Los iSGLT2 en la insuficiencia cardiaca. ¿Sus beneficios pueden extenderse a todo el espectro de la fracción de eyección? / SGLT2i in heart failure: can their benefits be expanded across the entire spectrum of ejection fraction?

La publicación del estudio EMPEROR-Preserved y la extensión del beneficio cardiovascular de los inhibidores del cotransportador de sodio-glucosa tipo 2 (iSGLT2) a pacientes con insuficiencia cardiaca IC y fracción de eyección (FE)> 40% supone un importante hito en el tratamiento de la IC con FE conservada (IC-FEc). A raíz de estos resultados, en febrero de 2022 la Food and Drug Administration estadounidense aprobó el uso de la empagliflozina para el tratamiento de pacientes con IC independientemente de la FE. Sin embargo, un análisis más detallado del estudio EMPEROR-Preserved genera ciertas dudas en relación con la banda de FE más alta (> 60%). Este grupo de pacientes presenta una gran heterogeneidad y probablemente no se pueda considerar un único fenotipo para fines terapéuticos y de abordaje clínico. Además, la FE es un parámetro continuo. Por ello, no parece que una diferenciación basada en puntos de corte matemáticos concuerde con la evidencia más reciente, que apunta precisamente a un cambio más gradual en cuanto a mecanismos subyacentes, etiologías y respuesta al tratamiento a lo largo del espectro de la FE. Un mejor conocimiento de los mecanismos fisiopatológicos es fundamental para establecer nuevas dianas terapéuticas, interpretar los resultados de los ensayos clínicos y desarrollar tratamientos dirigidos y eficaces (AU)

The publication of the EMPEROR-Preserved trial and data on the benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with ejection fraction (EF)> 40% represent a significant step forward in the treatment of HF with preserved EF. Given these results, in February 2022 the US Food and Drug Administration approved the use of empaglifozin in adults with HF with reduced or preserved EF. However, more detailed analysis of the EMPEROR-Preserved trial led to doubts about the effect of empagliflozin in patients with an EF of> 60% this patient group is widely heterogeneous and, probably, a single phenotype cannot be considered in treatment goals or the clinical approach. Moreover, EF occurs on a continuum and classifications of HF according to arbitrary cut-points in EF do not appear consistent with recent evidence, which points to a gradual shift and considerable overlap in underlying mechanisms, phenotypes and treatment response over the spectrum of EF. Enhanced knowledge of pathophysiological mechanisms is essential to establish new therapeutic targets, interpret the results of clinical trials, and develop targeted and effective therapies (AU)

HDL therapy today: from atherosclerosis, to stent compatibility to heart failure.

Epidemiologically, high-density lipoprotein (HDL) cholesterol levels have been inversely associated to cardiovascular (CV) events, although a Mendelian Randomisation Study had failed to establish a clear causal role. Numerous atheroprotective mechanisms have been attributed to HDL, the main being the ability to promote cholesterol efflux from arterial walls; anti-inflammatory effects related to HDL ligands such as S1P (sphingosine-1-phosphate), resolvins and others have been recently identified. Experimental studies and early clinical investigations have indicated the potential of HDL to slow progression or induce regression of atherosclerosis. More recently, the availability of different HDL formulations, with different phospholipid moieties, has allowed to test other indications for HDL therapy. Positive reports have come from studies on coronary stent biocompatibility, where the use of HDL from different sources reduced arterial cell proliferation and thrombogenicity. The observation that low HDL-C levels may be associated with an enhanced risk of heart failure (HF) has also suggested that HDL therapy may be applied to this condition. HDL infusions or apoA-I gene transfer were able to reverse heart abnormalities, reduce diastolic resistance and improve cardiac metabolism. HDL therapy may be effective not only in atherosclerosis, but also in other conditions, of relevant impact on human health.Key messagesHigh-density lipoproteins have as a major activity that of removing excess cholesterol from tissues (particularly arteries).Knowledge on the activity of high-density lipoproteins on health have however significantly widened.HDL-therapy may help to improve stent biocompatibility and to reduce peripheral arterial resistance in heart failure.

LDL cholesterol-lowering therapies: emphasis on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

Atherosclerotic cardiovascular disease is the leading cause of death all over the world. Its etiopathogenesis involves many correlated processes, with hypercholesterolemia being one of the main risk factors. Several large clinical trials have established the association between low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular events. With the aim to take control over high LDL-C levels, several drugs with different targets in the cholesterol pathway have been developed. Statins are the cornerstone of pharmacological lipid-lowering treatment, although they are not always successful in attaining the recommended LDL-C levels. Therefore, newer and more potent therapies have been developed, being prominent among them ezetimibe and especially the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recent trials with these new therapies have reaffirmed the theory of 'the lower, the better' when it comes to LDL-C levels, and 'the earlier, the better' when it comes to atherosclerotic physiopathology.

Dual versus triple antithrombotic therapy: is there a role for direct oral anticoagulants in arterial thrombosis?

The number of patients receiving dual antiplatelet therapy with an additional indication for long-term oral anticoagulation has substantially increased over time. This population is facing an unacceptable risk of bleeding events, particularly among elderly individuals, who are especially vulnerable to complications. Further strategies to minimize this bleeding risk, including various drug combinations, different dosage regimens and even numerous attempts to find the appropriate duration of the treatment, have been evaluated in a multitude of randomized control trials. Moreover, the recent incorporation of the direct oral anticoagulants (DOACs) to the therapeutic armamentarium may represent an alternative to treat such patients, since they have demonstrated to be noninferior to the classic vitamin K antagonists and with lower bleeding rates. The aim of this review is to summarize the most recent literature on the use of DOACs in patients with an indication for dual antiplatelet therapy (mostly subjects with coronary artery disease) and also an established indication for chronic anticoagulation (chiefly individuals with nonvalvular atrial fibrillation). The role of DOACs in ischemic heart disease alone is also discussed.

[Baseline clinical characteristics and management of patients included in IBERICAN study]. / Características clínicas basales y manejo de los pacientes incluidos en el estudio IBERICAN.

AIMS: To determine the prevalence and incidence of cardiovascular risk factors and cardiovascular events in Spain, as well as the quality of the follow-up in clinical practice. In this study the baseline data of the first interim analysis of IBERICAN are shown (n=830). METHODS: IBERICAN is a multicenter, longitudinal and observational population-based study of patients daily attended in primary care setting according to clinical practice in Spain. Subjects between 18 and 85 years daily attended in primary care setting are being included consecutively. Treatment of patients will be performed according only to clinical criteria of investigators. Blood pressure control was defined according to 2013 European guidelines of hypertension; LDL-cholesterol control was defined according to 2012 European guidelines of cardiovascular prevention; diabetes control was defined as HbA1c<7%. RESULTS: Mean age was 57.9±14.1 years. 54.1% of patients had dyslipidemia, 47.5% hypertension, 17.7% diabetes, and 10.8% history of ischemic heart disease. Regarding drugs, despite 55% of hypertensive patients were taking≥2 antihypertensive agents, only 59.9% achieved blood pressure targets; 65.7% of patients with dyslipidemia were taking statins, but only 35.6% attained LDL-cholesterol goals. Only 51.4% of diabetics achieved HbA1c goals. CONCLUSIONS: Subjects attended in primary care showed a high prevalence of cardiovascular risk factors with a poor control.

Platelet function normalization after a prasugrel loading-dose: time-dependent effect of platelet supplementation.

BACKGROUND: Hemostatic benefits of platelet transfusions in thienopyridine-treated acute coronary syndrome (ACS) patients may be compromised by residual metabolite in circulation. OBJECTIVES: To estimate the earliest time after a prasugrel loading-dose when added platelets are no longer inhibited by prasugrel's active metabolite. METHODS: Baseline platelet reactivity of healthy subjects (n=25, 30 ± 5 years, 68% male) on ASA 325 mg was tested using maximum platelet aggregation (MPA, ADP 20 µm) and VerifyNow(®) P2Y12 and was followed by a 60 mg prasugrel loading-dose. At 2, 6, 12 and 24 h post-dose, fresh concentrated platelets from untreated donors were added ex-vivo to subjects' blood, raising platelet counts by 0% (control), 40%, 60% and 80%. To estimate the earliest time when prasugrel's active metabolite's inhibitory effect on the added platelets ceases, platelet function in supplemented samples was compared across time-points to identify the time when effect of supplementation on platelet function stabilized (i.e. the increase in platelet reactivity was statistically similar to that at the next time-point). RESULTS: Supplemented samples showed concentration-dependent increases in platelet reactivity vs. respective controls by both MPA and VerifyNow(®) at all assessment time-points. For each supplementation level, platelet reactivity showed a sharp increase from 2 to 6 h but was stable (P=NS) between 6 and 12 h. CONCLUSIONS: The earliest measured time when supplemented platelets were not inhibited by circulating active metabolite of prasugrel was 6 h after a prasugrel loading-dose. These findings may have important implications for prasugrel-treated ACS patients requiring platelet transfusions during surgery.

Effects of rivaroxaban, acetylsalicylic acid and clopidogrel as monotherapy and in combination in a porcine model of stent thrombosis.

BACKGROUND: Despite standard dual antiplatelet therapy (DAT) (acetylsalicylic acid [ASA] and clopidogrel), there is a ≥ 1.4% incidence of in-stent thrombosis in patients with acute coronary syndrome. Factor Xa inhibitors are being investigated for secondary prevention after acute coronary syndrome. OBJECTIVE: To study the antithrombotic effects of the FXa inhibitor rivaroxaban alone or in combination with DAT. METHODS: Bare metal stents (12 per animal, three per intervention period) were deployed in a porcine ex vivo arteriovenous shunt and exposed to flowing arterial blood (shear rate: 1500 s(-1)). In-stent thrombus formation was analyzed under different treatments: vehicle (n = 7 animals); intravenous (i.v.) rivaroxaban (0.11, 0.33, and 1.0 µg kg(-1) min(-1)) (n = 8); rivaroxaban + ASA (1.0 mg kg(-1) i.v.) (n = 6); rivaroxaban + ASA (1.0 mg kg(-1) i.v.) + clopidogrel (0.5 mg kg(-1) i.v.) (n = 7); and ASA (1.0 mg kg(-1) i.v.) + clopidogrel (0.5 mg kg(-1) i.v.) (n = 6). RESULTS: Rivaroxaban dose-dependently reduced stent thrombus weight by ≤ 66% vs. vehicle (P < 0.05, all doses). Rivaroxaban + ASA further reduced thrombus weight vs. vehicle (86% at the highest rivaroxaban dose; P < 0.001). DAT reduced thrombus weight by ≤ 79%. However, rivaroxaban + ASA + clopidogrel almost completely abolished in-stent thrombus formation (98% reduction vs. vehicle at the highest rivaroxaban dose; P < 0.001). CONCLUSIONS: Our data on the inhibitory effect of rivaroxaban alone or with DAT are consistent with the ATLAS 2 trial findings, and support its potential use for preventing stent thrombosis after stent deployment.

Anti-inflammatory effects of anti-platelet treatment in atherosclerosis.

Atherosclerosis is considered an inflammatory disease. T-cells, macrophages, and mast cells infiltrate atherosclerotic plaques and platelets play an essential role releasing inflammatory mediators that stimulate plaque progression. This is important in acute coronary syndromes but it is also the mechanism involved in plaque progresion and endothelial dysfunction. Antiplatelet drugs exert their effects not only by inhibition of platelet aggregation but also through their antiinflammatory effect. Aspirin, thyenopiridines and GPIIb/IIIa inhibitors have antiinflammatory properties that involve different mechanisms of action, especially related to the blockade of platelet activation and platelet-leukocyte interactions. Testing platelet function in addition to assessing levels of inflammatory markers, and not only the risk of bleeding, could help in decision-making to balance the risk-benefit of anti-thrombotic treatment. Different clinical settings are associated with variable inflammatory states, and this could be, in part, responsible for variable response to treatment.

Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway.

BACKGROUND: Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor-kappaBeta ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis. MATERIALS AND METHODS: Age-matched sexually mature rabbits were randomized to ovariectomy (OVX, n = 12) or sham procedure (SHAM, n = 12). One month post-procedure, atherosclerosis was induced by 15 months 0.2%-cholesterol diet and endothelial balloon denudations (at months 1 and 3). Aortic atherosclerosis was assessed in vivo by magnetic resonance imaging (MRI) at months 9 and 15. At sacrifice, aortas were harvested for ex vivo microcomputed tomography (microCT) and molecular analysis of the vascular tissue. RESULTS: Vascular calcification density and calcific particle number were significantly greater in OVX than SHAM (8.4 +/- 2.8 vs. 1.9 +/- 0.6 mg cm(-3), P = 0.042, and 94 +/- 26 vs. 33 +/- 7 particles cm(-3), P = 0.046, respectively). Calcification morphology, as assessed by the arc angle subtended by the largest calcific particle, showed no difference between groups (OVX 33 +/- 7 degrees vs. SHAM 33 +/- 5 degrees , P = 0.99). By Western blot analysis, OVX increased the vascular OPG:RANKL ratio by 66%, P = 0.029, primarily by decreasing RANKL (P = 0.019). At month 9, MRI demonstrated no difference in atheroma volume between OVX and SHAM, and no significant change was seen by the end of the study. CONCLUSIONS: In contrast to bone, vascular OPG:RANKL ratio increased in response to ovariectomy with a corresponding fourfold increase in arterial calcification. This diametrical organ-specific response may explain the comorbid association of osteoporosis with calcifying atherosclerosis in post-menopausal women.

Plaque progression and regression in atherothrombosis.

Atherosclerotic disease is a pathological process characterized by the deposition of lipid and other blood-borne material within the arterial wall. The deposition of these materials and the subsequent thickening of the wall may significantly compromise the vessel lumen. Atherosclerosis is a diffuse disease with focal clinical manifestations that are the consequence of thrombotic complications on disrupted atherosclerotic lesions. Until recently, atherosclerosis development was envisaged as an incessant progressing process; however, new evidence has shown that atherosclerotic plaque homeostasis is not necessarily a constantly progressing process. There are many data showing that atherosclerotic plaque formation can be slowed, stopped or even reversed. Comprehension of the underlying mechanisms involved in the homeostasis of atherosclerotic plaque (progression/regression) should allow the development of interventions enhancing the regression pathway. Novel imaging technology has allowed the accurate evaluation of plaque progression, vital in the assessment of the efficacy of interventions. In this review we discuss the processes involved in the formation and progression of atherosclerotic lesions, the triggers for plaque disruption, as well as new therapies. We also deal with the potential pathways of plaque regression, as well as tools for accurate serial atherosclerotic quantification.

Effects of percutaneous transluminal angioplasty and endovascular brachytherapy on vascular remodeling of human femoropopliteal artery: 2 years follow-up by noninvasive magnetic resonance imaging.

OBJECTIVES: We aimed to assess in vivo the long-term effects of percutaneous transluminal angioplasty (PTA) and endovascular brachytherapy (EVBT) on vessel wall by serial MRI. METHODS: Twenty patients with symptomatic stenosis of the femoropopliteal artery were randomly assigned to PTA (n=10) or PTA+EVBT (n=10, 14Gy by gamma-source). High-resolution MRI was performed prior, at 24-hours, 3-months, and 24-months after intervention. MRI data were analyzed by an independent, blinded observer. RESULTS: The effects of both procedures on vessel wall at 24-hours and 3-months have been reported. Despite similar percent decrease in lumen area between 3- and 24-months in both groups (-8% for PTA and -11% for PTA+EVBT), at 24-months lumen area gain compared to baseline was +30% in PTA versus +82% in PTA+EVBT (p<0.05). Total vessel area, which was increased at 24-hours and 3-months, returned to pre-treatment value in both groups. CONCLUSIONS: We demonstrated non-invasively that restenosis and inward remodeling after PTA are delayed by EVBT. At 24-months, patients treated with brachytherapy have larger lumen than those treated with PTA alone. The decrease in luminal and total vessel area between 3- and 24-months after EVBT indicates that the restenotic and remodeling process is not abolished but delayed with this therapy.

A novel anti-ischemic nitric oxide donor (LA419) reduces thrombogenesis in healthy human subjects.

BACKGROUND: Platelet and endothelial production of nitric oxide (NO) is known to be impaired in coronary artery disease patients. Compounds that release NO (e.g. nitrates) have antiplatelet effects, but at supratherapeutic doses with hypotensive side effects. OBJECTIVES: To investigate the antithrombotic effect on human blood of a novel NO donor (LA419) with known anti-ischemic properties but without hypotensive side effects and to compare with abciximab. PATIENTS/METHODS: Healthy subjects (n = 8; 32 +/- 3 years) received daily aspirin starting three days prior to the study day. Treatments (LA419 10 and 20 microm, and abciximab 4 microm) were added ex vivo to non-anticoagulated blood, and the antithrombotic properties were assessed by measuring changes in thrombus size from pretreatment baseline in the Badimon perfusion chamber at low and high shear rates. Platelet surface adhesion using a Cone and Platelet Analyzer (CPA) and platelet fibrinogen-receptor activation with flow cytometry were also evaluated. RESULTS: At low shear rates, LA419 displayed a reduction in thrombus area of 43% +/- 8% (10 microm) and 56% +/- 6% (20 microm), whereas at high shear rates the reductions were 44% +/- 3% (10 microm) and 62% +/- 6% (20 microm). Platelet surface adhesion with the CPA was also reduced. Abciximab exhibited a strong inhibitory effect on thrombus formation, platelet surface adhesion and fibrinogen receptor activation. CONCLUSIONS: The novel NO donor, LA419, shows a strong antithrombotic effect in human blood, which is comparable to abciximab, especially under high shear rate conditions. Our observations suggest that the availability of an NO donor could prove beneficial in the prevention of thrombotic complications of cardiovascular disease. Further clinical studies are warranted.

Normalization of platelet reactivity in clopidogrel-treated subjects.

BACKGROUND: Aspirin (ASA) + clopidogrel are commonly used in acute coronary syndrome (ACS), but persistent antiplatelet effects may complicate surgery. METHODS AND RESULTS: To study the possibility of normalizing platelet reactivity after ASA + clopidogrel treatment, 11 healthy subjects received a 325-mg ASA + clopidogrel loading dose (300 or 600 mg dependent on study arm), followed by 81 mg of ASA + 75 mg of clopidogrel daily for 2 days. Platelet reactivity was assessed by light transmittance aggregometry (LTA) [challenged by adenosine diphosphate (ADP), arachidonic acid (AA), collagen, and thrombin receptor activating peptide (TRAP)] and flow cytometry for platelet activation by GPIIb/IIIa receptor exposure pretreatment, 4 and 72 h postload. To normalize platelet reactivity, increasing amounts of pooled platelets from five untreated volunteers [volunteers (V)-platelet-rich plasma (PRP)] were added ex vivo to the subject's PRP (S-PRP). At both 4 and 72 h, 40% and 50% V-PRP were needed to overcome platelet disaggregation in the 300 or 600 mg arms, respectively, after ADP challenge; an additional 10% V-PRP fully normalized aggregation. Recovery of function was linear with each incremental increase of V-PRP. ADP-induced GPIIb/IIIa activation showed the same pattern as LTA (r = 0.74). Forty percent V-PRP was required to normalize platelet function to AA, collagen, and TRAP. CONCLUSION: Our results suggest that the pre-operative transfusion of 10 platelet concentrate units (the equivalent of 40% V-PRP) after a 300-mg clopidogrel loading or 12.5 units (50% V-PRP) after a 600 mg loading may adequately reverse clopidogrel-induced platelet disaggregation to facilitate postoperative hemostasis. An additional 2.5 units fully normalized platelet function. The potential clinical implications of our observations could include shorter hospitalizations and reduced bleeding complications. But these observations should be fully explored in an in vivo clinical setting with clopidogrel-treated patients before and after surgery.

Atherothrombosis: role of tissue factor; link between diabetes, obesity and inflammation.

Atherothrombotic vascular disease is a complex disorder in which inflammation and coagulation play a pivotal role. Rupture of high-risk, vulnerable plaques with the subsequent tissue factor (TF) exposure is responsible for coronary thrombosis, the main cause of unstable angina, acute myocardial infarction, and sudden cardiac death. Tissue factor (TF), the key initiator of coagulation is an important modulator of inflammation. TF is widely expressed in atherosclerotic plaques and found in macrophages, smooth muscle cells, extracellular matrix and acellular lipid-rich core. TF expression can be induced by various stimulants such as C-reactive protein, oxLDL, hyperglycemia and adipocytokines. The blood-born TF encrypted on the circulating microparticles derived from vascular cells is a marker of vascular injury and a source of procoagulant activity. Another form of TF, called alternatively spliced has been recently identified in human and murine. It is soluble, circulates in plasma and initiates coagulation and thrombus propagation. Evidence indicates that elevated levels of blood-borne or circulating TF has been associated with metabolic syndrome, type 2 diabetes and cardiovascular risk factors and is a candidate biomarker for future cardiovascular events. Therapeutic strategies have been developed to specifically interfere with TF activity in the treatment of cardiovascular disease.