The Renin-Angiotensin-Aldosterone System: Genomics, Proteomics and Therapeutic Implications

Since its discovery in 1898, the renin-angiotensin-aldosterone system (RAAS) has been intensely studied in the medical community, which led to important breakthroughs concerning the treatment of heart diseases. The main role of RAAS is to maintain the circulatory homeostasis, by maintaining the fluid volume. Angiotensin II (ANG II) can act on two receptors: angiotensin type 1 and angiotensin type 2 (AT1R and AT2R). The effect of AT1R consists in increased sodium retention, promotes vasoconstriction (mostly on the efferent arteriole), induces sympathetic nervous system activity, determines thirst and promotes the release of aldosterone. Abnormal activation of RAAS will determine hypertension and cardiac hypertrophy that may lead to heart failure. This is the reason why the pharmacological inhibition of this system has proven to induce such a beneficial effect in cardiovascular diseases such as hypertension and congestive heart failure. Later studies of patients with coronary artery disease revealed that angiotensin-converting enzyme (ACE) gene is also involved in the process of atherosclerosis and those mutations in its gene account for an increased susceptibility to severe acute coronary events. The most common ACE gene mutation is represented by deletions and insertions in the 16th intron (presence or absence of the 287-bp Alu repeat sequence), resulting in three possible genotypes, identified by the length of the fragments: II (490 bp), ID (490, 190 bp) and DD (190 bp). Scientific evidence suggests that the D allele plays a major role in the determination of coronary artery disease. The next step would be to develop new treatment strategies according to the genetic background of each patient

Correlations between Inflammation and Thrombosis in the Pathogeny of Myocardial Infarction

Atherosclerosis is the main cause of myocardial infarction. This process involves a complex interplay between metabolic pathways governing lipid deposition, inflammatory and immune responses to oxidized lipids, and endothelial dysfunction. Myocardial infarction appears when these processes culminate with a thrombotic event. Markers of inflammation, such as C-reactive protein (CRP), myeloperoxidase (MPO) and leukocyte levels are strong predictors of cardiovascular death, myocardial infarction, and stroke. This process involves a complex interplay between metabolic pathways governing lipid deposition, inflammatory and immune responses to oxidized lipids, and endothelial dysfunction. Myocardial infarction appears when these processes culminate with a thrombotic event. Markers of inflammation, such as C-reactive protein (CRP), myeloperoxidase (MPO) and leukocyte levels are strong predictors of cardiovascular death, myocardial infarction, and stroke. This review will summarize the molecular and cellular links between inflammation and thrombosis in the context of myocardial infarction, which support the concept of a thrombo inflammatory state leading to the vessel obstruction and to the subsequent myocardial necrosis

Optimal Management of Elective Joint Replacement Surgery in Patients with Hemophilia

Hemophilia is a genetic or acquired disease that leads to spontaneous and recurrent bleedings, which affect the joints and muscles, thus determining chronic damage to the cartilage which will lead to joint disease and hemophilic arthropathy. Even though hemophilic patients were initially thought to have a low incidence of atherothrombotic complications, it is now clear that atherothrombotic events occur. The administration of plasmatic factor VIII has better clinical results in type A hemophilic patients than the transfusion with plasma. We analyzed five patients with hemophilia type A, aged between 35 and 62 years. Two of them had a severe form of hemophilia with factor VIII less than 1%, while the other three had a moderate form with factor VIII ranging between 1 and 5%. The five patients underwent total knee repair interventions and received substitution treatment with clotting factors but also prophylactic anticoagulant treatment. The postsurgical evolution of these patients was favorable, with similar hemostatic profile as the non-hemophilic patients. Moroctocog alfa is an efficient substitutive treatment that manages to normalize the hemostatic profile of patients. Therefore, it is recommended to provide prophylactic antithrombotic therapy after the orthopedic interventions

Anticoagulation in Thrombophilia

Thrombophilia is a condition of hypercoagulability, which is defined as an abnormality of blood clotting, disturbing the balance between procoagulants and anticoagulants in favor of the former, thus increasing the risk of thrombosis. It can be classified into different categories, such as genetic/administered; primary/secondary; permanent/transient; low risk/high risk. Venous thromboembolism is the main and most common complication of a hypercoagulable condition, with an enormous impact on any national health system. The pathophysiological mechanisms involved are at various stages of research, some of which are far from being fully elucidated. Treatment of thrombophilia differs—while most conditions do not require anticoagulation as primary prophylaxis, secondary prophylaxis may require transient or permanent anticoagulation. Treatment options include parenteral unfractionated heparin, low molecular weight heparin (LMWH), fondaparinux or orally administered vitamin K antagonists, and direct oral anticoagulants (DOAC), such as rivaroxaban, apixaban, dabigatran, with increasing indications as data accumulate from recent and ongoing studies and trials

Molecular and Cellular Mechanisms Involved in Aortic Wall Aneurysm Development

Aortic aneurysms represent a very common pathology that can affect any segment of the aorta. These types of aneurysms can be localized on the thoracic segment or on the abdominal portion, with the latter being more frequent. Though there are similarities between thoracic and abdominal aortic aneurysms, these pathologies are distinct entities. In this article, we undertook a review regarding the different mechanisms that can lead to the development of aortic aneurysm, and we tried to identify the different manners of treatment. For a long time, aortic wall aneurysms may evolve in an asymptomatic manner, but this progressive dilatation of the aneurysm can lead to a potentially fatal complication consisting in aortic rupture. Because there are limited therapies that may delay or prevent the development of acute aortic syndromes, surgical management remains the most common manner of treatment. Even though, surgical management has improved much in the last years, thus becoming less invasive and sophisticated, the morbi-mortality linked to these therapies remains increased. The identification of the cellular and molecular networks triggering the formation of aneurysm would permit the discovery of modern therapeutic targets. Molecular and cellular mechanisms are gaining a bigger importance in the complex pathogenesis of aortic aneurysms. Future studies must be developed to compare the findings seen in human tissue and animal models of aortic aneurysm, so that clinically relevant conclusions about the aortic aneurysm formation and the pharmacological possibility of pathogenic pathways blockage can be drawn

Concept, Design, and Early Prototyping of a Low-Cost, Minimally Invasive, Fully Implantable Left Ventricular Assist Device

Despite evidence associating the use of mechanical circulatory support (MCS) devices with increased survival and quality of life in patients with advanced heart failure (HF), significant complications and high costs limit their clinical use. We aimed to design an innovative MCS device to address three important needs: low cost, minimally invasive implantation techniques, and low risk of infection. We used mathematical modeling to calculate the pump characteristics to deliver variable flows at different pump diameters, turbomachinery design software CFturbo (2020 R2.4 CFturbo GmbH, Dresden, Germany) to create the conceptual design of the pump, computational fluid dynamics analysis with Solidworks Flow Simulation to in silico test pump performance, Solidworks (Dassault Systèmes SolidWorks Corporation, Waltham, MA, USA) to further refine the design, 3D printing with polycarbonate filament for the initial prototype, and a stereolithography printer (Form 2, Formlabs, Somerville, MA, USA) for the second variant materialization. We present the concept, design, and early prototyping of a low-cost, minimally invasive, fully implantable in a subcutaneous pocket MCS device for long-term use and partial support in patients with advanced HF which unloads the left heart into the arterial system containing a rim-driven, hubless axial-flow pump and the wireless transmission of energy. We describe a low-cost, fully implantable, low-invasive, wireless power transmission left ventricular assist device that has the potential to address patients with advanced HF with higher impact, especially in developing countries. In vitro testing will provide input for further optimization of the device before proceeding to a completely functional prototype that can be implanted in animals

Hereditary Thrombophilia in the Era of COVID-19

Thrombophilia, also called hypercoagulability or prothrombotic condition, usually reflects a certain imbalance that occurs either in the coagulation cascade or in the anticoagulation/fibrinolytic system. A similar imbalance may be induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thrombotic complications are associated with multiorgan failure and increased mortality. In this context, activation of coagulation and thrombocytopenia appeared as prognostic markers in COVID-19. Our work provides a structured and updated analysis of inherited thrombophilia and its involvement in COVID-19, emphasizing the importance of diagnosing and initiating thromboprophylaxis. Since the state of hypercoagulation is directly correlated with COVID-19, we consider that studies on the genetic profiles of proteins involved in thrombophilia in patients who have had COVID-19 and thrombotic events are of great importance, both in treating and in preventing deaths due to COVID-19

Cardiovascular Risk Factors in Patients with Congenital Hemophilia: A Focus on Hypertension

Aging hemophiliacs face cardiovascular disease. Lots of evidence has been gathered that hemophiliacs have a more unfavorable cardiovascular profile than the general population does, especially due to the increased prevalence of hypertension (HTN). Among the existing scattered evidence, our study provides the most comprehensive and systematized analysis of the determinants of HTN in hemophiliacs. We discussed the contribution to the HTN substrate of hemophilia-specific factors, such as type, severity and the presence of inhibitors. The complex mechanism of kidney dysfunction in relation to hematuria and viral infections was meticulously addressed. Furthermore, we highlighted the new pathogenic concepts of endothelial dysfunction and the association between HTN and hemophilic arthropathy. The clustering of cardiovascular risk factors is common in hemophiliacs, and it enhances the negative vascular effect of HTN and aggravates HTN. It usually leads to an increased risk for coronary and cerebrovascular events. Our work provides reliable evidence to guide and improve the management of HTN in hemophiliacs

Thromboembolic Disease in Haemophilic Patients Undergoing Major Orthopaedic Surgery: Is Thromboprophylaxis Mandatory?

Haemophilia is a rare genetic disorder, that results from various degrees of deficiency of coagulation factor VIII (haemophilia A), or factor IX (haemophilia B), with an X-linked transmission. The patients affected are in the majority of cases males (who inherit the affected X-chromosome from the maternal side), with rare cases of females with haemophilia (FVIII or FIX < 40 IU/dL), situations in which both X-chromosomes are affected, or one is affected, and the other one is inactive (known as carrier). The hypocoagulable state due to the deficiency of clotting factors, manifests as an excessive, recurrent tendency to bleeding, which positively correlates with plasmatic levels. Severe haemophilia results in hemarthrosis, although recent data have shown that moderate or even mild disease can lead to joint bleeding. Recurrent episodes of haemorrhages, usually affecting large joints such as knees, elbows, or ankles, lead to joint remodelling and subsequent haemophilic arthropathy, which may require arthroplasty as a last therapeutic option. Orthopaedic patients have the highest risk among all for deep vein thrombosis (DVT) and venous thromboembolism (VTE) with morbid and potentially fatal consequences. While for the rest of the population thromboprophylaxis in orthopaedic surgery is efficient, relatively safe, and widely used, for patients with haemophilia who are considered to have a low thromboembolic risk, there is great controversy. The great heterogeneity of this particular population, and the lack of clinical trials, with only case reports or observational studies, makes thromboprophylaxis in major orthopaedic surgery a tool to be used by every clinician based on experience and case particularities. This review aims to briefly summarise the latest clinical data and to offer an insight into the current recommendations that readers would find useful in daily practice

Myocardial Ischemia Related to Common Cancer Therapy—Prevention Insights

Modern antineoplastic therapy improves survival and quality of life in cancer patients, but its indisputable benefits are accompanied by multiple and major side effects, such as cardiovascular ones. Endothelial dysfunction, arterial spasm, intravascular thrombosis, and accelerated atherosclerosis affect the coronary arteries, leading to acute and chronic coronary syndromes that negatively interfere with the oncologic treatment. The cardiac toxicity of antineoplastic agents may be mitigated by using adequate prophylactic measures. In the absence of dedicated guidelines, our work provides the most comprehensive, systematized, structured, and up-to-date analyses of the available literature focusing on measures aiming to protect the coronary arteries from the toxicity of cancer therapy. Our work facilitates the implementation of these measures in daily practice. The ultimate goal is to offer clinicians the necessary data for a personalized therapeutic approach for cancer patients receiving evidence-based oncology treatments with potential cardiovascular toxicity