Newly detected diabetes mellitus patients with acute coronary syndrome have an adverse cardiometabolic profile similar to patients with prior diabetes and a more extensive ischemic myocardial insult.

AIMS: The impact of newly detected diabetes mellitus (NDDM) on metabolic parameters and extent of myocardial necrosis in patients with acute coronary syndrome (ACS) is not fully explored. We examined the impact of NDDM on cardiometabolic characteristics and myocardial necrosis in ACS patients. METHODS: CALLINICUS-Hellas Registry is an ongoing prospective multicenter observational study evaluating the adherence to lipid-lowering therapy (LLT) among ACS patients in Greece. Three groups were created: a) patients with NDDM (abnormal fasting glucose, HbA1c ≥ 6.5 % and no previous history of DM), b) patients without known DM and HbA1c < 6.5 % (non-DM) and c) patients with prior DM. RESULTS: The prevalence of NDDM among 1084 patients was 6.9 %. NDDM patients had lower HDL-C [38 (32-45) vs 42 (36-50) mg/dL] and higher triglycerides levels [144 (104-231) vs 115 (87-152) mg/dL] compared to non-DM patients (p < 0.05). NDDM patients featured both higher body mass index [29.5 (26.4-34.3) vs 27.1 (24.9-29.9) kg/m2] and waist circumference [107 (100-114) vs 98 (91-106) cm] compared to non-DM patients (p < 0.05). In addition, NDDM patients had more extensive myocardial necrosis than patients with prior DM. CONCLUSIONS: ACS patients with NDDM have an adverse cardiometabolic profile similar to patients with prior DM and have more extensive myocardial insult.

Physical signs and atherosclerotic cardiovascular disease in familial hypercholesterolemia: the HELLAS-FH Registry.

AIMS: Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals. METHODS: Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD. RESULTS: Adult patients ( n  = 2156, mean age 50 ±â€Š15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets. CONCLUSION: The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD.

Gender Differences Among Very Young Patients With Acute Coronary Syndrome: Long-Term Follow-Up of the STAMINA Study.

The rate of hospitalization for acute coronary syndrome (ACS) among young patients is increasing. Healthcare disparities remain unsolved among female patients. We explored gender differences regarding risk factors, clinical presentation, in-hospital treatment, and long-term outcomes among ACS patients. A total of 445 patients with very early ACS (men ≤ 35 years and women ≤ 40 years of age) were followed for a median of 5 years. Primary clinical endpoint was the composite of cardiac death, non-fatal myocardial infarction, stroke, and coronary revascularization. Women accounted for 16% of cases. Smoking was the most prevalent risk factor, 56% and 60% of the females and males, respectively, continued to smoke after ACS. Chest pain was typical in 85% and 83% of the female and male patients, respectively. In-hospital treatment (pharmacological and reperfusion) as well as the composite clinical endpoint during follow-up did not differ between female and male patients. Lipid-lowering therapy was suboptimal in both genders, and persistence of smoking was the sole predictor for the composite clinical endpoint (hazard ratio: 2.30 [95% CI: 1.26-4.20]; P = .007). In conclusion, in-hospital treatment was similar between male and female patients. However, the majority of them continued smoking, and this was an independent predictor for future adverse outcomes.

Is inverse association between lipoprotein(a) and diabetes mellitus another paradox in cardiometabolic medicine?

INTRODUCTION: The impact of Type II Diabetes mellitus (T2DM) on cardiovascular disease (CVD) is well-established, while lipoprotein(a) [Lp(a)] has recently emerged as a recognized CVD risk factor. The rising prevalence of T2DM resulting from modern lifestyles and the development of specific Lp(a)-lowering agents brought the association between T2DM and Lp(a) in the forefront. AREAS COVERED: Despite advancements in T2DM treatment, diabetic patients remain at very-high risk of CVD. Lp(a) may, to some extent, contribute to the persistent CVD risk seen in diabetic patients, and the coexistence of T2DM and elevated Lp(a) levels appears to synergistically amplify overall CVD risk. The relationship between T2DM and Lp(a) is paradoxical. On one hand, high Lp(a) plasma concentrations elevate the risk of diabetic microvascular and macrovascular complications. On the other hand, low Lp(a) plasma concentrations have been linked to an increased risk of developing T2DM. EXPERT OPINION: Comprehending the association between T2DM and Lp(a) is critical due to the pivotal roles both entities play in overall CVD risk, as well as the unique aspects of their relationship. The mechanisms underlying the inverse association between T2DM and Lp(a) remain incompletely understood, necessitating further meticulous research.

NT-proBNP/cardiac troponin T ratio >7.5 on the second day of admission can differentiate Takotsubo from acute coronary syndrome with good accuracy.

BACKGROUND: Takotsubo syndrome (TTS) is not usually diagnosed until patients with suspected acute coronary syndrome (ACS) and echocardiographically detected apical aneurysm are found to have "normal" coronary angiography (CA). Our aim was to explore whether cardiac biomarkers can contribute to the early diagnosis of TTS. METHODS: Ratios of N-terminal-pro brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT) both expressed in pg/mL [admission and the 3 following days] were compared in 38 patients with TTS and 114 ACS patients of whom 58 had non-ST-elevation myocardial infarction (NSTEMI). RESULTS: NT-proBNP/cTnT ratio at admission and during the following 3 days was significantly higher in TTS compared to patients with ACS [18.4 (8.7-41.7) vs 2.9 (0.8-6.8), 29.6 (14.3-53.7) vs 1.2 (0.5-2.7), 30.0 (11.6-50.9) vs 1.7 (0.5-3.0), 27.8 (11.3-42.6) vs 1.4 (0.6-2.8), respectively, all <0.001]. Βest discrimination of TTS from ACS was possible with the ratio of NT-proBNP/cTnT on the 2nd day. A cut-off value of NT-proBNP/cTnT ratio >7.5 had a sensitivity of 97.3%, a specificity of 95.4% and an accuracy of ∼96% in detecting TTS as opposed to ACS. Furthermore, the ratio of NT-proBNP/cTnT preserved its discriminatory value in the subgroup of patients with NSTEMI. In particular, an NT-proBNP/cTnT ratio >7.5 on the 2nd day had a sensitivity of 97.3%, a specificity of 91.4%, and an accuracy of 93.7% in differentiating TTS from NSTEMI. CONCLUSIONS: An NT-proBNP/cTnT ratio >7.5 on the 2nd day of admission can be useful for the early identification of TTS among selected patients initially presenting with ACS, a ratio more clinically useful in the setting of NSTEMI.

A Posteriori Dietary Patterns and Coronary Artery Disease in a Greek Case-Control Study.

INTRODUCTION: Diet is one of the most important modifiable risk factors associated with cardiovascular health (CH). Research identifying dietary patterns (DPs) through data-driven analysis and reporting associations between DPs and coronary artery disease (CAD) outcomes is rather limited. OBJECTIVE: The aim of the present report was to generate DPs through factor analysis (FA) and to examine their association with CAD risk. METHODS: Participants (n = 1017) consisted of cases diagnosed with CAD (n = 356) and controls (n = 661) drawn from the THISEAS study. Demographic, anthropometric and lifestyle data were collected. Dietary components were generated through FA. Logistic regression analysis was performed to estimate CAD relative risks. RESULTS: FA generated seven dietary components, explaining 53.5% of the total variation in intake. The Western-type DP showed a modest significant association with CAD risk, after controlling for confounders (OR = 1.20; 95% CI = 1.09-1.32, p < 0.001). The vegetarian-type DP was not significantly associated with the likelihood of CAD (OR = 0.95; 95% CI = 0.84-1.04, p = 0.259). DISCUSSION: The Western-type DP was positively associated with CAD risk and the odds were further increased after controlling for confounders. This finding is in concordance with previously reported positive associations between Western patterns and CAD risk. Limited data exist regarding a posteriori DPs and their effect on CAD risk.

Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a).

Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.

Emergent Inflammatory Markers and Echocardiographic Indices in Patients with Bronchial Asthma.

Asthma is a heterogeneous disease, characterized by chronic inflammation and oxidative stress of the airways. Several inflammatory pathways including activation of the receptor for advanced glycation end products (RAGE) have been described in the course of the disease. DJ-1 is a redox-sensitive protein with multifaceted roles in mast cell homeostasis and an emerging role in the pathogenesis of asthma. Moreover, cardiac function abnormalities have been described via echocardiography in patients with asthma. The main aim of this study was to investigate the plasma levels of RAGE, its ligands and DJ-1 in asthmatic patients pre- and post-treatment along with echocardiographic indices of cardiovascular function. The study population was divided into two groups. Group A included 13 patients with newly diagnosed bronchial asthma who were free of treatment for at least two weeks and Group B included 12 patients without asthma. An echocardiography examination was performed on all patients. The plasma levels of RAGE, its ligands (AGEs, S100A12, S100B, S100A8/A9), the interleukins (IL-6, IL-1ß) and DJ-1 were measured. No differences were noted among the two groups for baseline characteristics and echocardiographic indices of cardiac function. In Group A, 31% suffered from mild asthma, 54% from moderate asthma and 15% from severe asthma. Plasma levels of IL-6, AGEs and AGE/RAGE ratio were increased and those of S100A12 and DJ-1 were decreased in asthmatics. Pharmacotherapy with corticosteroids/ß2-agonists decreased IL-6, and AGEs, and increased DJ-1. In search of novel approaches in diagnosing and treating patients with asthma, S100A12, ratio AGE/sRAGE, and DJ-1 in addition to IL-6 may prove to be useful tools.

Lipoprotein(a) is associated with premature coronary artery disease: a meta-analysis.

BACKGROUND: Lipoprotein(a) is associated with adverse cardiovascular outcomes and its association with premature coronary artery disease (pCAD) is underexamined. The primary aim of the study is to compare serum lipoprotein(a) levels between pCAD cases and controls. METHODS: We conducted a systematic review and the MEDLINE database, ClinicalTrials.gov, medRxiv and Cochrane Library were searched for studies evaluating lipoprotein(a) and pCAD. Standardized mean differences (SMD) of lipoprotein(a) in pCAD patients versus the controls were pooled by a random-effects meta-analysis. The presence of statistical heterogeneity was evaluated with the Cochran Q chi-square test and the quality of the included studies was assessed via the Newcastle-Ottawa Scale. RESULTS: A total of 11 studies were found eligible, reporting on the difference in lipoprotein(a) levels between pCAD patients and controls. Serum lipoprotein(a) concentration was found significantly increased in patients with pCAD (SMD = 0.97; 95% confidence intervals, 0.52-1.42; P < 0.0001; I2 = 98%) as compared to controls. High statistical heterogeneity and relatively small case-control studies of moderate quality are the main limitations of this meta-analysis. CONCLUSION: Lipoprotein(a) levels are significantly increased in patients with pCAD as compared to controls. Further studies are needed to clarify the clinical significance of this finding.

Lipoprotein(a): Its Association with Calcific Aortic Valve Stenosis, the Emerging RNA-Related Treatments and the Hope for a New Era in "Treating" Aortic Valve Calcification.

The treatment of patients with aortic valve calcification (AVC) and calcific aortic valve stenosis (CAVS) remains challenging as, until today, all non-invasive interventions have proven fruitless in preventing the disease's onset and progression. Despite the similarities in the pathogenesis of AVC and atherosclerosis, statins failed to show a favorable effect in preventing AVC progression. The recognition of lipoprotein(a) [Lp(a)] as a strong and potentially modifiable risk factor for the development and, perhaps, the progression of AVC and CAVS and the evolution of novel agents leading in a robust Lp(a) reduction, have rekindled hope for a promising future in the treatment of those patients. Lp(a) seems to promote AVC via a 'three hit' mechanism including lipid deposition, inflammation and autotaxin transportation. All of these lead to valve interstitial cells transition into osteoblast-like cells and, thus, to parenchymal calcification. Currently available lipid-lowering therapies have shown a neutral or mild effect on Lp(a), which was proven insufficient to contribute to clinical benefits. The short-term safety and the efficacy of the emerging agents in reducing Lp(a) have been proven; nevertheless, their effect on cardiovascular risk is currently under investigation in phase 3 clinical trials. A positive result of these trials will probably be the spark to test the hypothesis of the modification of AVC's natural history with the novel Lp(a)-lowering agents.

Emerging markers of inflammation and oxidative stress as potential predictors of coronary artery disease.

BACKGROUND AND AIMS: The multi-ligand receptor for advanced glycation end products (RAGE) and its ligands AGEs and S100/calgranulin proteins are important mediators of inflammation and oxidative stress whereas the soluble form of RAGE (sRAGE) by acting as a decoy and the antioxidant PARK7/DJ-1 exert antiatherogenic effects. We examined whether sRAGE and its ligands AGEs, S100A8/A9, S100B, S100A12 and DJ-1 are associated with the presence of angiographic coronary artery disease (CAD) in asymptomatic patients with and without diabetes. METHODS AND RESULTS: Plasma levels of RAGE ligands, sRAGE and DJ-1 were determined in 50 patients with angiographically proven CAD and in 50 age-matched healthy controls. In the whole cohort, lower levels of sRAGE and higher levels of interleukin-6 (IL-6), the RAGE ligands S100B, S100A12 and the AGEs/sRAGE ratio were associated with CAD. In patients without diabetes (n = 72), lower levels of sRAGE and DJ-1 and higher levels of IL-6 and AGEs/sRAGE ratio were associated with CAD. In multivariable analysis, AGEs/sRAGE ratio was an independent predictor of CAD both in the whole cohort (p = 0.034, OR = 1.247, [95%CI: 1.024, 1.0519]) and in the subgroup of patients without diabetes (p = 0.021, OR = 1.363, 95%CI [1.048, 1.771]) on top of established cardiovascular risk factors. CONCLUSION: Alterations in plasma RAGE axis inflammatory mediators are associated with atherosclerosis, and higher levels of AGEs/sRAGE ratio are independently associated with CAD in asymptomatic patients and may act as a novel biomarker for predicting CAD. DJ-1 emerges as promising marker of oxidative stress in CAD patients without diabetes, a finding that deserves further study.

Myocardial infarction due to left main coronary artery total occlusion: A unique electrocardiographic presentation.

Left main coronary artery (LMCA) total occlusion typically presents as anterolateral ST-segment myocardial infarction with or without right bundle branch block with left anterior fascicular block, and ST-segment elevation in aVR. On the contrary to the previously described electrocardiographic pattern we describe a distinct electrocardiographic presentation in a patient with total LMCA occlusion characterized by the presence of complete LBBB co-existing with upsloping ST-segment depression in precordial leads leading to symmetrical, tall, positive T waves, the so called de Winter's sign.

Differential Expression of Circulating Damage-Associated Molecular Patterns in Patients with Coronary Artery Ectasia.

Coronary artery ectasia (CAE) is defined as abnormal dilation of a coronary artery with a diameter exceeding that of adjacent normal arterial segment by >1.5 times. CAE is a pathological entity of the coronary arteries and characterized as a variant of coronary atherosclerosis. CAE frequently coexists with coronary artery disease (CAD). While inflammation appears to be involved, the pathophysiology of CAE remains unclear. Damage-associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue, are deemed as alarm signals by the innate immune system. Inflammatory agents can generate DAMPs and DAMPs can create a pro-inflammatory state. In a prospective cross-sectional study, we enrolled 29 patients with CAE and non-obstructive CAD, 19 patients with obstructive CAD without CAE, and 14 control subjects with normal (control) coronary arteries age- and sex-matched with the CAE patients, to investigate the differential expression of plasma DAMPs. Patients with CAE and non-obstructive CAD had increased plasma levels of the DAMPs S100B, S100A12, HMGB1, and HSP70, the DAMPs receptor TLR4, and miR328a-3p compared to CAD and controls. Plasma levels of the mir328a-3p target the protective soluble form of the DAMPs receptor for advanced glycation end products (sRAGE), and the antioxidant DJ-1 was decreased in both CAE and CAD compared to controls. In an in vitro human umbilical vein endothelial cells model, circulating levels of S100B, HMGB1, HSP70 as well as CAE patient plasma induced inflammatory responses. The differential expression of the DAMPs S100B, HSP70, HMGB1, and their receptors TLR4 and sRAGE in CAE versus CAD makes them attractive novel biomarkers as therapeutic targets and therapeutics.

Direct Oral Anticoagulants in Patients on Chronic Dialysis and Concomitant Atrial Fibrillation: A Common Clinical Impasse.

The most frequent arrhythmia treated is atrial fibrillation (AF), which necessitates the use of oral anticoagulants (OACs) to reduce the risk of thromboembolism and stroke. Patients with chronic kidney disease are more likely to develop AF, with a 10% frequency among those on chronic dialysis. Warfarin is the most widely prescribed OAC for individuals with end-stage kidney disease (ESKD). On the other hand, direct OACs (DOACs) are generally safer than warfarin, with fewer fatal bleeding events and a fixed dose that does not require close international normalized ratio (INR) monitoring. For those patients, warfarin and apixaban appear to be FDA-approved, whereas dabigatran, rivaroxaban, and edoxaban are not recommended yet. Due to a lack of large randomized studies, data from major trials cannot be extended to dialysis patients. In this review, we summarize the available data and literature referring to patients on chronic hemodialysis with concomitant AF. Due to the scarcity of data, we try to assist clinicians in selecting the appropriate therapy according to the specific characteristics of each patient. Finally, future directions are provided in two key areas of focus: left atrial appendage closure therapies and genetic research.

Causes, Angiographic Characteristics, and Management of Premature Myocardial Infarction: JACC State-of-the-Art Review.

Among patients presenting with acute myocardial infarction (AMI), the proportion of young individuals has increased in recent years. Although coronary atherosclerosis is less extensive in young patients with AMI, with higher prevalence of single-vessel disease and rare left main involvement, the long-term prognosis is not benign. Young patients with AMI with obstructive coronary artery disease have similar risk factors as older patients except for higher prevalence of smoking, lipid disorders, and family history of premature coronary artery disease, and lower prevalence of diabetes mellitus and hypertension. Smoking cessation is by far the most effective secondary preventive measure. Myocardial infarction with nonobstructive coronary arteries is a relatively common clinical entity (10%-20%) among young patients with AMI, with intravascular and cardiac magnetic resonance imaging being key for diagnosis and potentially treatment. Spontaneous coronary artery dissection is a frequent pathogenetic mechanism of AMI among young women, requiring a high degree of suspicion, especially in the peripartum period.

Differential prognostic value of resistin for cardiac death in patients with coronary artery disease according to the presence of metabolic syndrome.

Resistin is associated with atherosclerosis progression by affecting inflammation and insulin resistance. There are controversial data regarding the prognostic value of resistin in stable coronary artery disease (CAD) patients. We prospectively investigated the long-term prognostic value of resistin in patients with stable CAD. A total 741 consecutive patients with stable CAD were followed for a median of 5.5 years. Serum resistin, lipids, high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) levels were measured at baseline. Primary endpoints were cardiac death and secondary hospitalizations for acute coronary syndrome, arrhythmic event or ischemic stroke. Follow-up data were obtained from 703 patients of whom 79 had a cardiac death (11.2%) and 205 (29.2%) met the secondary endpoints. Resistin was positively correlated with hsCRP (r = 0.159, p < 0.001) and IL-6 (r = 0.165, p = 0.002), and negatively with high-density lipoprotein-cholesterol (r = - 0.176, p < 0.001). Resistin levels could not predict cardiac death [HR 1.044; 95% CI 0.994-1.096; p = 0.087] neither secondary endpoints [HR 1.025; 95% CI 0.983-1.068; p = 0.250). Among 298 patients (42.4%) with metabolic syndrome (MS) resistin levels were independently associated with cardiac death after adjustment for conventional risk factors [HR 1.121; 95% CI 1.045-1.204; p = 0.002). Further adjustment for ejection fraction of left ventricle (LVEF) did not change the association (HR 1.145; 95% CI 1.057-1.240; p = 0.001). Patients with resistin values ≥ 7.6 ng/mL (median level) had 2.8 times higher risk of cardiac death compared to those with resistin levels < 7.6 ng/mL after adjustment for traditional risk factors and LVEF (HR 2.882; 95% CI 1.311-6.336; p = 0.008). Resistin is independently associated with cardiac death in patients with stable CAD and MS.