Patient-reported muscle symptoms and their characterization in a hypertensive population eligible for statin therapy: An exploratory study.

BACKGROUND AND AIMS: Statin-associated muscle symptoms (SAMS) are claimed to be frequent in clinical practice. We evaluated the prevalence and characteristics of patient-reported muscle symptoms (PRMS) attributed to drugs/nutraceuticals in hypertensive patients, focusing the attention on statin treatment. METHODS AND RESULTS: Observational study on 390 consecutive outpatients. All patients were asked the following question: "Have you ever taken a drug/nutraceutical that you think gave you muscle symptoms?". Patients who answered "yes" were evaluated with a modified version of the SAMS-clinical index (SAMS-CI). Mean age: 60.5 ± 13.5 years (males 53.8%.). Patients who have ever taken a statin: 250. Patients who have never taken a statin: 140. Prevalence of PRMS (48.5% of the entire study population) did not differ between groups (p = 0.217). Only age, followed by number of drugs taken, was significantly associated with PRMS at multivariate analysis. A high prevalence of low scores to all the questions of "modified" SAMS-CI was found in both groups. Localization and pattern of PRMS did not differ between groups (p = 0.170). Timing of PRMS onset after starting the drug (p = 0.036) and timing of improvement after withdrawal (p = 0.002) were associated with statin therapy. CONCLUSION: PRMS are highly prevalent among the hypertensive population and are believed to be drug-related, especially with aging and regardless of whether the drug taken is a statin or not. These findings are in line with the growing evidence that subjective muscle symptoms are often misattributed to statins, while they may more likely be related to the nocebo/drucebo effect or to other common undiagnosed conditions.

Cardiovascular Risk Assessment and Control in Outpatients Evaluated by 24-hour Ambulatory Blood Pressure and Different LDL-C Equations.

INTRODUCTION: Office blood pressure (OBP) and low-density lipoprotein cholesterol (LDL-C) calculated by the Friedewald formula (F) are the cornerstones of the cardiovascular risk (CVR) assessment and management based on the SCORE2/SCORE2-OP model proposed by the 2021 ESC Guidelines on Cardiovascular Disease Prevention. AIM: We compared the CVR stratification estimated by the old SCORE and the SCORE2/SCORE2-OP using OBP and ambulatory blood pressure measurement (ABPM), and we evaluated the prevalence of LDL-C control, after calculating it using three validated equations, in outpatients referred for arterial hypertension. METHODS: A cross-sectional study on 1539 consecutive patients with valid ABPM. LDL-C was calculated using the Friedewald formula (F), its modification by Martin (M), and the Sampson (S) equation. SCORE and SCORE2/SCORE2-OP were estimated using OBP, mean daytime (+ 5 mmHg adjustment), and mean 24-hour systolic blood pressure (+ 10 mmHg adjustment). Individual CVR by 2021 ESC Guidelines (and SCORE2/SCORE2-OP) was compared to the 2019 ESC/EAS Guidelines (and SCORE). Differences in the prevalence of LDL-C control according to the three methods to calculate LDL-C were also analysed. RESULTS: Mean age was 60 ± 12 years, with male prevalence (54%). Mean LDL-C values were 118 ± 38 mg/dL (F), 119 ± 37 mg/dL (M), and 120 ± 38 mg/dL (S), respectively. Within the same population, SCORE and SCORE2/SCORE2-OP significantly varied, but no differences emerged after comparing the average SCORE2/SCORE2-OP calculated with OBP (6% IQR 3-10), mean 24-hour systolic BP (7% IQR 4-11), and mean daytime systolic BP (7% IQR 4-11). SCORE2/SCORE2-OP and 2021 ESC Guidelines reclassified the CVR independently of the method used for BP measurement. The low-moderate risk group decreased by 32%, whereas the high and veryhighrisk groups increased by 18% and 12%, respectively. We found a significant reduction in reaching the LDL-C goals regardless of the equation used to calculate it, except for those > 65 years, in whom results were confirmed only by using the M. CONCLUSION: SCORE2/SCORE2-OP and 2021 ESC Guidelines recommendations led to a non-negligible CVR reclassification and subsequent lack of LDL-C goal, regardless of estimating SCORE2 using OBP or ABPM. Calculating the LDL-C with the M may be the best choice in specific settings.

Role of Cardio-Renal Dysfunction, Inflammation Markers, and Frailty on In-Hospital Mortality in Older COVID-19 Patients: A Cluster Analysis.

Our study aimed to identify clusters of hospitalized older COVID-19 patients according to their main comorbidities and routine laboratory parameters to evaluate their association with in-hospital mortality. We performed an observational study on 485 hospitalized older COVID-19 adults (aged 80+ years). Patients were aggregated in clusters by a K-medians cluster analysis. The primary outcome was in-hospital mortality. Medical history and laboratory parameters were collected on admission. Frailty, defined by the Clinical Frailty Scale (CFS), referred to the two weeks before hospitalization and was used as a covariate. The median age was 87 (83-91) years, with a female prevalence (59.2%). Three different clusters were identified: cluster 1 (337), cluster 2 (118), and cluster 3 (30). In-hospital mortality was 28.5%, increasing from cluster 1 to cluster 3: cluster 1 = 21.1%, cluster 2 = 40.7%, and cluster 3 = 63.3% (p < 0.001). The risk for in-hospital mortality was higher in clusters 2 [HR 1.96 (95% CI: 1.28-3.01)] and 3 [HR 2.87 (95% CI: 1.62-5.07)] compared to cluster 1, even after adjusting for age, sex, and frailty. Patients in cluster 3 were older and had a higher prevalence of atrial fibrillation, higher admission NT-proBNP and C-reactive protein levels, higher prevalence of concurrent bacterial infections, and lower estimated glomerular filtration rates. The addition of CFS significantly improved the predictive ability of the clusters for in-hospital mortality. Our cluster analysis on older COVID-19 patients provides a characterization of those subjects at higher risk for in-hospital mortality, highlighting the role played by cardio-renal impairment, higher inflammation markers, and frailty, often simultaneously present in the same patient.

Painful and recurring injection site reaction to alirocumab and evolocumab in a young woman with familial hypercholesterolemia and effective therapeutic alternative based on inclisiran: a case report.

A 28-year-old woman with autosomal dominant familial hypercholesterolemia (FH) with a probable coexistent polygenic contribution causing very high low-density lipoprotein-cholesterol (LDL-C) levels, started therapy with the proprotein convertase subtilisin/kexin type 9-inhibitor (PCSK9i) alirocumab, in addition to high-intensity statin plus ezetimibe. Forty-eight hours after the second injection of alirocumab, the patient developed a painful palpable injection site reaction (ISR) that recurred after the third administration of the drug. Treatment was then switched to evolocumab, another PCSK9i, but the patient had an ISR with similar features. The most conceivable cause of the ISR was a cell-mediated hypersensitivity reaction to polysorbate, an excipient contained in both drugs. Although ISR after PCSK9i administration is usually transient and does not compromise the continuation of treatment, in this case the recurrence of such side effect in an exacerbated way led to treatment withdrawal, with a subsequent re-exposure to increased cardiovascular (CV) risk. As soon as it became available in clinical practice, the patient started treatment with inclisiran, a small interfering RNA targeting hepatic PCSK9 synthesis. No adverse events were reported after inclisiran administration and LDL-C levels decreased significantly, confirming the evidence that this innovative approach to hypercholesterolemia is a safe and effective resource in patients at high CV risk who cannot achieve LDL-C goal with conventional lipid-lowering therapies and antibody-based PCSK9i.

Radiological lung sequelae, functional status and symptoms in older patients 3 and 6 months after hospitalization for COVID-19 pneumonia.

The aim of our study was to assess the lung sequelae and clinical consequences 3 and 6 months after hospitalization for COVID-19 pneumonia in older patients. An observational study was conducted on 55 patients aged 65 years and older. Activities of daily living (ADL) and clinical frailty scale (CFS) were assessed at baseline and after 3 months. Both quantitative assessment at chest high-resolution computed tomography (CT) and semi-quantitative severity score (CTSS) were performed at baseline and after 3 and 6 months. Mean age: 82.3 ± 7.1 years. Male prevalence: 56.4%. After 6 months, ground-glass opacities (GGO) were still detectable in 22% of subjects, while consolidations were no longer appreciable. During follow-up, CTSS reached an overall median score of zero after 6 months. Fibrotic-like changes were found in 40% of subjects with an overall median score of 0 (0-5) points, being more prevalent in males. Patients reporting worsening ADL and CFS were 10.9% and 45.5%, respectively. They were associated with the burden of comorbidities, especially history of heart failure and chronic obstructive pulmonary disease at baseline. Amnesic disorders, exertional dyspnea, and fatigue were the most relevant symptoms reported. No association emerged between persistent or new-onset symptoms and evidence of fibrotic-like changes. The typical chest CT abnormalities of the COVID-19 pneumonia acute phase resolved in most of our older patients. Mild fibrotic-like changes persisted in less than half of the patients, especially males, without significantly affecting the functional status and frailty condition, which instead were more likely associated with pre-existing comorbidities.

Molecular Therapies in Cardiovascular Diseases: Small Interfering RNA in Atherosclerosis, Heart Failure, and Hypertension.

Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through RNA interference. In the cardiovascular (CV) field, several siRNAs have been developed in the last decade. Inclisiran has been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) circulating levels with a reassuring safety profile, also in older patients, by hampering proprotein convertase subtilisin/kexin type 9 (PCSK9) production. Olpasiran, directed against apolipoprotein(a) mRNA, prevents the assembly of lipoprotein(a) [Lp(a)] particles, a lipoprotein linked to an increased risk of ischemic CV disease and heart valve damage. Patisiran, binding transthyretin (TTR) mRNA, has demonstrated an ability to improve heart failure and polyneuropathy in patients with TTR amyloidosis, even in older patients with wild-type form. Zilebesiran, designed to reduce angiotensinogen secretion, significantly decreases systolic and diastolic blood pressure (BP). Thanks to their effectiveness, safety, and tolerability profile, and with a very low number of administrations in a year, thus overcoming adherence issues, these novel drugs are the leaders of a new era in molecular therapies for CV diseases.

Role of Cardiac Natriuretic Peptides in Heart Structure and Function.

Cardiac natriuretic peptides (NPs), atrial NP (ANP) and B-type NP (BNP) are true hormones produced and released by cardiomyocytes, exerting several systemic effects. Together with C-type NP (CNP), mainly expressed by endothelial cells, they also exert several paracrine and autocrine activities on the heart itself, contributing to cardiovascular (CV) health. In addition to their natriuretic, vasorelaxant, metabolic and antiproliferative systemic properties, NPs prevent cardiac hypertrophy, fibrosis, arrhythmias and cardiomyopathies, counteracting the development and progression of heart failure (HF). Moreover, recent studies revealed that a protein structurally similar to NPs mainly produced by skeletal muscles and osteoblasts called musclin/osteocrin is able to interact with the NPs clearance receptor, attenuating cardiac dysfunction and myocardial fibrosis and promoting heart protection during pathological overload. This narrative review is focused on the direct activities of this molecule family on the heart, reporting both experimental and human studies that are clinically relevant for physicians.

Plasma Levels of Proprotein Convertase Subtilisin/Kexin Type 9 Are Inversely Associated with N-Terminal Pro B-Type Natriuretic Peptide in Older Men and Women.

BACKGROUND AND AIMS: Cardiac natriuretic peptides (NPs) exert several metabolic effects, including some on lipid metabolism. Higher NPs levels are likely to be associated with a favorable lipid profile. In in vitro studies, NPs have been found to modulate low-density lipoprotein receptor (LDLR) trafficking by preventing proprotein convertase subtilisin/kexin type 9 (PCSK9) overexpression. The aim of our study is to investigate a possible association between plasma levels of PCSK9 and N-terminal pro B-type natriuretic peptide (NT-proBNP) in vivo. METHODS: We performed a cross-sectional study on 160 consecutive older male and female patients hospitalized for medical conditions. Patients taking lipid-lowering drugs and patients with an admission diagnosis of acute heart failure were excluded. Fasting blood samples were collected after clinical stabilization of the acute illness, the day before discharge. RESULTS: The mean age was 87.8 ± 6.4 years with a female prevalence (62.5%). The median NT-proBNP was 2340 (814-5397) pg/mL. The mean plasma PCSK9 was 275.2 ± 113.2 ng/mL. We found an inverse correlation between plasma PCSK9 and NT-proBNP (r = -0.280; p = 0.001). This association was confirmed after taking into account NT-proBNP tertiles (plasma PCSK9 levels: 317.4 ± 123.6 ng/mL in the first tertile, 283.3 ± 101.8 ng/mL in the second tertile, 231.3 ± 99.0 ng/mL in the third tertile, p = 0.001) and even after an adjustment for confounding factors (beta = -0.361, p = 0.001 for ln(NT-proBNP); beta = -0.330, p = 0.001 for NT-proBNP tertiles). The strength of the correlation between plasma PCSK9 and NT-proBNP was likely greater in patients affected by type 2 diabetes mellitus (r = -0.483; p = 0.006) and in male patients (r = -0.431, p = 0.001). CONCLUSION: The inverse association found between PCSK9 and NT-proBNP plasma levels in our real-life clinical study supports the hypothesis that NPs may play a role in cholesterol metabolism, possibly through an inhibitory action on circulating PCSK9 concentrations, thus increasing the availability of LDLR.

Renin-Angiotensin-System Inhibitors Are Associated With Lower In-hospital Mortality in COVID-19 Patients Aged 80 and Older.

Background: Older adults are at higher risk of morbidity and mortality for coronavirus disease 2019 (COVID-19). Renin-angiotensin-system inhibitors (RASi) were found to have a neutral or protective effect against mortality in COVID-19 adult patients. Aims: We investigated whether this association was confirmed also in COVID-19 older patients. Methods: This is a prospective observational study on 337 hospitalized older adults (aged 80 years and older). We classified the study population according to usage of RASi before and during hospitalization. A propensity score analysis was also performed to confirm the findings. Results: The mean age was 87.4 ± 6.1 years. Patients taking RASi at home were 147 (43.6%). During hospitalization, 38 patients (11.3% of the entire study population) discontinued RASi, while 57 patients (16.9% of the entire study population) started RASi. In-hospital mortality was 43.9%. Patients taking RASi during hospitalization (patients who maintained their home RASi therapy + patients who started RASi during hospitalization) had a significantly lower in-hospital mortality than untreated patients [HR 0.48 (95% CI: 0.34-0.67)], even after adjustment for required respiratory support, functional status, albumin, inflammation, and cardiac biomarkers. The analysis of the groups derived from the "propensity score matching" (58 patients in each group) confirmed these results [HR 0.46 (95% CI: 0.23-0.91)]. Discussion: Despite the high risk of death in older COVID-19 patients, RASi therapy during hospitalization was associated with a clinically relevant lower in-hospital mortality, likely due to the benefit of RAS modulation on the cardiopulmonary system during the acute phase of the disease. Conclusion: Our findings confirm the protective role of RASi even in COVID-19 patients aged 80 years and older.

The Identikit of Patient at Risk for Severe COVID-19 and Death: The Dysregulation of Renin-Angiotensin System as the Common Theme.

Since the first months of the coronavirus disease 2019 (COVID-19) pandemic, several specific physiologic traits, such as male sex and older age, or health conditions, such as overweight/obesity, arterial hypertension, metabolic syndrome, and type 2 diabetes mellitus, have been found to be highly prevalent and associated with increased risk of adverse outcomes in hospitalized patients. All these cardiovascular morbidities are widespread in the population and often coexist, thus identifying a common patient phenotype, characterized by a hyper-activation of the "classic" renin-angiotensin system (RAS) and mediated by the binding of angiotensin II (Ang II) to the type 1-receptor. At the same time, the RAS imbalance was proved to be crucial in the genesis of lung injury after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, where angiotensin-converting-enzyme-2 (ACE2) is not only the receptor for SARS-CoV-2, but its down-regulation through internalization and shedding, caused by the virus binding, leads to a further dysregulation of RAS by reducing angiotensin 1-7 (Ang 1-7) production. This focused narrative review will discuss the main available evidence on the role played by cardiovascular and metabolic conditions in severe COVID-19, providing a possible pathophysiological link based on the disequilibrium between the two opposite arms of RAS.

The Number of Pills, Rather Than the Type of Renin-Angiotensin System Inhibitor, Predicts Ambulatory Blood Pressure Control in Essential Hypertensives on Triple Therapy: A Real-Life Cross-Sectional Study.

INTRODUCTION: We evaluated the prevalence and predictors of ambulatory blood pressure (BP) control in patients taking a triple antihypertensive therapy (renin-angiotensin system inhibitor + calcium channel blocker + thiazide/thiazide-like diuretic, in either free or fixed-dose combinations) containing an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB). METHODS: We performed an observational cross-sectional study on 520 consecutive patients with essential hypertension taking a stable triple therapy in whom 24-h ambulatory BP was evaluated. Both number of pills and antihypertensive treatment intensity (ATI), as possible pharmacological predictors of ambulatory BP control, were taken into account. RESULTS: A total of 189 (36.3%) patients were taking triple therapy with ACEi and 331 (63.7%) patients were taking triple therapy with ARB. Mean age was 62.7 ± 12.2 years. Patients on triple therapy with ACEi had a significantly lower ATI and took fewer antihypertensive pills than patients on triple therapy with ARB (22.2% of patients took a single-pill triple fixed-dose combination). Patients taking triple therapy with ACEi had higher prevalence of both 24-h (54.8% vs 44.0%; p = 0.019) and daytime BP control (61.8% vs 49.2%; p = 0.006) than patients taking triple therapy with ARB, even after adjusting for age, sex, body mass index, smoking habit, type 2 diabetes mellitus, estimated glomerular filtration rate, and ATI [OR 1.5 (95% CI 1.1-2.2) and OR 1.6 (95% CI 1.1-2.4), respectively]. However, these independent associations with ambulatory BP control were lost when the number of antihypertensive pills was included in the model. CONCLUSION: The higher prevalence of ambulatory BP control found in patients taking a triple therapy with ACEi was affected by the lower number of antihypertensive pills taken, which was also the key predictor of ambulatory BP control in our study. This confirms the importance of fixed-dose combinations in the management of essential hypertension.