Journal of Cardiovascular Pharmacology and Therapeutics最新文献

Neonatal megakaryopoiesis and platelet turnover form a developmentally unique pattern by generating a pool of newly released reticulated platelets from the bone marrow into the circulation. Reticulated platelets are more reactive and hyperaggregable compared to mature platelets, due to their high residual mRNA content, large size, increased expression of platelet surface receptors, and degranulation. The proportion of reticulated platelets in neonates is higher compared to that in adults. Due to the emergence of an uninhibited platelet subpopulation, the newly formed reticulated platelet pool is inherently hyporesponsive to antiplatelets. An elevated population of reticulated platelets is often associated with increased platelet reactivity and is inversely related to high on-treatment platelet reactivity, which can contribute to ischemia. Measurements of the reticulated platelet subpopulation could be a useful indicator of increased tendency for platelet aggregation. Future research is anticipated to define the distinct functional properties of newly formed reticulated or immature platelets in neonates, as well as determine the impact of enhanced platelet turnover and high residual platelet reactivity on the response to antiplatelet agents.

Background: Flecainide is a useful antiarrhythmic for atrial fibrillation (AF). However, because of ventricular proarrhythmia risk, a history of myocardial infarction (MI) or coronary artery disease (CAD) is a flecainide exclusion, and stress testing is used to exclude ischemia. We assessed whether absent/mild coronary artery calcium (CAC) can supplement or avoid the need for stress testing.

Methods: We assessed ischemic burden using regadenoson Rb-82 PET/CT in 1372 AF patients ≥50 years old without symptoms or signs of clinical CAD. CAC was determined qualitatively by low dose attenuation computed tomography (CT) (n = 816) or by quantitative CT (n = 556). Ischemic burden and clinical outcomes were compared by CAC burden.

Results: Patients with CAC absent or mild (n = 766, 57.2%) were younger, more frequently female, and had higher BMI but lower rates of diabetes, hypertension, and dyslipidemia. Average ischemic burden was lower in CAC-absent/mild patients, and CAC-absent/mild patients showed greater coronary flow reserve, had fewer referrals for coronary angiography, and less often had obstructive CAD. Revascularization at 90 days was lower, and the rate of longer-term major adverse cardiovascular events was favorable.

Conclusions: An easily administered, inexpensive, low radiation CAC scan can identify a subset of flecainide candidates with a low ischemic burden on PET stress testing that rarely needs coronary angiography/intervention and has favorable outcomes. Absent or mild CAC-burden combined with other clinical information may avoid or complement routine stress testing. However, additional, ideally randomized and multicenter trials are indicated to confirm these findings before replacing stress testing with CAC screening in selecting patients for flecainide therapy in clinical practice.

In the era of the coronavirus disease 2019 (COVID-19) pandemic, acute cardiac injury (ACI), as reflected by elevated cardiac troponin above the 99th percentile, has been observed in 8%-62% of patients with COVID-19 infection with highest incidence and mortality recorded in patients with severe infection. Apart from the clinically and electrocardiographically discernible causes of ACI, such as acute myocardial infarction (MI), other cardiac causes need to be considered such as myocarditis, Takotsubo syndrome, and direct injury from COVID-19, together with noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis. Acute coronary syndromes (ACS) with normal or near-normal coronary arteries (ACS-NNOCA) appear to have a higher prevalence in both COVID-19 positive and negative patients in the pandemic compared to the pre-pandemic era. Echocardiography, coronary angiography, chest computed tomography and/or cardiac magnetic resonance imaging may render a correct diagnosis, obviating the need for endomyocardial biopsy. Importantly, a significant delay has been recorded in patients with ACS seeking advice for their symptoms, while their routine care has been sharply disrupted with fewer urgent coronary angiographies and/or primary percutaneous coronary interventions performed in the case of ST-elevation MI (STEMI) with an inappropriate shift toward thrombolysis, all contributing to a higher complication rate in these patients. Thus, new challenges have emerged in rendering a diagnosis and delivering treatment in patients with ACI/ACS in the pandemic era. These issues, the various mechanisms involved in the development of ACI/ACS, and relevant current guidelines are herein reviewed.

Arterial perivascular adipose tissue (PVAT) can elicit vasodilator signals complementary to those elicited by the endothelium in SHRSP.Z-Lepr^fa/IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS). Here, we tested whether a glucose cotransporter 2 inhibitor (SGLT2-i; tofogliflozin) increased this PVAT effect to prevent the deterioration of cardiac function in aging SHRSP.ZF rats. Tofogliflozin treatments (1 or 10 mg/kg/day) or vehicle (control) were administered for 10 weeks by oral gavage to SHRSP.ZF rats, starting at 13 weeks of age. At 23 weeks of age, glucose levels in the serum and urine (24 h after the last administration) were determined using commercial kits. Vasodilator responsiveness of PVAT-surrounded or PVAT-free superior mesenteric arteries was determined using acetylcholine with organ-bath methods. Cardiac ventricular function and coronary flow were determined using Langendorff heart preparations. Serum and urine glucose levels in SGLT2-i treatment groups did not differ from those in the controls, but the ratios of glycated to non-glycated albumin were lower than those in the controls. Tofogliflozin treatments did not alter relaxations in the presence of PVAT or affect relaxations of PVAT-free arteries. Left ventricular systolic pressures, maximum rate of pressure decline, and coronary flow in ex vivo hearts did not differ among the treatment groups. PVAT effects and cardiac dysfunction were not altered by tofogliflozin treatment in SHRSP.ZF rats with MetS. These results do not provide strong evidence to support the use of SGLT2-i as a cardiovascular protective therapy in MetS, which occurs prior to the onset of type 2 diabetes.

Background: Atherothrombosis is the principal mechanism of type 1 (T1) myocardial infarction (MI), while type 2 (T2) MI is typically diagnosed in the presence of triggers (anemia, arrhythmia, etc.). We aimed to evaluate the proportions of T1 vs. T2 MI based on angiographic and clinical definitions, their concordance and prognosis.

Methods: Consecutive MI patients [n = 712, 61% male; age 64.6 ± 12.3 years] undergoing coronary angiography were classified according to the presence of atherothrombosis and identifiable triggers. Association of angiographic and clinical MI type criteria with adverse outcomes (Time follow-up was 1.5 years) was evaluated. Predictive ability of GRACE risk score for all-cause mortality was then assessed.

Results: Atherothrombosis and clinical triggers were identified in 397 (55.6%) and 324 (45.5%) subjects, respectively. Only 247 (34.7%) patients had "true" T1MI (atherothrombosis+ / triggers-); 174 (24.4%) were diagnosed with "true" T2MI (atherothrombosis- / triggers+), while 291 (40.9%) had discordant clinical and angiographic characteristics. All-cause mortality in T2MI (20.1%) patients was higher than in T1MI (9.3%), P = 0.002. Presence of triggers [odds ratio (OR) 2.4, 95% CI 1.5-3.6, P < 0.0001] but not atherothrombosis [OR 0.8, 95% confidence interval (CI) 0.5-1.3, P = 0.26] was associated with worse prognosis. GRACE score is a better predictor of death in T1MI vs. T2MI: area under curve 0.893 (95% CI 0.830-0.956) vs 0.748 (95% CI 0.652-0.843), P = 0.013.

Conclusion: Angiographic and clinical definitions of MI type are discordant in a substantial proportion of patients. Clinical triggers are associated with all-cause mortality. Predictive performance of GRACE score is worse in T2MI patients.

Background: There is a lack of robust data evaluating outcomes of enoxaparin "bridge" therapy in left ventricular assist device (LVAD) patients.

Methods: We performed a retrospective study of HeartMate II (HM II) and HeartWare HVAD recipients that received therapeutic enoxaparin as "bridge" therapy to describe bleeding and thrombotic events and compare outcomes between devices. The primary endpoint was the incidence of bleeding within 30 days of "bridge" episode. Major bleeding was defined by INTERMACS criteria.

Results: We evaluated 257 "bridge" episodes in 54 patients, 35 with a HM II device and 19 with an HVAD device that underwent 176 and 81 bridging episodes, respectively. The median INR prior to "bridge" was lower in the HM II group compared to the HVAD group (1.5 vs 1.7, P < .01), however, there was no difference in the median duration of "bridge" therapy (7 vs 7 days, P = .42). There were a total of 30 (12%) bleeding episodes, with the majority in the HM II group vs HVAD (26 [15%] vs 4 [5%], P = .02). We observed 3 (1%) thromboembolic events in 2 (4%) patients with an HVAD device. On multivariate analysis, the presence of a HM II device was associated with a 4-fold increased risk of bleeding.

Conclusion: We found the use of enoxaparin "bridge" therapy to be associated with a higher incidence of bleeding in patients with a HM II device compared with an HVAD device. Assessment of device- and patient-specific factors should be evaluated to minimize bleeding events.

Diabetes mellitus (DM) is a chronic and complex metabolic disorder and also an important cause of cardiovascular (CV) disease (CVD). Patients with type 2 DM (T2DM) and obesity show a greater propensity for visceral fat deposition (and excessive fat deposits elsewhere) and the link between adiposity and CVD risk is greater for visceral than for subcutaneous (SC) adipose tissue (AT). There is growing evidence that epicardial AT (EAT) and pericardial AT (PAT) play a role in the development of DM-related atherosclerosis, atrial fibrillation (AF), myocardial dysfunction, and heart failure (HF). In this review, we will highlight the importance of PAT and EAT in patients with DM. We also consider therapeutic interventions that could have a beneficial effect in terms of reducing the amount of AT and thus CV risk. EAT is biologically active and a likely determinant of CV morbidity and mortality in patients with DM, given its anatomical characteristics and proinflammatory secretory pattern. Consequently, modification of EAT/PAT may become a therapeutic target to reduce the CV burden. In patients with DM, a low calorie diet, exercise, antidiabetics and statins may change the quantity of EAT, PAT or both, alter the secretory pattern of EAT, improve the metabolic profile, and reduce inflammation. However, well-designed studies are needed to clearly define CV benefits and a therapeutic approach to EAT/PAT in patients with DM.

Clinical guidelines suggest the combination of 2 drugs as a strategy to treat hypertension. However, some antihypertensive combinations have been shown to be ineffective. Therefore, it is necessary to determine whether differences exist between the results of monotherapy and combination therapy by temporal monitoring of the responses to angiotensin II and norepinephrine, which are vasoconstrictors involved in the development of hypertension. Thus, the purpose of this work was to determine the vascular reactivity to angiotensin II and norepinephrine in spontaneously hypertensive rat (SHR) aortic rings after treatment with valsartan, lisinopril, nebivolol, nebivolol-lisinopril, and nebivolol-valsartan for different periods of time. In this study, male SHR and Wistar Kyoto normotensive (WKY) rats were divided into 7 groups treated for 1, 2, and 4 weeks: (1) WKY + vehicle, (2) SHR + vehicle; (3) SHR + nebivolol; (4) SHR + lisinopril; (5) SHR + valsartan; (6) SHR + nebivolol-lisinopril; and (7) SHR + nebivolol-valsartan. Blood pressure was measured by the tail-cuff method, and vascular reactivity was determined from the concentration-response curve to angiotensin II and norepinephrine in aortic rings. The results showed that the combined and individual treatments reduced mean blood pressure at all times evaluated. All treatments decreased vascular reactivity to angiotensin II; however, in the case of lisinopril and nebivolol-lisinopril, the effect observed was significant up to 2 weeks. All treatments decreased the reactivity to norepinephrine up to week 4. These results show a time-dependent difference in vascular reactivity between the pharmacological treatments, with nebivolol-valsartan and nebivolol-lisinopril being both effective combinations. Additionally, the results suggest crosstalk between the renin-angiotensin and sympathetic nervous systems to reduce blood pressure and to improve treatment efficacy.

Pulmonary arterial hypertension (PAH) is a chronic and progressive disorder characterized by vascular remodeling of the small pulmonary arteries, resulting in elevated pulmonary vascular resistance and ultimately, right ventricular failure. Expanded understanding of PAH pathophysiology as it pertains to the nitric oxide (NO), prostacyclin (prostaglandin I₂) (PGI₂) and endothelin-1 pathways has led to recent advancements in targeted drug development and substantial improvements in morbidity and mortality. There are currently several classes of drugs available to target these pathways including phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase (sGC) stimulators, prostacyclin class agents and endothelin receptor antagonists (ERAs). Combination therapy in PAH, either upfront or sequentially, has become a widely adopted treatment strategy, allowing for simultaneous targeting of more than one of these signaling pathways implicated in disease progression. Much of the current treatment landscape has focused on initial combination therapy with ambrisentan and tadalafil, an ERA and PDE5I respectively, following results of the AMBITION study demonstrating combination to be superior to either agent alone as upfront therapy. Consequently, clinicians often consider combination therapy with other drugs and drug classes, as deemed clinically appropriate, for patients with PAH. An alternative regimen that targets the NO and PGI₂ pathways has been adopted by some clinicians as an effective and sometimes preferred therapeutic combination for PAH. Although there is a paucity of prospective data, preclinical data and results from secondary data analysis of clinical studies targeting these pathways may provide novel insights into this alternative combination as a reasonable, and sometimes preferred, alternative approach to combination therapy in PAH. This review of preclinical and clinical data will discuss the current understanding of combination therapy that simultaneously targets the NO and PGI₂ signaling pathways, highlighting the clinical advantages and theoretical biochemical interplay of these agents.