Fabrizio Ricci

Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies

BACKGROUND Whether orthostatic hypotension (OH) is a risk factor for cardiovascular morbidity and death is uncertain. Currently available evidence derives from non-homogeneous and partly ambiguous studies. OBJECTIVE We aimed at assessing the relationship between OH and death or major adverse cardiac and cerebrovascular events (MACCEs) by integrating results of previous studies. METHODS We performed a meta-analysis of prospective observational studies reporting on the association between prevalent OH, mortality, and incident MACCE, published from 1966 through 2013. Mantel-Haenszel pooled estimates of relative risk (RR) and 95% confidence intervals (CIs) for all-cause death were assessed as the primary endpoint at the longest follow-up; incident coronary heart disease (CHD), heart failure (HF), and stroke were assessed as secondary endpoints. We also performed post hoc subgroup analyses stratified by age and a meta-regression analysis. RESULTS We identified a total of 13 studies, including an overall population of 121 913 patients, with a median follow-up of 6 years. Compared with the absence of OH, the occurrence of OH was associated with a significantly increased risk of all-cause death (RR 1.50; 95% CI 1.24-1.81), incident CHD (RR 1.41; 95% CI 1.22-1.63), HF (RR 2.25; 95% CI 1.52-3.33), and stroke (RR 1.64; 95% CI 1.13-2.37). When analysed according to age, pooled estimates of RR (95% CI) for all-cause death were 1.78 (1.25-2.52) for patients <65 years old, and 1.26 (0.99-1.62) in the older subgroup. CONCLUSION Orthostatic hypotension is associated with a significantly increased risk of all-cause death, incident CHD, HF, and stroke.

Late Thrombosis After Double Versus Single Drug-Eluting Stent in the Treatment of Coronary Bifurcations A Meta-Analysis of Randomized and Observational Studies

OBJECTIVES This study sought to hypothesize that the higher risk of myocardial infarction (MI) documented after a routine double drug-eluting stent (DES) strategy (DDS) compared with a single DES strategy (SDS) with provisional stenting in percutaneous coronary interventions (PCI) of bifurcation lesions is driven by an increased rate of DES thrombosis. BACKGROUND The results of currently available randomized, controlled trials (RCTs) were inconclusive in the choice between SDS and DDS. Meta-analyses have shown an increased risk of MI in the DDS group, without identifying the underlying mechanism(s). METHODS We performed a meta-analysis of 12 major (>100 patients) studies of bifurcation DES PCI: 5 RCTs and 7 nonrandomized observational studies, for a total of 6,961 patients. Random-effects models were used to calculate summary risk ratios (RRs). As a primary endpoint, we assessed the RRs and 95% confidence intervals (CIs) of definite DES thrombosis; death, MI, and target vessel revascularization (TVR) were evaluated as secondary endpoints. RESULTS Compared with SDS, DDS had an increased risk of DES thrombosis (RR: 2.31; 95% CI: 1.33 to 4.03) and MI (RR: 1.86; 95% CI: 1.34 to 2.60). Mortality (RR: 1.18; 95% CI: 0.85 to 1.65) and TVR (RR: 1.02; 95% CI: 0.80 to 1.30) were similar. The RRs of MI and DES thrombosis were associated (p = 0.040). CONCLUSIONS In PCI of coronary bifurcations, SDS should be the preferred approach, as DDS is associated with an increased risk of MI, likely driven by DES thrombosis.

Complete myocardial revascularization confers a larger clinical benefit when performed with state‐of‐the‐art techniques in high‐risk patients with multivessel coronary artery disease: A meta‐analysis of randomized and observational studies

To test whether a strategy of complete revascularization (CR) as compared with incomplete myocardial revascularization (IR)—both performed with current “state‐of‐the‐art” percutaneous coronary interventions (PCI) or coronary artery bypass graft (CABG)—would provide a clinical benefit in patients with multivessel coronary artery disease (MVCAD).

Oral anticoagulants in coronary heart disease (Section IV) Position paper of the ESC Working Group on Thrombosis – Task Force on Anticoagulants in Heart Disease

Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients, most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel. Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice.

ACE-inhibitors versus angiotensin receptor blockers for prevention of events in cardiovascular patients without heart failure — A network meta-analysis

BACKGROUND Angiotensin receptor blockers (ARBs) are a valuable option to reduce cardiovascular (CV) mortality and morbidity in cardiac patients in whom ACE-inhibitors (ACE-Is) cannot be used. However, clinical outcome data from direct comparisons between ACE-Is and ARBs are scarce, and some data have recently suggested superiority of ACE-Is over ARBs. METHODS We performed a Bayesian network-meta-analysis, with data from both direct and indirect comparisons, from 27 randomized controlled trials (RCTs), including a total population of 125,330 patients, to assess the effects of ACE-Is and ARBs on the composite endpoint of CV death, myocardial infarction (MI) and stroke, and on all-cause death, new-onset heart failure (HF) and new-onset diabetes mellitus (DM) in high CV risk patients without HF. RESULTS Using placebo as a common comparator, we found no significant differences between ACE-Is and ARBs in preventing the composite endpoint of CV death, MI and stroke (RR: 0.92; 95% CI 0.78-1.08). When components of the composite outcome were analysed separately, ACEi and ARBs were associated with a similar risk of CV death (RR: 0.92; 95% CI 0.73-1.10), MI (RR: 0.91; 95% CI 0.78-1.07) and stroke (RR: 0.97; 95% CI 0.79-1.19), as well as a similar incident risk of all-cause death (RR: 0.94; 95% CI 0.85-1.05), new-onset HF (RR: 0.92; 95% CI 0.77-1.15) and new-onset DM (RR: 99; 95% CI 0.81-1.21). CONCLUSIONS With the limitations of indirect comparisons, we found that in patients at high CV risk without HF, ARBs were similar to ACE-Is in preventing the composite endpoint of CV death, MI and stroke. Compared with ARBs, we found no evidence of statistical superiority for ACE-Is, as a class, in preventing incident risk of all-cause death, CV death, MI, stroke, new-onset DM and new-onset HF.

Role and importance of ultrasound lung comets in acute cardiac care.

Lung ultrasonography is an emerging, user-friendly and easy-to-use technique that can be performed quickly at the patient’s bedside to evaluate several pathologic conditions affecting the lung. Ultrasound lung comets (ULCs) are an echographic sign of uncertain biophysical characterisation mostly attributed to water-thickened subpleural interlobular septa, but invariably associated with increased extravascular lung water. ULCs have thus been proposed as a complementary tool for the assessment and monitoring of acute heart failure and are now entering into statements in international recommendation documents. Adding lung ultrasonography to conventional echocardiography allows for performing an integrated cardiopulmonary ultrasound examination, and this is an important opportunity for the cardiologist. The technique allows the simultaneous gathering of considerable information about the heart and the lungs to investigate acute and chronic cardio-pulmonary conditions within a non-invasive, radiation-free, single-probe, all-in-one examination. We have here reviewed the pertinent literature on the physical origin of ULCs and on their role and importance in intensive and acute cardiac care settings. We also here propose a new algorithm aimed at implementing evaluation in the diagnostic work-up of patients with suspected acute heart failure.

Hospital admissions for orthostatic hypotension and syncope in later life : insights from the Malmö Preventive Project

Objective(s): We explored incidence, predictors, and long-term prognosis of hospital admissions attributed to reflex syncope and orthostatic hypotension. Methods: We analyzed a cohort of 32 628 individuals (68.2% men; age, 45.6 ± 7.4 years) without prevalent cardiovascular disease over a follow-up period of 26.6 ± 7.5 years. Results: One thousand and fourteen persons (3.1%, 1.2 per 1000 person-years) had at least 1 hospitalization for orthostatic hypotension (n = 462, 1.42%) or syncope (n = 632, 1.94%). Orthostatic hypotension-related hospitalizations were predicted by age [per 1-year increase, hazard ratio 1.14, 95% confidence interval (CI): 1.12–1.16], smoking (hazard ratio 1.35, 95% CI: 1.12–1.64), diabetes (hazard ratio 1.50, 95% CI: 1.00–2.25), baseline orthostatic hypotension (hazard ratio 1.45, 95% CI: 1.05–1.98), in particular, by SBP fall at least 30 mmHg (hazard ratio 3.93, 95% CI: 2.14–7.23), whereas syncope hospitalizations by age (per 1-year increase, hazard ratio 1.09, 95% CI: 1.07–1.11), smoking (hazard ratio 1.27, 95% CI: 1.08–1.49), and hypertension (hazard ratio 1.42, 95% CI: 1.20–1.69). Both syncope-hospitalized and orthostatic hypotension hospitalized patients had higher burden of hospital admissions for other reasons such as cardiovascular, pulmonary, renal disease, or diabetes. During the follow-up, 10 727 (32.9%) died, with 419 deaths preceded by syncope/orthostatic hypotension hospitalization. After adjustment for traditional risk factors, syncope-hospitalization predicted all-cause mortality (hazard ratio 1.16, 95% CI: 1.02–1.31), whereas orthostatic hypotension hospitalization predicted cardiovascular mortality (hazard ratio 1.13, 95% CI: 1.07–1.19). Conclusion: Hospital admissions due to syncope and orthostatic hypotension occur in ≈3% of older individuals and increase with age and comorbidities. Admissions due to syncope are associated with prevalent hypertension, whereas those due to orthostatic hypotension overlap with diabetes and previously identified orthostatic hypotension. Syncope-related admissions predict higher all-cause mortality, whereas orthostatic hypotension-related admissions herald increased cardiovascular mortality.

Cardiovascular risk after hospitalisation for unexplained syncope and orthostatic hypotension

Objective To investigate the relationship of hospital admissions due to unexplained syncope and orthostatic hypotension (OH) with subsequent cardiovascular events and mortality. Methods We analysed a population-based prospective cohort of 30 528 middle-aged individuals (age 58±8 years; males, 40%). Adjusted Cox regression models were applied to assess the impact of unexplained syncope/OH hospitalisations on cardiovascular events and mortality, excluding subjects with prevalent cardiovascular disease. Results After a median follow-up of 15±4 years, 524 (1.7%) and 504 (1.7%) participants were hospitalised for syncope or OH, respectively, yielding 1.2 hospital admissions per 1000 person-years for each diagnosis. Syncope hospitalisations increased with age (HR, per 1 year: 1.07, 95% CI 1.05 to 1.09), higher systolic blood pressure (HR, per 10 mm Hg: 1.06, 95% CI 1.01 to 1.12), antihypertensive treatment (HR: 1.26, 95% CI 1.00 to 1.59), use of diuretics (HR: 1.77, 95% CI 1.31 to 2.38) and prevalent cardiovascular disease (HR: 1.59, 95% CI 1.14 to 2.23), whereas OH hospitalisations increased with age (HR: 1.11, 95% CI 1.08 to 1.12) and prevalent diabetes (HR: 1.82, 95% CI 1.23 to 2.70). After exclusion of 1399 patients with prevalent cardiovascular disease, a total of 473/464 patients were hospitalised for unexplained syncope/OH before any cardiovascular event. Hospitalisation for unexplained syncope predicted coronary events (HR: 1.85, 95% CI 1.49 to 2.30), heart failure (HR: 2.24, 95% CI 1.65 to 3.04), atrial fibrillation (HR: 1.84, 95% CI 1.50 to 2.26), aortic valve stenosis (HR: 2.06, 95% CI 1.28 to 3.32), all-cause mortality (HR: 1.22, 95% CI 1.09 to 1.37) and cardiovascular death (HR: 1.72, 95% CI 1.23 to 2.42). OH-hospitalisation predicted stroke (HR: 1.66, 95% CI 1.24 to 2.23), heart failure (HR: 1.78, 95% CI 1.21 to 2.62), atrial fibrillation (HR: 1.89, 95% CI 1.48 to 2.41) and all-cause mortality (HR: 1.14, 95% CI 1.01 to 1.30). Conclusions Patients discharged with the diagnosis of unexplained syncope or OH show higher incidence of cardiovascular disease and mortality with only partial overlap between these two conditions.

Right heart-pulmonary circulation unit and cardiac resynchronization therapy

&NA; Clinical response to cardiac resynchronization therapy (CRT) has been known for years to be highly variable, with a spectrum of responses from no change or even deterioration of cardiac function to spectacular improvements. In the plethora of clinical, echocardiographic, biohumoral, and electrophysiological predictors of response to CRT and postimplant issues besides patient selection, the role of right ventricular (RV) function has been largely overlooked. In reviewing current evidence, we noticed conflicting results between observational studies and randomized trials not only concerning the impact of baseline RV function on CRT efficacy but also on the effects of CRT on RV size and function. Hence, we aimed to provide a critical reappraisal of current knowledge and unresolved issues on the reciprocal interactions between RV function and CRT, shifting the spotlight on the concept of right heart pulmonary circulation unit and on the clinical and prognostic significance of impaired ventricular‐arterial coupling reserve. In this viewpoint, we propose that (1) CRT should not be denied to potential candidate because of “isolated” RV dysfunction and (2) assessment of baseline right heart pulmonary circulation unit and its dynamic response to pharmacological stress should be considered in future studies, as well as in the preimplant evaluation of individual candidates among other clinical factors.

Proteomic Profiling for Cardiovascular Biomarker Discovery in Orthostatic HypotensionNovelty and Significance

Orthostatic hypotension (OH) has been linked with higher incidence of cardiovascular disease, but little is known about the mechanisms behind this association. We aimed to identify cardiovascular disease biomarkers associated with OH through a proteomic profiling approach. Seven hundred seventy-eight patients with unexplained syncope or orthostatic intolerance underwent head-up tilt test and supine blood samples. Of these, 220 met diagnostic criteria of OH, and 179 demonstrated normal hemodynamic response during head-up tilt test. Blood samples were analyzed by antibody-based Proximity Extension Assay technique simultaneously measuring 92 cardiovascular disease-related human protein biomarkers. The discovery algorithm was a sequential 2-step process of biomarker signature identification by supervised, multivariate, principal component analysis and verification by univariate ANOVA with Bonferroni correction. Patients with OH were older (67 versus 60 years; P<0.001) and more likely to be women (48% versus 41%; P>0.001) but did not differ from OH-negative patients in medical history. Principal component analysis identified MMP-7 (matrix metalloproteinase-7), TM (thrombomodulin), MB (myoglobin), TIM-1 (T-cell immunoglobulin and mucin domain-1), CASP-8 (caspase-8), CXCL-1 (C-X-C motif chemokine-1), Dkk-1 (dickkopf-related protein-1), lectin-like LOX-1 (oxidized low-density lipoprotein receptor-1), PlGF (placenta growth factor), PAR-1 (proteinase-activated receptor-1), and MCP-1 (monocyte chemotactic protein-1) as the most robust proteomic signature for OH. From this proteomic feature selection, MMP-7 and TIM-1 met Bonferroni-adjusted significance criteria in univariate and multivariate regression analyses. Proteomic profiling in OH reveals a biomarker signature of atherothrombosis and inflammation. Circulating levels of MMP-7 and TIM-1 are independently associated with OH and may be involved in cardiovascular disease promotion.