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The article focuses on a case study by Baris Feldman et al. describing siblings with biallelic loss-of-function variants in the GORIN gene, associated with left atrial cardiomyopathy, hypertension, atrial fibrillation, and fibrosis. Exome sequencing of a large Pakistani cohort revealed additional mutations in the GORIN gene linked to similar cardiovascular phenotypes.

The study observation shows that explosive generation of plasmin in blood or plasma which diminishes streptokinase's therapeutic effects is attributated to the formation of SK-Pg* that is governed by kringle domains.

Bacterial plasminogen (Pg) activators generate plasmin to degrade fibrin blood clots and other proteins that modulate the pathogenesis of infection, yet despite strong homology between mammalian Pgs, the activity of bacterial Pg activators is thought to be restricted to the Pg of their host mammalian species. Thus, we found that Streptococcus uberis Pg activator (SUPA), isolated from a Streptococcus species that infects cows but not humans, robustly activated bovine but not human Pg in purified systems and in plasma. Consistent with this, SUPA formed a higher avidity complex (118-fold) with bovine Pg than with human Pg and non-proteolytically activated bovine but not human Pg. Surprisingly, however, the presence of human fibrin overrides the species- restricted action of SUPA. First, human fibrin enhanced the binding avidity of SUPA for human Pg by 4-8-fold in the presence and absence of chloride ion (a negative regulator). Second, although SUPA did not protect plasmin from inactivation by α2-antiplasmin, fibrin did protect human plasmin, which formed a 31-fold higher avidity complex with SUPA than Pg. Third, fibrin significantly enhanced Pg activation by reducing the Km (4-fold) and improving the catalytic efficiency of the SUPA complex (6-fold). Taken together, these data suggest that indirect molecular interactions may override the species-restricted activity of bacterial Pg activators; this may affect the pathogenesis of infections or may be exploited to facilitate the design of new blood clot-dissolving drugs. [ABSTRACT FROM AUTHOR]

Background: Myocardial contrast two-dimensional echocardiography (MC-2DE) is widely used to address alcohol septal ablation (ASA) in obstructive hypertrophic cardiomyopathy (HCM). Owing to its limited cut-planes, MC-2DE may inaccurately identify the contrast misplacement associated with an unsuccessful or complicated ASA outcome. Objective: The aim of this study was to assess the added value of myocardial contrast three-dimensional echocardiography (MC-3DE) compared with MC-2DE to identify the appropriate matching between the target septal zone (TSZ) and coronary artery branch for safe and long-term effective ASA in HCM patients. Methods: A consecutive series of 52 symptomatic obstructive HCM patients referred for isolated surgical myectomy (SM) was analyzed with MC-2DE and MC-3DE following injection of echocontrast into one or more septal branches. MC-2DE and MC-3DE patterns were categorized according to complete (Type 1) or incomplete (Type 2) TSZ covering, high-risk (Type 3) exceeding TSZ, or life-threatening outside TSZ distribution (Type 4). Results: MC-2DE per patient analysis showed a Type 1 pattern in 32 patients and Types 2–4 in the remaining 20 patients; subsequent MC-3DE analysis provided a re-phenotyping of MC-2DE findings in 22 of the 52 patients (42%), showing a high-risk Type 2 pattern in 17 of the 32 patients with Type 1, and a new life-threatening Type 4 in three patients with Type 2, respectively. All patients with MC-3DE Type 1 pattern underwent safe and effective ASA with a long-term uneventful follow-up, while the remaining patients underwent SM. Conclusions: Refining high risk or life-threatening contrast misplacement, MC-3DE is more accurate than conventional MC-2DE to target safe and long-term effective septal reduction with ASA in obstructive HCM patients referred for isolated SM. [ABSTRACT FROM AUTHOR]

Hyperuricemia is nowadays an established cardiovascular risk factor. Experimental studies linked elevated serum uric acid (SUA) levels with endothelial dysfunction (ED), inflammation, and prothrombotic state. The purpose of this review is to summarize the current evidence that emphasizes the possible role of uric acid as a biomarker for a prothrombotic state. A large number of clinical trials correlated SUA levels with both incident and recurrent cases of venous thromboembolism (VTE), independent of other confounding risk factors. Moreover, increased SUA levels may be an important tool for the risk stratification of patients with pulmonary embolism (PE). Left atrial thrombosis was correlated with high SUA levels in several studies and its addition to classical risk scores improved their predictive abilities. In patients with acute myocardial infarction (MI), hyperuricemia was associated with increased mortality, and the idea that hyperuricemia may be able to act as a surrogate to unstable coronary plaques was advanced. Finally, SUA was correlated with an increased risk of thromboembolic events in different systemic diseases. In conclusion, uric acid has been considered a marker of a thrombotic milieu in several clinical scenarios. However, this causality is still controversial, and more experimental and clinical data is needed. [ABSTRACT FROM AUTHOR]

Despite important advancements in acute myocardial infarction (AMI) management, it continues to represent a leading cause of mortality worldwide. Fast and reliable AMI diagnosis can significantly reduce mortality in this high-risk population. Diagnosis of AMI has relied on biomarker evaluation for more than 50 years. The upturn of high-sensitivity cardiac troponin testing provided extremely sensitive means to detect cardiac myocyte necrosis, but this increased sensitivity came at the cost of a decrease in diagnostic specificity. In addition, although cardiac troponins increase relatively early after the onset of AMI, they still leave a time gap between the onset of myocardial ischemia and our ability to detect it, thus precluding very early management of AMI. Newer biomarkers detected in processes such as inflammation, neurohormonal activation, or myocardial stress occur much earlier than myocyte necrosis and the diagnostic rise of cardiac troponins, allowing us to expand biomarker research in these areas. Increased understanding of the complex AMI pathophysiology has spurred the search of new biomarkers that could overcome these shortcomings, whereas multi-omic and multi-biomarker approaches promise to be game changers in AMI biomarker assessment. In this review, we discuss the evolution, current application, and emerging blood biomarkers for the diagnosis of AMI; we address their advantages and promises to improve patient care, as well as their challenges, limitations, and technical and diagnostic pitfalls. Questions that remain to be answered and hotspots for future research are also emphasized. [ABSTRACT FROM AUTHOR]

Canagliflozin is a sodium-glucose co-transporter 2 inhibitor that reduces glycemia as well as the risk of cardiovascular events. Our main objective was to analyze antidiabetic treatment de-intensification and the glycemic efficacy of replacing antidiabetic agents (excluding metformin) with canagliflozin in patients with heart failure and type 2 diabetes with poor glycemic control. In this observational, retrospective, real-world study, we selected patients treated with metformin in combination with ≥2 non-insulin antidiabetic agents or metformin in combination with basal insulin plus ≥1 non-insulin antidiabetic agent. Non-insulin antidiabetic agents were replaced with canagliflozin. Patients were followed-up on at three, six, and 12 months after the switch and a wide range of clinical variables were recorded. A total of 121 patients were included. From baseline to 12 months, the number of antidiabetic agents (3.1 ± 1.0 vs. 2.1 ± 0.8, p < 0.05), basal insulin dose (20.1 ± 9.8 vs. 10.1 ± 6.5 units, p < 0.01), and percentage of patients who used basal insulin (47.9% vs. 31.3%, p < 0.01) decreased. The proportion of patients who used diuretics also declined significantly. In addition, we observed improvement in glycemic control, with an increase in the proportion of patients with glycated hemoglobin <7% from 16.8% at three months to 63.5% at 12 (p < 0.001). Canagliflozin use was also beneficial in terms of body weight, blood pressure, heart failure status, functional class, and cardiovascular-renal risk. There were also reductions in the number of emergency department visits and hospitalizations for heart failure. Moreover, canagliflozin was well-tolerated, with a low rate of drug-related discontinuation. Mounting evidence from randomized controlled trials and real-world studies point to the beneficial profile of sodium-glucose co-transporter type 2 inhibitors such as canagliflozin in patients with heart failure. [ABSTRACT FROM AUTHOR]

Racial disparities in utilization and outcomes of mechanical circulatory support (MCS) in patients with acute myocardial infarction-cardiogenic shock (AMI-CS) are infrequently studied. This study sought to evaluate racial disparities in the outcomes of MCS in AMI-CS. The National Inpatient Sample (2012–2017) was used to identify adult AMI-CS admissions receiving MCS support. MCS devices were classified as intra-aortic balloon pump (IABP), percutaneous left ventricular assist device (pLVAD) or extracorporeal membrane oxygenation (ECMO). Self-reported race was classified as white, black and others. Outcomes included in-hospital mortality, hospital length of stay and discharge disposition. During this period, 90,071 admissions were included with white, black and other races constituting 73.6%, 8.3% and 18.1%, respectively. Compared to white and other races, black race admissions were on average younger, female, with greater comorbidities, and non-cardiac organ failure (all p < 0.001). Compared to the white race (31.3%), in-hospital mortality was comparable in black (31.4%; adjusted odds ratio (aOR) 0.98 (95% confidence interval (CI) 0.93–1.05); p = 0.60) and other (30.2%; aOR 0.96 (95% CI 0.92–1.01); p = 0.10). Higher in-hospital mortality was noted in non-white races with concomitant cardiac arrest, and those receiving ECMO support. Black admissions had longer lengths of hospital stay (12.1 ± 14.2, 10.3 ± 11.2, 10.9 ± 1.2 days) and transferred less often (12.6%, 14.2%, 13.9%) compared to white and other races (both p < 0.001). In conclusion, this study of AMI-CS admissions receiving MCS devices did not identify racial disparities in in-hospital mortality. Black admissions had longer hospital stay and were transferred less often. Further evaluation with granular data including angiographic and hemodynamic parameters is essential to rule out racial differences. [ABSTRACT FROM AUTHOR]

Background: The first admission for acute heart failure with preserved ejection fraction (HFpEF) drastically influences the short-term prognosis. Baseline characteristics may predict repeat hospitalization or death in these patients. Methods: A 103 patient-cohort, admitted for the first acute HFpEF episode, was monitored for six months. Baseline characteristics were recorded and their relation to the primary outcome of heart failure readmission (HFR) and secondary outcome of all-cause mortality was assessed. Results: We identified six independent determinants for HFR: estimated glomerular filtration rate (eGFR) (p = 0.07), hemoglobin (p = 0.04), left ventricle end-diastolic diameter (LVEDD) (p = 0.07), E/e' ratio (p = 0.004), left ventricle outflow tract velocity-time integral (LVOT VTI) (p = 0.045), and diabetes mellitus (p = 0.06). Three of the variables were used to generate a risk score for HFR: LVEDD, E/e', LVOT VTI -DEI Score = − 28.763 + 4.558 × log (LVEDD (mm)) + 1.961 × log (E/e' ratio) + 1.759 × log (LVOT VTI (cm)). Our model predicts a relative amount of 20.50% of HFR during the first 6 months after the first acute hospitalization within the general population with HFpEF with a DEI Score over −0.747. Conclusions: We have identified three echocardiographic parameters (LVEDD, E/e', and LVOT VTI) that predict HFR following an initial acute HFpEF hospitalization. The prognostic DEI score demonstrated good accuracy. [ABSTRACT FROM AUTHOR]

Humans with dilated cardiomyopathy (DCM) and heart failure (HF) develop low levels of corin, a multi-domain, cardiac-selective serine protease involved in natriuretic peptide cleavage and sodium and water regulation. However, experimental restoration of corin levels markedly attenuates HF progression. To determine whether the beneficial effects of corin in HF require catalytic activity, we engineered cardiac overexpression of an enzymatically inactive corin transgene (corin-Tg(i)). On a wild-type (WT) background, corin-Tg(i) had no evident phenotypic effects. However, in a well-established genetic model of DCM, corin-Tg(i)/DCM mice had increased survival (p < 0.01 to 0.001) vs. littermate corin-WT/DCM controls. Pleural effusion (p < 0.01), lung edema (p < 0.05), systemic extracellular free water (p < 0.01), and heart weight were decreased (p < 0.01) in corin-Tg(i)/DCM vs. corin-WT/DCM mice. Cardiac ejection fraction and fractional shortening improved (p < 0.01), while ventricular dilation decreased (p < 0.0001) in corin-Tg(i)/DCM mice. Plasma atrial natriuretic peptide, cyclic guanosine monophosphate, and neprilysin were significantly decreased. Cardiac phosphorylated glycogen synthase kinase-3β (pSer9-GSK3β) levels were increased in corin(i)-Tg/DCM mice (p < 0.01). In summary, catalytically inactive corin-Tg(i) decreased fluid retention, improved contractile function, decreased HF biomarkers, and diminished cardiac GSK3β activity. Thus, the protective effects of cardiac corin on HF progression and survival in experimental DCM do not require the serine protease activity of the molecule. [ABSTRACT FROM AUTHOR]

The mechanism of action of plasminogen (Pg) activators may affect their therapeutic properties in humans. Streptokinase (SK) is a robust Pg activator in physiologic fluids in the absence of fibrin. Deletion of a "catalytic switch" (SK residues 1-59), alters the conformation of the SK alpha domain and converts SKDelta59 into a fibrin-dependent Pg activator through unknown mechanisms. We show that the SK alpha domain binds avidly to the Pg kringle domains that maintain Glu-Pg in a tightly folded conformation. By virtue of deletion of SK residues 1-59, SKDelta59 loses the ability to unfold Glu-Pg during complex formation and becomes incapable of nonproteolytic active site formation. In this manner, SKDelta59 behaves more like staphylokinase than like SK; it requires plasmin to form a functional activator complex, and in this complex SKDelta59 does not protect plasmin from inhibition by alpha(2)-antiplasmin. At the same time, SKDelta59 is unlike staphylokinase or SK and is more like tissue Pg activator, because it is a poor activator of the tightly folded form of Glu-Pg in physiologic solutions. SKDelta59 can only activate Glu-Pg when it was unfolded by fibrin interactions or by Cl(-)-deficient buffers. Taken together, these studies indicate that an intact alpha domain confers on SK the ability to nonproteolytically activate Glu-Pg, to unfold and process Glu-Pg substrate in physiologic solutions, and to alter the substrate-inhibitor interactions of plasmin in the activator complex. The loss of an intact alpha domain makes SKDelta59 activate Pg through classical "fibrin-dependent mechanisms" (akin to both staphylokinase and tissue Pg activator) that include: 1) a marked preference for a fibrin-bound or unfolded Glu-Pg substrate, 2) a requirement for plasmin in the activator complex, and 3) the creation of an activator complex with plasmin that is readily inhibited by alpha(2)-antiplasmin.