Arterial hypertension is the most frequent cardiovascular risk factor all over the world, and it is one of the leading drivers of the risk of cardiovascular events and death. It is a complex trait influenced by heritable and environmental factors. To date, the World Health Organization estimates that 1.28 billion adults aged 30-79 years worldwide have arterial hypertension (defined by European guidelines as office systolic blood pressure ≥ 140 mmHg or office diastolic blood pressure ≥ 90 mmHg), and 7.1 million die from this disease. The molecular genetic basis of primary arterial hypertension is the subject of intense research and has recently yielded remarkable progress. In this review, we will discuss the genetics of arterial hypertension. Recent studies have identified over 900 independent loci associated with blood pressure regulation across the genome. Comprehending these mechanisms not only could shed light on the pathogenesis of the disease but also hold the potential for assessing the risk of developing arterial hypertension in the future. In addition, these findings may pave the way for novel drug development and personalized therapeutic strategies.
BACKGROUND: Most Hypertension Guidelines grade hypertension according to various cut-off values. We sought to investigate the prognostic impact of Grades 1 (140-159 and/or 90-99 mmHg), 2 (160-179 and/or 100-109 mmHg) and 3 (≥180 and/or ≥110 mmHg). METHODS: We followed for an average of 10 years a cohort of 3,150 initially untreated hypertensive patients (mean age 50 years, 44 % women) with no previous cardiovascular disease at entry. All patients underwent diagnostic tests including 24-hour ambulatory blood pressure (BP) monitoring. RESULTS: At entry, average clinic BP was 156/97 mmHg and average 24-hour BP was 137/87 mmHg. During follow-up, 314 patients experienced a first major cardiovascular event (composite of non-fatal myocardial infarction or stroke, cardiovascular death, or hospitalization for heart failure). Event rate was not formally dissimilar between Grade 1 and Grade 2 (0.73 vs 0.95 per 100 patient-years, respectively; p = 0.06). It was higher in Grade 3 (1.93 per 100 patient-years; p < 0.01 vs Grade 1 and Grade 2). After adjustment for a robust set of covariables, the hazard ratio was not dissimilar between Grade 1 and Grade 2 (p = 0.27), and higher in Grade 3 than in Grade 1 (p < 0.01), but the excess risk in Grade 3 was no longer significant (hazard ratio: 1.25, 95 % CI 0.87-1.78; p = 0.22) after adjustment for 24-hour ambulatory systolic BP. CONCLUSIONS: We were unable to find a significant difference in the relative hazard of cardiovascular events tied to hypertension Grades 1 and 2. Conversely, Grade 3 (clinic BP ≥180/110 mmHg) portends a higher cardiovascular risk, which is associated with higher levels of 24-hour ambulatory BP.
PURPOSE: Recently, a novel index (triglyceride-glucose index-TyG) was considered a surrogate marker of insulin resistance (IR); in addition, it was estimated to be a better expression of IR than widely used tools. Few and heterogeneous data are available on the relationship between this index and mortality risk in non-Asian populations. Therefore, we estimated the predictive role of baseline TyG on the incidence of all-cause and cardiovascular (CV) mortality in a large sample of the general population. Moreover, in consideration of the well-recognized role of serum uric acid (SUA) on CV risk and the close correlation between SUA and IR, we also evaluated the combined effect of TyG and SUA on mortality risk. METHODS: The analysis included 16,649 participants from the URRAH cohort. The risk of all-cause and CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. RESULTS: During a median follow-up of 144 months, 2569 deaths occurred. We stratified the sample by the optimal cut-off point for all-cause (4.62) and CV mortality (4.53). In the multivariate Cox regression analyses, participants with TyG above cut-off had a significantly higher risk of all-cause and CV mortality, than those with TyG below the cut-off. Moreover, the simultaneous presence of high levels of TyG and SUA was associated with a higher mortality risk than none or only one of the two factors. CONCLUSIONS: The results of this study indicate that these TyG (a low-cost and simple non-invasive marker) thresholds are predictive of an increased risk of mortality in a large and homogeneous general population. In addition, these results show a synergic effect of TyG and SUA on the risk of mortality.
Several studies have detected a direct association between serum uric acid (SUA) and cardiovascular (CV) risk. In consideration that SUA largely depends on kidney function, some studies explored the role of the serum creatinine (sCr)-normalized SUA (SUA/sCr) ratio in different settings. Previously, the URRAH (URic acid Right for heArt Health) Study has identified a cut-off value of this index to predict CV mortality at 5.35 Units. Therefore, given that no SUA/sCr ratio threshold for CV risk has been identified for patients with diabetes, we aimed to assess the relationship between this index and CV mortality and to validate this threshold in the URRAH subpopulation with diabetes; the URRAH participants with diabetes were studied (n = 2230). The risk of CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. During a median follow-up of 9.2 years, 380 CV deaths occurred. A non-linear inverse association between baseline SUA/sCr ratio and risk of CV mortality was detected. In the whole sample, SUA/sCr ratio > 5.35 Units was not a significant predictor of CV mortality in diabetic patients. However, after stratification by kidney function, values > 5.35 Units were associated with a significantly higher mortality rate only in normal kidney function, while, in participants with overt kidney dysfunction, values of SUA/sCr ratio > 7.50 Units were associated with higher CV mortality. The SUA/sCr ratio threshold, previously proposed by the URRAH Study Group, is predictive of an increased risk of CV mortality in people with diabetes and preserved kidney function. While, in consideration of the strong association among kidney function, SUA, and CV mortality, a different cut-point was detected for diabetics with impaired kidney function. These data highlight the different predictive roles of SUA (and its interaction with kidney function) in CV risk, pointing out the difference in metabolic- and kidney-dependent SUA levels also in diabetic individuals.
Superiority trials are designed to test the hypothesis that a given diagnostic or therapeutic strategy is better than (i.e. "superior to") placebo or an active control. Conversely, non-inferiority trials test the hypothesis that a newer (i.e. alternative) strategy is not "unacceptably worse" than a control (i.e. "traditional", or "older") strategy. Non-inferiority trials are increasingly conducted in clinical medicine more often when a "newer" strategy is supposed to offer a relevant advantage in terms other than clinical efficacy (i.e. better tolerability, less cost, simpler regimen, etc.) versus a "gold standard" traditional strategy. The principle underlying non-inferiority trials is that the above advantage justifies the preferential use of the newer strategy in the clinical practice even if the clinical efficacy of the "new" appears to be a bit worse than that of the "old", albeit not unacceptably worse (i.e. not beyond a pre-specified value). The demonstration of non-inferiority requires that the confidence interval of the point estimate (e.g. the hazard ratio) does not cross a pre-specified limit. The definition of such pre-specified limit, the so called "non-inferiority margin", is a pivotal point when planning non-inferiority trials. It denotes the maximally tolerated worse effect of the alternative strategy, compared with the traditional one, required to conclude that an alternative strategy is non-inferior to the traditional "gold standard". The non-inferiority margin is derived from previous trials evaluating the efficacy of the traditional strategy vs placebo. We reviewed the principles and the practical aspects in the design and conduct of non-inferiority trials.
BACKGROUND: Despite longstanding epidemiologic data on the association between increased serum triglycerides and cardiovascular events, the exact level at which risk begins to rise is unclear. The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension has conceived a protocol aimed at searching for the prognostic cutoff value of triglycerides in predicting cardiovascular events in a large regional-based Italian cohort. METHODS AND RESULTS: Among 14 189 subjects aged 18 to 95 years followed-up for 11.2 (5.3-13.2) years, the prognostic cutoff value of triglycerides, able to discriminate combined cardiovascular events, was identified by means of receiver operating characteristic curve. The conventional (150 mg/dL) and the prognostic cutoff values of triglycerides were used as independent predictors in separate multivariable Cox regression models adjusted for age, sex, body mass index, total and high-density lipoprotein cholesterol, serum uric acid, arterial hypertension, diabetes, chronic renal disease, smoking habit, and use of antihypertensive and lipid-lowering drugs. During 139 375 person-years of follow-up, 1601 participants experienced cardiovascular events. Receiver operating characteristic curve showed that 89 mg/dL (95% CI, 75.8-103.3, sensitivity 76.6, specificity 34.1, P<0.0001) was the prognostic cutoff value for cardiovascular events. Both cutoff values of triglycerides, the conventional and the newly identified, were accepted as multivariate predictors in separate Cox analyses, the hazard ratios being 1.211 (95% CI, 1.063-1.378, P=0.004) and 1.150 (95% CI, 1.021-1.295, P=0.02), respectively. CONCLUSIONS: Lower (89 mg/dL) than conventional (150 mg/dL) prognostic cutoff value of triglycerides for cardiovascular events does exist and is associated with increased cardiovascular risk in an Italian cohort.
Cardiovascular Diseases , Hypertension , Humans , Triglycerides , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Uric Acid , Prognosis , Hypertension/epidemiology , Italy/epidemiology , Risk Factors
The optimal blood pressure (BP) target for prevention of cardiovascular complications of hypertension remains uncertain. Most Guidelines suggest different targets depending on age, comorbidities and treatment tolerability, but the underlying evidence is not strong. Results of randomized strategy trials comparing lower (i.e., more intensive) versus higher (i.e., less intensive) BP targets should drive the definition. However, these trials tested different BP targets based on systolic BP, diastolic BP or combined systolic and diastolic BP goals. Overall, the more intensive treatment targets reduced the risk of major cardiovascular complications of hypertension when compared with the less intensive targets, despite a higher incidence of unwanted effects including, but not limited to, hypotension, electrolyte abnormalities and renal dysfunction. Consequently, some Guidelines defined low BP thresholds (i.e., 120/70 mmHg) not to exceed downward because of the expectation that unwanted effects may outweigh the outcome benefits. The present review discusses the evidence underlying the choice of BP targets, which remains an important step in the management of hypertensive patients. We conclude that, on the ground of the heterogeneity of available data in support to fixed BP targets, their definition should be personalized in all patients and based on best trade-off between efficacy and safety, i.e., the lowest well tolerated BP.
Antihypertensive Agents , Blood Pressure , Hypertension , Humans , Hypertension/drug therapy , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Practice Guidelines as Topic , Randomized Controlled Trials as Topic , Cardiovascular Diseases/prevention & control , Precision Medicine
Several reports documented a specific effect of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on blood pressure (BP), during and after the acute phase of infection. Clinical studies demonstrated that coronavirus disease 2019 (COVID-19) is associated with an increased risk of a persistent increase in BP requiring a new or intensified anti-hypertensive treatment during hospitalization. The picture is further complicated by the evidence from large databases showing an increased risk of new-onset hypertension in COVID-19 survivors on the long term. To further elucidate the epidemiological burden of this phenomenon, we performed a pooled analysis of 4 studies reporting crude incidence rates of new-onset hypertension among COVID-19 patients and contemporary controls. Overall, COVID-19 was associated with a 65% increased risk of new-onset hypertension when compared with controls (p<0.0001); furthermore, incidence of new-onset hypertension was 9% and 5% among COVID-19 patients and controls, respectively. In both the acute phase and recovery from infection, the interaction between spike proteins of SARS-CoV-2 and angiotensin converting enzyme 2 (ACE2) receptors remain the most plausible mechanism explaining the raise in BP (ranking new onset hypertension as one of the most prevalent cardiovascular sequelae of COVID-19). In this area of research, it is worth to mention that new variants of SARS-CoV-2 exhibit specific mutations in the spike protein that promotes entry into viral cells via ACE2. Thus, the enhanced spike affinity for ACE2 of new variants has the potential to increase the risk of new-onset hypertension when compared with the original Wuhan strain.
COVID-19 , Hypertension , Humans , COVID-19/complications , SARS-CoV-2 , Peptidyl-Dipeptidase A/metabolism , Hypertension/epidemiology , Mutation
INTRODUCTION: In a large nationwide administrative database including â¼35 % of Italian population, we analyzed the impact of oral anticoagulant treatment (OAT) in patients with a hospital diagnosis of non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: Of 170404 OAT-naïve patients (mean age 78.7 years; 49.4 % women), only 61.1 % were prescribed direct oral anticoagulants, DOACs, or vitamin-K antagonists, VKAs; 14.2 % were given aspirin (ASA), and 24.8 % no anti-thrombotic drugs (No Tx). We compared ischemic stroke (IS), IS and systemic embolism (IS/SE), intracranial hemorrhage (ICH), major bleeding (MB), major gastro-intestinal bleeding, all-cause deaths and the composite outcome, across four propensity-score matched treatment cohorts with >15400 patients each. Over 2.9±1.5 years, the incidence of IS and IS/SE was slightly less with VKAs than with DOACs (1.62 and 1.84 vs 1.81 and 1.99 events.100 person-years; HR=0.85, 95%CI=0.76-0.95 and HR=0.87, 95%CI=0.78-0.97). This difference disappeared in a sensitivity analysis which excluded those patients treated with low-dose of apixaban, edoxaban, or rivaroxaban (41.7% of DOACs cohort). Compared with DOACs, VKAs were associated with greater incidence of ICH (1.09 vs 0.81; HR=1.38, 95%CI=1.17-1.62), MB (3.78 vs 3.31; HR=1.14, 95%CI=1.02-1.28), all-cause mortality (9.66 vs 10.10; HR=1.07, 95%CI=1.02-1.11), and composite outcome (13.72 vs 13.32; HR=1.04, 95%CI=1.01-1.08). IS, IS/SE, and mortality were more frequent with ASA or No Tx than with VKAs or DOACs (p<0.001 for all comparisons). CONCLUSIONS: Beyond confirming the association with a better net clinical benefit of DOACs over VKAs, our findings substantiate the large proportion of NVAF patients still inappropriately anticoagulated, thereby reinforcing the need for educational programs.
Atrial Fibrillation , Ischemic Stroke , Stroke , Humans , Female , Aged , Male , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Stroke/epidemiology , Stroke/etiology , Stroke/prevention & control , Anticoagulants/adverse effects , Rivaroxaban/therapeutic use , Intracranial Hemorrhages/chemically induced , Aspirin/therapeutic use , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/epidemiology , Administration, Oral , Dabigatran
The relationship between Serum Uric Acid (UA) and Cardiovascular (CV) diseases has already been extensively evaluated, and it was found to be an independent predictor of all-cause and cardiovascular mortality but also acute coronary syndrome, stroke and heart failure. Similarly, also many papers have been published on the association between UA and kidney function, while less is known on the role of UA in metabolic derangement and, particularly, in metabolic syndrome. Despite the substantial number of publications on the topic, there are still some elements of doubt: (1) the better cut-off to be used to refine CV risk (also called CV cut-off); (2) the needing for a correction of UA values for kidney function; and (3) the better definition of its role in metabolic syndrome: is UA simply a marker, a bystander or a key pathological element of metabolic dysregulation?. The Uric acid Right for heArt Health (URRAH) project was designed by the Working Group on uric acid and CV risk of the Italian Society of Hypertension to answer the first question. After the first papers that individuates specific cut-off for different CV disease, subsequent articles have been published responding to the other relevant questions. This review will summarise most of the results obtained so far from the URRAH research project.
Acute Coronary Syndrome , Hyperuricemia , Kidney Diseases , Metabolic Syndrome , Humans , Hyperuricemia/diagnosis , Hyperuricemia/epidemiology , Uric Acid , Risk Factors , Metabolic Syndrome/diagnosis , Metabolic Syndrome/epidemiology
BACKGROUND: Atrial fibrillation (AFIB), the most frequent cardiac arrhythmia, is a major risk factor for stroke, heart failure, and death. Because of the recent advances in AFIB management and the availability of new oral anticoagulants (OACs), there is a need for a systematic and predefined collection of contemporary data regarding its management and treatment. METHODS: The objective of the ongoing ITALY-AFIB registry is to evaluate the long-term morbidity and mortality in patients with AFIB and to verify the implementation of the current guidelines for stroke prevention in these patients. The registry includes consecutive in- and out-patients with first diagnosed, paroxysmal, persistent, or permanent AFIB. In patients in sinus rhythm at entry, the qualifying episode of AFIB, confirmed by ECG diagnosis, had to have occurred within 1 year before entry. The clinical record form is web-based and accessible by personal keyword. RESULTS: Enrolment into the registry started in the year 2013. In a current cohort of 2470 patients (mean age 75 ± 11 years, males 56%), the mean CHA2DS2-VASc score was 3.7 ± 1.8, and the mean HAS-BLED was 1.6 ± 0.9. There were no significant sex differences in the AFIB subtypes. At the end of the inclusion visit and after receiving knowledge of the web-based electronic estimate of risk for stroke and bleeding, the proportion of patients discharged with OACs was 80%. After exclusion of patients with first diagnosed AFIB (n = 397), the proportion of patients with prescription of OACs rose from 66% before the visit to 82% on discharge (p < 0.0001). Prescription of aspirin or other antiplatelet drugs fell from 18% before the visit to 10% on discharge (p < 0.0001). CONCLUSIONS: A web-based management of AFIB with automated estimation of risk profiles appears to favorably affect adherence to AFIB guidelines, based on a high proportion of patients treated with OACs and a substantial decline in the use of antiplatelet drugs.
Catheter-based renal artery denervation (RAD) is entering a new era. After the disappointing results of SYMPLICITY-HTN 3 trial in year 2014, several technical and methodological advancements led to execution of important SHAM-controlled randomized trials with promising results. Now, the 2023 ESH Guidelines give RAD a class of recommendation II with a Level of Evidence B. Currently, catheter-based RAD has two main areas of application: (a) Hypertensive patients who are still untreated, in whom RAD is a sort of a first-line treatment; (b) Difficult-to-control or true resistant hypertensive patients. Notably, randomized SHAM-controlled trials met their primary end-point in both these conditions. So far, we do not dispose of established predictors of the antihypertensive response to RAD. Some data suggest that younger patients with systo-diastolic hypertension, absence of diffuse atherosclerosis and evidence of sympathetic nervous system overactivity experience a better BP response to the procedure. We reviewed the available data on catheter-based RAD and included an updated meta-analysis of the results of the available SHAM-controlled trials. Overall, the reduction in 24-h systolic blood pressure (BP) after RAD exceeded that after SHAM by 4.58 mmHg (95% CI 3.07-6.10) in untreated patients, and by 3.82 mmHg (95% CI 2.46-5.18) in treated patients, without significant heterogeneity across trials, patient phenotype (untreated versus treated patients) and technique (radiofrequency versus ultrasound). There were no important safety signals related to the procedure. Notably, some data suggest that RAD could be an effective additional approach in patients with atrial fibrillation and other conditions characterized by sympathetic nervous system overactivity.
Hypertension , Renal Artery , Humans , Renal Artery/surgery , Motivation , Sympathectomy/adverse effects , Sympathectomy/methods , Hypertension/therapy , Blood Pressure , Antihypertensive Agents/therapeutic use , Catheters , Kidney , Treatment Outcome
INTRODUCTION: Vaccination strongly reduces the risk of hospitalization and death due to coronavirus disease 2019 (COVID-19). However, the severity of the acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and the degree of protection exerted over time by vaccination remains to be fully elucidated among hospitalized comorbid and vulnerable patients with SARS-CoV-2 infection. METHODS: We report a case series of nine hospitalized vulnerable patients who developed a SARS-CoV-2 infection during a cardiac rehabilitation inpatient program. RESULTS: Age ranged from 50 to 81 years. All but one patient had received at least three doses of anti-COVID-19 vaccine more than 4 months before the cardiac event. Indications for cardiac rehabilitation included acute coronary syndromes, congestive heart failure, heart valve surgery, and coronary artery bypass graft. After the confirmed diagnosis of SARS-CoV-2 infection, all patients developed symptoms. Eight patients developed at least one SARS-CoV-2-related complication, including a significant increase in high-sensitivity troponin I levels, new-onset hypoxemia, persistent atrial fibrillation, non-sustained ventricular tachycardia and recurrent sinus arrest, pericardial effusion, and a persistent increase in blood pressure. CONCLUSION: Almost all patients developed complications which, however, did not evolve towards more severe expressions of the disease. These data suggest that even in this new phase of the pandemic, vaccination may exert a potential role to reduce the risk of progression towards more severe disease of SARS-CoV-2 infection in vulnerable patients with cardiovascular comorbidities.
