Modern Treatment of Valvulopathies in Patients with Congenital Hemophilia.

Hemophiliacs can develop cardiovascular diseases, including valvulopathies of various etiologies and severities. Some require surgical treatment. Performing cardiac surgery in hemophiliacs is a challenge because they maintain an increased risk of bleeding throughout their lives. Our review shows that with a multidisciplinary team and careful planning, cardiac surgery can be safely performed in these patients. Valve repair and bioprosthetic valves should be preferred over mechanical valves to avoid life-long anticoagulation. In patients who cannot receive a bioprosthetic valve, the use of the On-X mechanical valve might be considered because it requires less intensive anticoagulation after 3 months of treatment. Antithrombotic treatment is feasible in hemophiliacs only if the coagulation factor level is kept constantly above a specific trough limit. Our review is valuable because, for the first time, the available data on the modern surgical treatment of valvular disease in hemophiliacs have been synthesized and systematized.

Managing Anemia: Point of Convergence for Heart Failure and Chronic Kidney Disease?

The pathologic triangle formed by chronic heart failure (HF), chronic kidney disease (CKD), and anemia carries high morbidity and mortality rates and decreases quality of life. Anemia represents a common condition in patients with advanced HF and CKD, with a total prevalence in cardiorenal syndrome (CRS) ranging from 5% to 55%. Searching for a pragmatic approach for these patients with guided and disease-specific recommendations beyond just targeted hemoglobin therapeutic behavior represents the core of research for ongoing clinical trials. It is well known that the prevalence of anemia increases with the advancement of CKD and HF. The physiopathological mechanisms of anemia, such as the reduction of endogenous erythropoietin and the decrease in oxygen transport, are leading to tissue hypoxia, peripheral vasodilation, stimulating neurohormonal activity, and maintenance of the progressive renal and cardiac dysfunction. Given the challenges with the treatment options for patients with cardiorenal anemia syndrome (CRSA), new therapeutic agents such as hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PH) or hepcidin antagonists are emerging in the light of recent research. This review summarizes the potential therapeutic tools for anemia therapy in the cardiorenal population.

Portrayal of NLRP3 Inflammasome in Atherosclerosis: Current Knowledge and Therapeutic Targets.

We are witnessing the globalization of a specific type of arteriosclerosis with rising prevalence, incidence and an overall cardiovascular disease burden. Currently, atherosclerosis increasingly affects the younger generation as compared to previous decades. While early preventive medicine has seen improvements, research advances in laboratory and clinical investigation promise to provide us with novel diagnosis tools. Given the physio-pathological complexity and epigenetic patterns of atherosclerosis and the discovery of new molecules involved, the therapeutic field of atherosclerosis has room for substantial growth. Thus, the scientific community is currently investigating the role of nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a crucial component of the innate immune system in different inflammatory disorders. NLRP3 is activated by distinct factors and numerous cellular and molecular events which trigger NLRP3 inflammasome assembly with subsequent cleavage of pro-interleukin (IL)-1ß and pro-IL-18 pathways via caspase-1 activation, eliciting endothelial dysfunction, promotion of oxidative stress and the inflammation process of atherosclerosis. In this review, we introduce the basic cellular and molecular mechanisms of NLRP3 inflammasome activation and its role in atherosclerosis. We also emphasize its promising therapeutic pharmaceutical potential.

Direct Oral Anticoagulants for Stroke and Systemic Embolism Prevention in Patients with Left Ventricular Thrombus.

In recent years, direct oral anticoagulants (DOAC) have accumulated evidence of efficacy and safety in various clinical scenarios and are approved for a wide spectrum of indications. Still, they are currently used off-label for left ventricular thrombus owing to a paucity of evidence. For the same reason, there is a lack of guideline indication as well. Our work is based on an exhaustive analysis of the available literature and provides a structured and detailed update on the use of DOACs in patients with left ventricle thrombus. The safety and efficacy of DOACs were analyzed in particular clinical scenarios. As far as we know, this is the first paper that analyzes DOACs in this approach.

Hereditary Hemorrhagic Telangiectasia and Arterio-Venous Malformations-From Diagnosis to Therapeutic Challenges.

Hereditary hemorrhagic telangiectasia is a rare autosomal dominant vascular disease defined by the presence of mucosal and cutaneous telangiectasia and visceral arterio-venous malformations. The latter are abnormal capillary-free direct communications between the pulmonary and systemic circulations with the following consequences: arterial hypoxemia caused by right-to-left shunts; paradoxical embolism with transient ischemic attack or stroke and brain abscess caused by the absence of the normally filtering capillary bed; and hemoptysis or hemothorax due to the rupture of the thin-walled arterio-venous malformations (particularly during pregnancy). It is frequently underdiagnosed, commonly presenting as complications from shunting through arterio-venous malformations: dyspnea, chronic bleeding, or embolism. Arterio-venous malformations are present not only in the lungs, but can also be found in the liver, central nervous system (mainly in the brain), nasal mucosa, or the gastrointestinal tract. The first choice of therapy is embolization of the afferent arteries of the arterio-venous malformations, a minimally invasive procedure with a high efficacy, a low morbidity, and low mortality. Other therapeutic modalities are surgery (resection) or stereotactic radiosurgery (using radiation). Routine screening for arterio-venous malformations is indicated in patients diagnosed with this condition and can prevent severe complications such as acute hemorrhages, brain abscesses, or strokes. Clinicians should provide a long-term follow-up for patients with arterio-venous malformations, in an effort to detect their growth or reperfusion in case of previously treated malformations. In spite of two experts' consensuses, it still possesses multiple therapeutic challenges for physicians, as several aspects regarding the screening and management of arterio-venous malformations still remain controversial. Multidisciplinary teams are especially useful in complex cases.

MicroRNAs (miRNAs) in Cardiovascular Complications of Rheumatoid Arthritis (RA): What Is New?

Rheumatoid Arthritis (RA) is among the most prevalent and impactful rheumatologic chronic autoimmune diseases (AIDs) worldwide. Within a framework that recognizes both immunological activation and inflammatory pathways, the exact cause of RA remains unclear. It seems however, that RA is initiated by a combination between genetic susceptibility, and environmental triggers, which result in an auto-perpetuating process. The subsequently, systemic inflammation associated with RA is linked with a variety of extra-articular comorbidities, including cardiovascular disease (CVD), resulting in increased mortality and morbidity. Hitherto, vast evidence demonstrated the key role of non-coding RNAs such as microRNAs (miRNAs) in RA, and in RA-CVD related complications. In this descriptive review, we aim to highlight the specific role of miRNAs in autoimmune processes, explicitly on their regulatory roles in the pathogenesis of RA, and its CV consequences, their main role as novel biomarkers, and their possible role as therapeutic targets.

Beyond the Cardiorenal Syndrome: Pathophysiological Approaches and Biomarkers for Renal and Cardiac Crosstalk.

Cardiorenal syndrome encompasses complex multifactorial facets and carries significant morbidity and mortality worldwide. The bi-directional relationship between the heart and kidneys, where dysfunction in one organ worsens the function of the other, has been the leading motor for research in the last few years. In the pathophysiological process, small noncoding RNAs, epigenetics, vascular growth factors, oxidative stress, hemodynamic factors, and biomarkers play a pivotal role in the development of cardiorenal syndrome. It is therefore important to elucidate all the mechanisms in order to provide diagnostic and treatments tools. This review summarizes the hemodynamic and non-hemodynamic pathways along with biomarkers that could be the next target for diagnosis, treatment, and prognosis in cardiorenal syndrome.

Current Knowledge of MicroRNAs (miRNAs) in Acute Coronary Syndrome (ACS): ST-Elevation Myocardial Infarction (STEMI).

Regardless of the newly diagnostic and therapeutic advances, coronary artery disease (CAD) and more explicitly, ST-elevation myocardial infarction (STEMI), remains one of the leading causes of morbidity and mortality worldwide. Thus, early and prompt diagnosis of cardiac dysfunction is pivotal in STEMI patients for a better prognosis and outcome. In recent years, microRNAs (miRNAs) gained attention as potential biomarkers in myocardial infarction (MI) and acute coronary syndromes (ACS), as they have key roles in heart development, various cardiac processes, and act as indicators of cardiac damage. In this review, we describe the current available knowledge about cardiac miRNAs and their functions, and focus mainly on their potential use as novel circulating diagnostic and prognostic biomarkers in STEMI.

Current Therapeutic Approach to Acute Myocardial Infarction in Patients with Congenital Hemophilia.

Advances in the treatment of hemophilia have made the life expectancy of hemophiliacs similar to that of the general population. Physicians have begun to face age-related diseases not previously encountered in individuals with hemophilia. Treatment of acute myocardial infarction (AMI) is particularly challenging because the therapeutic strategies influence both the patient's thrombotic and hemorrhagic risk. As progress has been made in the treatment of AMI over the last decade, we performed an in-depth analysis of the available literature, highlighting the latest advances in the therapy of AMI in hemophiliacs. It is generally accepted that after the optimal substitution therapy has been provided, patients with hemophilia should be treated in the same way as those in the general population. New-generation stents that allow short dual antiplatelet therapy and potent P2Y12 receptor inhibitors have begun to be successfully used. At a time when specific recommendations and relevant data are scarce, our study provides up-to-date information to physicians involved in the treatment of AMI in hemophiliacs.

Hyponatremia-Long-Term Prognostic Factor for Nonfatal Pulmonary Embolism.

Over recent years, studies have shown that in patients with left-sided heart failure, arterial hypertension, and acute coronary syndrome, hyponatremia is a negative prognostic factor. In this context, there is raising interest in the association between hyponatremia and pulmonary embolism (PE). This retrospective cohort study includes 404 consecutive patients with confirmed acute nonfatal pulmonary embolism divided into four groups according to their sodium fluctuation pattern. The primary outcome was all-cause mortality and determining the recurrence rate among patients with nonfatal PE using serum sodium levels as a continuous variable. Patients with acquired and persistent hyponatremia had a significantly higher rate of mortality rate than those in the normonatremia group (12.8% and 40.4%, OR- 7.206, CI: 2.383-21.791, p = 0.000 and OR-33.250, CI: 11.521-95.960, p = 0.000 vs. 2%, p < 0.001, respectively). Mean survival time decreases from 23.624 months (95% CI: (23.295-23.953)) in the normonatremia group to 16.426 months (95% CI: (13.17-19.134)) in the persistent hyponatremia group, statistically significant (p = 0.000). The mean survival time for all patients was 22.441 months (95% CI: (21.930-22.951)). The highest recurrence rate was recorded at 12 and 24 months in the acquired hyponatremia group (16.7% and 14.1%, respectively). Serum sodium determination is a simple and cost-effective approach in evaluating the short and long-term prognosis in patients with acute PE.

Cardiac Optogenetics in Atrial Fibrillation: Current Challenges and Future Opportunities.

Although rarely life-threatening on short term, atrial fibrillation leads to increased mortality and decreased quality of life through its complications, including heart failure and stroke. Recent studies highlight the benefits of maintaining sinus rhythm. However, pharmacological long-term rhythm control strategies may be shadowed by associated proarrhythmic effects. At the same time, electrical cardioversion is limited to hospitals, while catheter ablation therapy, although effective, is invasive and is dedicated to specific patients, usually with low amounts of atrial fibrosis (preferably Utah I-II). Cardiac optogenetics allows influencing the heart's electrical activity by applying specific wavelength light pulses to previously engineered cardiomyocytes into expressing microbial derived light-sensitive proteins called opsins. The resulting ion influx may give rise to either hyperpolarizing or depolarizing currents, thus offering a therapeutic potential in cardiac electrophysiology, including pacing, resynchronization, and arrhythmia termination. Optogenetic atrial fibrillation cardioversion might be achieved by inducing a conduction block or filling of the excitable gap. The authors agree that transmural opsin expression and appropriate illumination with an exposure time longer than the arrhythmia cycle length are necessary to achieve successful arrhythmia termination. However, the efficiency and safety of biological cardioversion in humans remain to be seen, as well as side effects such as immune reactions and loss of opsin expression. The possibility of delivering pain-free shocks with out-of-hospital biological cardioversion is tempting; however, there are several issues that need to be addressed first: applicability and safety in humans, long-term behaviour, anticoagulation requirements, and fibrosis interactions.

The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) remain as one of the most global problematic metabolic diseases with rapidly increasing prevalence and incidence. Epidemiological studies noted that T2DM patients have by two-fold increase to develop NAFLD, and vice versa. This complex and intricate association is supported and mediated by insulin resistance (IR). In this review, we discuss the NAFLD immunopathogenesis, connection with IR and T2DM, the role of screening and noninvasive tools, and mostly the impact of the current antidiabetic drugs on steatosis liver and new potential therapeutic targets.

Left Atrial Structural Remodelling in Non-Valvular Atrial Fibrillation: What Have We Learnt from CMR?

Left atrial structural, functional and electrical remodelling are linked to atrial fibrillation (AF) pathophysiology and mirror the phrase "AF begets AF". A structurally remodelled left atrium (LA) is fibrotic, dysfunctional and enlarged. Fibrosis is the hallmark of LA structural remodelling and is associated with increased risk of stroke, heart failure development and/or progression and poorer catheter ablation outcomes with increased recurrence rates. Moreover, increased atrial fibrosis has been associated with higher rates of stroke even in sinus-rhythm individuals. As such, properly assessing the fibrotic atrial cardiomyopathy in AF patients becomes necessary. In this respect, late-gadolinium enhancement cardiac magnetic resonance (LGE-CMR) imaging is the gold standard in imaging myocardial fibrosis. LA structural remodelling extension offers both diagnostic and prognostic information and influences therapeutic choices. LGE-CMR scans can be used before the procedure to better select candidates and to aid in choosing the ablation technique, during the procedure (full CMR-guided ablations) and after the ablation (to assess the ablation scar). This review focuses on imaging several LA structural remodelling CMR parameters, including size, shape and fibrosis (both extension and architecture) and their impact on procedure outcomes, recurrence risk, as well as their utility in relation to the index procedure timing.

Arterial Hypertension and Interleukins: Potential Therapeutic Target or Future Diagnostic Marker?

Hypertension as a multifactorial pathology is one of the most important cardiovascular risk factors, affecting up to 30-40% of the general population. Complex immune responses are involved in the inflammatory mechanism of hypertension, with evidence pointing to increased inflammatory mediators even in prehypertensive patients. Increased vascular permeability, thrombogenesis, and fibrosis, effects that are associated with sustained hypertension, could be attributed to chronic inflammation. Chronic inflammation triggers endothelial dysfunction via increased production of ROS through proinflammatory cytokines. Increased serum level of proinflammatory cytokines such as IL-1ß, IL-6, IL-8, IL-17, IL-23, TGFß, and TNFα in hypertensive patients has been associated with either increased blood pressure values and/or end-organ damage. Moreover, some cytokines (i.e., IL-6) seem to determine a hypertensive response to angiotensin II, regardless of blood pressure values. Understanding hypertension as an inflammatory-based pathology gives way to new therapeutic targets. As such, conventional cardiovascular drugs (statins, calcium channels blockers, and ACEIs/ARBs) have shown additional anti-inflammatory effects that could be linked to their blood pressure lowering properties. Moreover, anti-inflammatory drugs (mycophenolate mofetil) have been shown to decrease blood pressure in hypertensive patients or prevent its development in normotensive individuals. Further research is needed to evaluate whether drugs targeting hypertensive-linked proinflammatory cytokines, such as monoclonal antibodies, could become a new therapeutic option in treating arterial hypertension.

Natriuretic Peptides in Heart Failure with Preserved Left Ventricular Ejection Fraction: From Molecular Evidences to Clinical Implications.

The incidence of heart failure with preserved ejection fraction (HFpEF) is increasing and its challenging diagnosis and management combines clinical, imagistic and biological data. Natriuretic peptides (NPs) are hormones secreted in response to myocardial stretch that, by increasing cyclic guanosine monophosphate (cGMP), counteract myocardial fibrosis and hypertrophy, increase natriuresis and determine vasodilatation. While their role in HFpEF is controversial, most authors focused on b-type natriuretic peptides (BNPs) and agreed that patients may show lower levels. In this setting, newer molecules with an increased specificity, such as middle-region pro-atrial natriuretic peptide (MR-proANP), emerged as promising markers. Augmenting NP levels, either by NP analogs or breakdown inhibition, could offer a new therapeutic target in HFpEF (already approved in their reduced EF counterparts) by increasing the deficient cGMP levels found in patients. Importantly, these peptides also retain their prognostic value. This narrative review focuses on NPs' physiology, diagnosis, therapeutic and prognostic implication in HFpEF.

QT interval variations and mortality risk: is there any relationship?

Abnormal prolongation and shortening of the electrocardiographic QT interval duration, which occur in the hereditary forms of long and short QT syndromes, are associated with an increased risk of ventricular arrhythmias and sudden cardiac death. Even within the normal range, these altered durations are associated with an increased mortality risk in the general population. While extreme prolongation or reduction of the QT interval predisposes patients to malignant ventricular arrhythmias and sudden cardiac death, the precise dose-response relationship between the QT interval and cardiovascular disease mortality is still unknown. This paper describes the need for more standardized methods for measuring and reporting the QT interval and the need for more precise assessments of the risk associated with QT interval variation.