Developing technologies to assess vascular ageing: a roadmap from VascAgeNet.

Vascular ageing is the deterioration of arterial structure and function which occurs naturally with age, and which can be accelerated with disease. Measurements of vascular ageing are emerging as markers of cardiovascular risk, with potential applications in disease diagnosis and prognosis, and for guiding treatments. However, vascular ageing is not yet routinely assessed in clinical practice. A key step towards this is the development of technologies to assess vascular ageing. In this Roadmap, experts discuss several aspects of this process, including: measurement technologies; the development pipeline; clinical applications; and future research directions. The Roadmap summarises the state of the art, outlines the major challenges to overcome, and identifies potential future research directions to address these challenges.

Serum uric acid to eGFR ratio correlates with adverse outcomes in elderly hospitalized for acute heart failure.

BACKGROUND: Serum uric acid (SUA) is a known biomarker of severity in acute heart failure (AHF), reflecting the intricate interplay between cardiovascular and metabolic dysfunction. Since SUA can increase in response to worsening kidney function, and subjects with AHF often have cardiorenal syndrome or are on diuretic therapy, we tested whether the ratio of SUA to eGFR might provide prognostic value in elderly hospitalized for AHF. METHODS: The BOTERO-AHF Study (BOlogna study of Therapies, Epidemiology and Radiodiagnostic Outcomes in Acute Heart Failure patients) included 293 patients admitted for AHF who were consecutively enrolled from January 2020 onwards. We compared the baseline characteristics of participants who had a composite outcome (CO) (n = 203) of death or re-hospitalization for AHF within 12 months from discharge to those without CO (n = 90), and we assessed the prognostic impact of SUA/eGFR for 12-months CO. RESULTS: SUA/eGFR was significantly higher in participants who experienced a CO within 12 months from discharge for AHF, compared to those who did not experience any CO (17.8 (16.6) vs. 13.7 (12.1) mg/dl/ml/min*100, p = 0.008). SUA/eGFR, and not SUA alone, was associated with an increase in the rate of CO (unadjusted HR 1.011, CI 95% 1.004-1.019, p = 0.003). This association lost significance in participants under treatment with xanthine oxidase inhibitors but remained significant after adjustment for multiple confounders. CONCLUSION: The SUA/ eGFR ratio provides prognostic value in elderly patients hospitalized for AHF. Future studies may clarify if SUA/eGFR and XOI may represent novel diagnostic and therapeutic approaches for subgroups of patients with AHF.

Atrial Fibrillation and Early Vascular Aging: Clinical Implications, Methodology Issues and Open Questions-A Review from the VascAgeNet COST Action.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with adverse CV outcomes. Vascular aging (VA), which is defined as the progressive deterioration of arterial function and structure over a lifetime, is an independent predictor of both AF development and CV events. A timing identification and treatment of early VA has therefore the potential to reduce the risk of AF incidence and related CV events. A network of scientists and clinicians from the COST Action VascAgeNet identified five clinically and methodologically relevant questions regarding the relationship between AF and VA and conducted a narrative review of the literature to find potential answers. These are: (1) Are VA biomarkers associated with AF? (2) Does early VA predict AF occurrence better than chronological aging? (3) Is early VA a risk enhancer for the occurrence of CV events in AF patients? (4) Are devices measuring VA suitable to perform subclinical AF detection? (5) Does atrial-fibrillation-related rhythm irregularity have a negative impact on the measurement of vascular age? Results showed that VA is a powerful and independent predictor of AF incidence, however, its role as risk modifier for the occurrence of CV events in patients with AF is debatable. Limited and inconclusive data exist regarding the reliability of VA measurement in the presence of rhythm irregularities associated with AF. To date, no device is equipped with tools capable of detecting AF during VA measurements. This represents a missed opportunity to effectively perform CV prevention in people at high risk. Further advances are needed to fill knowledge gaps in this field.

Assessing the Accuracy of Systolic Aortic Pressure Estimation From a Brachial Cuff Alone: A Comparison With Radial Tonometry.

BACKGROUND: A novel method for estimating central systolic aortic pressure (cSAP) has emerged, relying solely on the peripheral mean (MBP) and diastolic (DBP) blood pressures. We aimed to assess the accuracy of this Direct Central Blood Pressure estimation using cuff alone (DCBPcuff = MBP2/DBP) in comparison to the use of a generalized transfer function to derive cSAP from radial tonometry (cSAPtono). METHODS: This retrospective analysis involved the International Database of Central Arterial Properties for Risk Stratification (IDCARS) data (Aparicio et al., Am J Hypertens 2022). The dataset encompassed 10,930 subjects from 13 longitudinal cohort studies worldwide (54.8% women; median age 46.0 years; office hypertension: 40.1%; treated: 61.0%), documenting cSAPtono via SphygmoCor calibrated against brachial systolic BP (SBP) and DBP. Our analysis focused on aggregate group data from 12/13 studies (89% patients) where a full BP dataset was available. A 35% form factor was used to estimate MBP = (DBP + (0.35 × (SBP-DBP)), from which DCBPcuff was derived. The predefined acceptable error for cSAPtono estimation was set at ≤ 5 mm Hg. RESULTS: The cSAPtono values ranged from 103.8-127.0 mm Hg (n = 12). The error between DCBPcuff and cSAPtono was 0.2 ±â€…1.4 mm Hg, with no influence of the mean. Errors ranged from -1.8 to 2.9 mm Hg across studies. No significant difference in errors was observed between BP measurements obtained via oscillometry (n = 9) vs. auscultation (n = 3) (P = 0.50). CONCLUSIONS: Using published aggregate group data and a 35% form factor, DCBPcuff demonstrated remarkable accuracy in estimating cSAPtono, regardless of the BP measurement technique. However, given that individual BP values were unavailable, further documentation is required to establish DCBPcuff's precision.

Non-Invasive Estimation of Central Systolic Blood Pressure by Radial Tonometry: A Simplified Approach.

BACKROUND: Central systolic blood pressure (cSBP) provides valuable clinical and physiological information. A recent invasive study showed that cSBP can be reliably estimated from mean (MBP) and diastolic (DBP) blood pressure. In this non-invasive study, we compared cSBP calculated using a Direct Central Blood Pressure estimation (DCBP = MBP2/DBP) with cSBP estimated by radial tonometry. METHODS: Consecutive patients referred for cardiovascular assessment and prevention were prospectively included. Using applanation tonometry with SphygmoCor device, cSBP was estimated using an inbuilt generalized transfer function derived from radial pressure waveform, which was calibrated to oscillometric brachial SBP and DBP. The time-averaged MBP was calculated from the radial pulse waveform. The minimum acceptable error (DCBP-cSBP) was set at ≤5 (mean) and ≤8 mmHg (SD). RESULTS: We included 160 patients (58 years, 54%men). The cSBP was 123.1 ± 18.3 mmHg (range 86-181 mmHg). The (DCBP-cSBP) error was -1.4 ± 4.9 mmHg. There was a linear relationship between cSBP and DCBP (R2 = 0.93). Forty-seven patients (29%) had cSBP values ≥ 130 mmHg, and a DCBP value > 126 mmHg exhibited a sensitivity of 91.5% and specificity of 94.7% in discriminating this threshold (Youden index = 0.86; AUC = 0.965). CONCLUSIONS: Using the DCBP formula, radial tonometry allows for the robust estimation of cSBP without the need for a generalized transfer function. This finding may have implications for risk stratification.

Serum uric acid to creatinine ratio and risk of preeclampsia and adverse pregnancy outcomes.

OBJECTIVE: Preeclampsia is one of the most severe diseases among the hypertensive disorders of pregnancy (HDP) and the leading cause of maternal and fetal morbidity and mortality. It is of crucial importance to early identify women at a high risk for preeclampsia to implement appropriate preventive strategies. In our study, we aimed to test the hypothesis that serum uric acid to creatinine ratio (SUA/sCr) is related to the development of preeclampsia and maternal and neonatal complications. METHODS: We searched for uric acid and creatine values in the medical records of 269 women who consecutively attended our HDP Clinic from December 2018 to December 2022. We compared the baseline characteristics of participants with normotensive pregnancy ( n  = 57), to those with HDP without preeclampsia (HDP-non-PE) ( n  = 100) and those with preeclampsia ( n  = 112), and we performed adjusted logistic regression analysis to test the associations between SUA/sCr and the development of preeclampsia and maternal and neonatal complications. RESULTS: SUA/sCr was consistently higher in women with preeclampsia in all trimesters of pregnancy. Higher SUA/sCr at the third trimester was associated with an increased odd of developing preeclampsia [odds ratio (OR) 1.29, confidence interval (CI) 1.15-1.50, P  = 0.001], preterm birth (OR 1.23, CI 1.05-1.45, P  = 0.011), and composite neonatal outcome (OR 1.33, CI 1.12-1.59, P  = 0.001), after adjustment for age, BMI before pregnancy, nulliparity, antihypertensive therapy, and acetylsalicylic acid therapy during pregnancy. CONCLUSIONS: Having higher SUA/sCr during pregnancy is associated with the development of PE and adverse pregnancy outcomes. Controlled prospective studies are warranted to clarify the predictive power of this novel marker during pregnancy.

Diagnostic and Prognostic Role of CD93 in Cardiovascular Disease: A Systematic Review.

INTRODUCTION: Cluster of Differentiation (CD) 93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp) is a transmembrane glycoprotein that can also be present in a soluble (sCD93) form. Recent studies have investigated the role of this protein in cardiovascular disease (CVD). The present systematic review aims to assess the associations between CD93 and cardiovascular (CV) risk factors and disease at both the proteomic and genomic levels. METHODS: We conducted systematic searches in the PubMed, EMBASE, and Web of Science databases to identify all human studies since inception to February 2023 that investigated the role of CD93 in CV risk factors, CVD, and CV-associated outcomes. The data collection and analysis have been independently conducted by two reviewers. The search terms included: cardiovascular, heart failure, acute stroke, myocardial infarction, stroke, peripheral artery disease, cardiovascular death, MACE, hypertension, metabolic syndrome, hyperuricemia, diabetes, cd93, c1qr, C1qR1, complement protein 1 q subcomponent receptor. RESULTS: A total of 182 references were identified, and 15 studies investigating the associations between CD93 protein levels or CD93 genetic polymorphisms and the development or prevalence of CV risk factors (i.e., hypertension, dyslipidemia, and obesity) and CVD (i.e., heart failure, coronary artery disease, and ischemic stroke) were included. Although promising, the quality and dimension of the analyzed studies do not allow for a definitive answer to the question of whether CD93 may hold diagnostic and prognostic value in CVD.

Controlling nutritional status score predicts 2-year outcomes in elderly patients admitted for acute heart failure.

BACKGROUND: Heart failure (HF) is a major cause of death among the elderly. Its prevalence increases dramatically with age. The prevalence of malnourished subjects is high in hospitalized elderly patients. We aimed to investigate the prognostic role of malnutrition, assessed by controlling nutritional status (CONUT) score, on adverse clinical outcomes in the elderly admitted for acute HF. METHODS: We enrolled 293 patients (mean age 84 years; 48% men) consecutively admitted for acute HF to the Internal Medicine or Geriatrics Divisions at the 'IRCCS Sacro Cuore-Don Calabria' Hospital of Negrar (Verona, Italy) from 2013 to 2015. We predicted the risk of all-cause death, re-hospitalizations for HF and non-HF causes, and the composite of all-cause death or hospitalizations over 2-year follow-up. Patients were divided into four groups according to CONUT score: normal-CONUT (0-1; n = 30); mild-CONUT (2-3; n = 56); moderate-CONUT (4-7; n = 171); and severe-CONUT (≥ 8; n = 36). RESULTS: Higher CONUT scores were associated with older age and lower entry blood pressures. No difference in hemodynamics was noted at the discharge. Kaplan-Meier curves showed a significant association between worsening CONUT scores and risk of all-cause death (p < 0.01), re-hospitalizations (p < 0.01), or both (p < 0.001). Cox regression analysis revealed these significant associations persisted after adjustment for age, sex, pre-existing cardiovascular disease, diabetes, chronic kidney disease, heart rate, systolic blood pressure, and plasma brain natriuretic peptide levels at discharge (all-cause mortality HR = 1.29 (1.00-1.66), p = 0.049; hospitalization for HF HR = 1.36 (1.03-1.81), p = 0.033; hospitalization for non-HF HR = 1.38 (1.03-1.86), p = 0.034; composite outcome HR = 1.33 (1.07-1.64), p = 0.01). CONCLUSIONS: Malnutrition, assessed by the CONUT score, is common among elderly patients admitted for acute HF and is strongly related to increased long-term risk of all-cause death and re-hospitalizations.

Advances in pharmacotherapies for hyperuricemia.

INTRODUCTION: Hyperuricemia is an overlooked cardiovascular and renal risk factor. Epidemiological and genetic studies have shown an independent role of uric acid in the risk of coronary artery disease, heart failure, chronic kidney disease, and cardiovascular mortality. Treatment options include xanthine oxidase inhibitors, uricosuric medications, and the recombinant uricases. Whether to treat asymptomatic hyperuricemia, and to which target, remains debated. However, the results of recent trials and meta-analysis seem to support this therapeutic strategy. AREAS COVERED: In the present review, we summarized current therapeutic indications and options for the treatment of symptomatic and asymptomatic hyperuricemia. Furthermore, we searched the recent literature (last 5 years: 2018 to 2022) to report the results of randomized controlled trials and meta-analysis on cardiovascular and nephroprotective effects of hypouricemic agents. EXPERT OPINION: Future large well-designed clinical trials on the role of hypouricemic agents in nephroprotection and cardiovascular prevention and treatment are warranted and may extend their indications and use, with a direct impact on morbidity and mortality. Differentiating between hyperproducing and hypoexcreting phenotypes may help designing future trials improving the consistency of results. Finally, medications with cardio and nephroprotective properties have shown to reduce serum uric acid levels and may be used in patients with hyperuricemia and other cardiovascular complications.

Pathophysiology of cough with angiotensin-converting enzyme inhibitors: How to explain within-class differences?

Angiotensin converting enzyme inhibitors (ACEi) have consistently demonstrated improved survival and reduced risk of major cardiovascular events, across the spectrum of cardiovascular disease, including hypertension, coronary artery disease, myocardial infarction, and heart failure. The cardioprotective effects of ACEi result from inhibiting the conversion of angiotensin I to angiotensin II, and inhibition of bradykinin degradation. They are generally well tolerated but may cause the onset of a dry cough in some patients. This review presents current evidence on the incidence and mechanisms of cough associated with ACEi use, and then considers how to manage ACEi-related cough in clinical practice. The incidence of ACEi-induced cough in the published literature varies widely due to heterogeneity in the source data and lack of adequate controls. Incidence also varies among individual ACEi with agents such as perindopril, which has a high tissue ACE affinity, associated with a lower rate of cough. Evidence from real-world studies shows that the incidence of ACEi-associated cough is lower than rates reported in clinical trials. Patients who experience any dry cough are often switched to angiotensin- receptor blockers or other classes of antihypertensive drugs, regardless of cough severity. To avoid inappropriate discontinuation of ACEi in clinical practice, an alternative approach in patients with persistent cough is to perform a challenge/re-challenge to determine if re-introduction of ACEi is associated with recurrence of symptoms. Incidence of cough should not be considered a class effect for ACEi, and the patient may benefit by a switch from one ACEi to another. Every effort should be made to enable patients to continue ACEi therapy to reduce adverse cardiovascular outcomes and improve survival.

Statin therapy may protect against acute kidney injury in patients hospitalized for interstitial SARS-CoV2 pneumonia.

BACKGROUND AND AIMS: COVID-19-associated acute kidney injury (AKI) represents an independent risk factor for all-cause in-hospital death in patients with COVID-19. Chronic statin therapy use is highly prevalent in individuals at risk for severe COVID-19. Our aim is to assess whether patients under treatment with statins have a lower risk of AKI and in-hospital mortality during hospitalization for interstitial SARS-CoV2 pneumonia. METHODS AND RESULTS: Our study is a prospective observational study on 269 consecutive patients admitted for COVID-19 pneumonia at the Internal Medicine Unit of IRCCS Sant'Orsola Hospital in Bologna, Italy. We compared the clinical characteristics between patients receiving statin therapy (n = 65) and patients not treated with statins and we assessed if chronic statin use was associated with a reduced risk for AKI, all-cause mortality, admission to ICU, and disease severity. Statin use was associated with a significant reduction in the risk of developing AKI (OR 0.47, IC 0.23 to 0.95, p 0.036) after adjustment for age, sex, BMI, hypertension, diabetes, and chronic kidney disease (CKD). Additionally, statin use was associated with reduced C-reactive protein (CRP) levels (p 0.048) at hospital admission. No significant impact in risk of all-cause mortality (HR 1.98, IC 0.71 to 5.50, p 0.191) and ICU admission (HR 0.93, IC 0.52 to 1.65, p 0.801) was observed with statin use, after adjustment for age, sex, BMI, hypertension, diabetes, and CKD. CONCLUSION: The present study shows a potential beneficial effect of statins in COVID-19-associated AKI. Furthermore, patients treated with statins before hospital admission for COVID-19 may have lower systemic inflammation levels.

Uric Acid and Hypertension: a Review of Evidence and Future Perspectives for the Management of Cardiovascular Risk.

Uric acid is the final product of purine metabolism, and its increased serum levels have been directly involved in the pathogenesis and natural history of hypertension. The relationship between elevated uric acid and hypertension has been proven in both animals and humans, and its relevance is already evident in childhood and adolescent population. The mechanism responsible for blood pressure increase in hyperuricemic subjects is implicating both oxidative stress and intracellular urate activity with a primary involvement of XOR (xanthine-oxidoreductase activity). An increase in the relative risk of hypertension has been confirmed by genetic data and by large meta-analyses of epidemiological data. The effects of urate-lowering treatment on blood pressure control in patients with elevated serum uric acid has been investigated in a small number of reliable studies with a large heterogeneity of patient populations and study designs. However, 2 large meta-analyses suggest a significant effect of urate-lowering treatment on blood pressure, thus confirming the significant relationship between high serum urate and blood pressure. The future research should be focused on a more appropriate identification of patients with cardiovascular hyperuricemia by considering the correct cardiovascular threshold of serum urate, the time-course of uricemia fluctuations, and the identification of reliable markers of urate overproduction that could significantly clarify the clinical and therapeutic implications of the interaction between serum uric acid and hypertension.

The Gut Microbiota and Vascular Aging: A State-of-the-Art and Systematic Review of the Literature.

The gut microbiota is a critical regulator of human physiology, deleterious changes to its composition and function (dysbiosis) have been linked to the development and progression of cardiovascular diseases. Vascular ageing (VA) is a process of progressive stiffening of the arterial tree associated with arterial wall remodeling, which can precede hypertension and organ damage, and is associated with cardiovascular risk. Arterial stiffness has become the preferred marker of VA. In our systematic review, we found an association between gut microbiota composition and arterial stiffness, with two patterns, in most animal and human studies: a direct correlation between arterial stiffness and abundances of bacteria associated with altered gut permeability and inflammation; an inverse relationship between arterial stiffness, microbiota diversity, and abundances of bacteria associated with most fit microbiota composition. Interventional studies were able to show a stable link between microbiota modification and arterial stiffness only in animals. None of the human interventional trials was able to demonstrate this relationship, and very few adjusted the analyses for determinants of arterial stiffness. We observed a lack of large randomized interventional trials in humans that test the role of gut microbiota modifications on arterial stiffness, and take into account BP and hemodynamic alterations.

Hypertension and Dyslipidemia Combined Therapeutic Approaches.

Treating blood pressure (BP) alone may provide only limited benefits while it is recommendable to manage the total cardiovascular risk. To date, several studies have shown that concomitant treatment of hypertension and dyslipidemia with non-pharmacological approaches and/or metabolically neutral antihypertensive drugs and statins produce a significantly greater reduction of the risk of developing cardiovascular disease. Thus, in this review article, we summarize the available evidence regarding non-pharmacological and pharmacological approaches with a favourable effect on both BP and lipids.

Reduction of High Cholesterol Levels by a Preferably Fixed-Combination Strategy as the First Step in the Treatment of Hypertensive Patients with Hypercholesterolemia and High/Very High Cardiovascular Risk: A Consensus Document by the Italian Society of Hypertension.

The primary and secondary prevention strategies of atherosclerotic cardiovascular disease (ASCVD) largely rely on the management of arterial hypertension and hypercholesterolemia, two major risk factors possibly linked in pathophysiological terms by the renin-angiotensin system activation and that often coexist in the same patient synergistically increasing cardiovascular risk. The classic pharmacologic armamentarium to reduce hypercholesterolemia has been based in the last two decades on statins, ezetimibe, and bile acid sequestrants. More recently numerous novel, additive resources targeting different pathways in LDL cholesterol metabolism have emerged. They include drugs targeting the proprotein convertase subtilisin/kexin type 9 (PCSK9) (inhibitory antibodies; small-interfering RNAs), the angiopoietin-like protein 3 (inhibitory antibodies), and the ATP-citrate lyase (the inhibitory oral prodrug, bempedoic acid), with PCSK9 inhibitors and bempedoic acid already approved for clinical use. With the potential of at least halving LDL cholesterol levels faster and more effectively with the addition of ezetimibe than with high-intensity statin alone, and even more with the addition of the novel available drugs, this document endorsed by the Italian Society of Hypertension proposes a novel paradigm for the treatment of the hypertensive patient with hypercholesterolemia at high and very high ASCVD risk. Our proposal is based on the use as a first-line of a preferably fixed combination of lipid-lowering drugs, under the motto "Our goal: achieve control. No setback: combine and check".

The Impact of Uric Acid and Hyperuricemia on Cardiovascular and Renal Systems.

The description of gout dates back almost 5000 years, and scientific interest in uric acid increased when it was found to be involved in the pathogenesis of gout. Since then, many basic and clinical studies have assessed the implications of uric acid for the oxidative system, inflammation, and cardiovascular and renal outcomes. Uric acid-lowering therapy failed to improve clinical hard outcomes in asymptomatic hyperuricemia, and it is retained in symptomatic hyperuricemia. Dietary and lifestyle modifications are critical to manage hyperuricemia. More studies are warranted to investigate the role of uric acid-lowering drugs on cardiovascular outcomes.