential indications for the clinical management of RHT patients are summarised in this systematic review article.

Malignant Hypertension:A Systemic Cardiovascular Disease: JACC Review Topic of the Week.

Malignant hypertension (MHT) is a hypertensive emergency with excessive blood pressure (BP) elevation and accelerated disease progression. MHT is characterized by acute microvascular damage and autoregulation failure affecting the retina, brain, heart, kidney, and vascular tree. BP must be lowered within hours to mitigate patient risk. Both absolute BP levels and the pace of BP rise determine risk of target-organ damage. Nonadherence to the antihypertensive regimen remains the most common cause for MHT, although antiangiogenic and immunosuppressant therapy can also trigger hypertensive emergencies. Depending on the clinical presentation, parenteral or oral therapy can be used to initiate BP lowering. Evidence-based outcome data are spotty or lacking in MHT. With effective treatment, the prognosis for MHT has improved; however, patients remain at high risk of adverse cardiovascular and kidney outcomes. In this review, we summarize current viewpoints on the epidemiology, pathogenesis, and management of MHT; highlight research gaps; and propose strategies to improve outcomes.

Potential Mechanisms of the Protective Effects of the Cardiometabolic Drugs Type-2 Sodium-Glucose Transporter Inhibitors and Glucagon-like Peptide-1 Receptor Agonists in Heart Failure.

Different multifactorial pathophysiological processes are involved in the development of heart failure (HF), including neurohormonal dysfunction, the hypertrophy of cardiomyocytes, interstitial fibrosis, microvascular endothelial inflammation, pro-thrombotic states, oxidative stress, decreased nitric oxide (NO) bioavailability, energetic dysfunction, epicardial coronary artery lesions, coronary microvascular rarefaction and, finally, cardiac remodeling. While different pharmacological strategies have shown significant cardiovascular benefits in HF with reduced ejection fraction (HFrEF), there is a residual unmet need to fill the gap in terms of knowledge of mechanisms and efficacy in the outcomes of neurohormonal agents in HF with preserved ejection fraction (HFpEF). Recently, type-2 sodium-glucose transporter inhibitors (SGLT2i) have been shown to contribute to a significant reduction in the composite outcome of HF hospitalizations and cardiovascular mortality across the entire spectrum of ejection fraction. Moreover, glucagon-like peptide-1 receptor agonists (GLP1-RA) have demonstrated significant benefits in patients with high cardiovascular risk, excess body weight or obesity and HF, in particular HFpEF. In this review, we will discuss the biological pathways potentially involved in the action of SGLT2i and GLP1-RA, which may explain their effective roles in the treatment of HF, as well as the potential implications of the use of these agents, also in combination therapies with neurohormonal agents, in the clinical practice.