cardiovascular-agents and Marfan-Syndrome

Over the past 4 decades, remarkable progress in understanding the cause, pathogenesis, and management of the MFS has led to an increase in life expectancy to near normal for most patients. Accompanying this increased life span has been the emergence of previously rare or unanticipated clinical problems. Despite much more detailed knowledge of the molecular, cellular, and tissue effects of a mutation in FBN1, targeted, effective therapy remains elusive. Until such precision medicine takes hold, management will depend on early diagnosis, regular scrutiny by imaging, chronic β-blockade, and perhaps ARBs, and prophylactic cardiothoracic surgery. Without question, MFS will remain a fertile subject for basic, translational, and clinical research for the foreseeable future.

Topics: Animals; Aortic Aneurysm; Cardiac Surgical Procedures; Cardiovascular Agents; Disease Progression; DNA Mutational Analysis; Fibrillin-1; Genetic Predisposition to Disease; Humans; Marfan Syndrome; Mutation; Phenotype; Precision Medicine; Predictive Value of Tests; Prognosis; Risk Factors

Acute aortic syndromes (AAS) comprise a group of potentially lethal conditions that require prompt recognition, diagnosis as well as acute medical stabilization and surgical intervention. The purpose of this article is to review the relevant variants of AAS presentation, as well as diagnostic and management issues, including adequate long-term medical therapy and follow-up imaging. In this context, the American College of Cardiology and the American Heart Association recently published guidelines on the management of thoracic aortic disease, drawing greater attention to these processes.

Topics: Acute Disease; Angioplasty; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Aortography; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Combined Modality Therapy; Echocardiography, Transesophageal; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Magnetic Resonance Angiography; Marfan Syndrome; Multidetector Computed Tomography; Postoperative Complications; Registries; Risk Factors; Stents; Survival Rate; Syndrome; Ulcer

Marfan syndrome is a common inherited disorder of connective tissue caused by deficiency of the matrix protein fibrillin-1. Effective surgical therapy for the most life-threatening manifestation, aortic root aneurysm, has led to a nearly normal lifespan for affected individuals who are appropriately recognized and treated. Traditional medical therapies, such as beta-adrenergic receptor blockade, are used to slow pathologic aortic growth and decrease the risk of aortic dissection by decreasing hemodynamic stress. New insights regarding the pathogenesis of Marfan syndrome have developed from investigation of murine models of this disorder. Fibrillin-1 deficiency is associated with excess signaling by transforming growth factor beta (TGFbeta). TGFbeta antagonists have shown great success in improving or preventing several manifestations of Marfan syndrome in these mice, including aortic aneurysm. These results highlight the potential for development of targeted therapies based on discovery of disease genes and interrogation of pathogenesis in murine models.

Topics: Aortic Aneurysm; Cardiovascular Agents; Endocarditis; Humans; Marfan Syndrome

Marfan syndrome (MFS) is the most common inherited disorder of connective tissue that affects multiple organ systems. This autosomal-dominant condition has an incidence of 2-3 per 10,000 individuals. Although genetic testing is available, the diagnosis is still primarily made using the Ghent criteria. Early identification and appropriate management is critical for patients with MFS who are prone to the life-threatening cardiovascular complications of aortic dissection and rupture. Advances in the understanding of the cause of MFS, early recognition of the disorder, and subsequent institution of medical and surgical therapy has resulted in dramatic improvement in the prognosis of this patient population over the past few decades. Beta-blockers have been demonstrated to slow aortic growth and thus delay the time to aortic surgery. Operative intervention has markedly changed the prognosis of patients with MFS and can be safely performed on an elective basis. Identification of presymptomatic patients is critical to reduce the frequency of catastrophic aortic events.

Topics: Adolescent; Adult; Bone and Bones; Cardiac Surgical Procedures; Cardiovascular Agents; Cardiovascular Diseases; Child; Echocardiography; Female; Humans; Lens Subluxation; Magnetic Resonance Imaging; Male; Marfan Syndrome; Pregnancy; Quality of Life; Stereotyping; Tomography, X-Ray Computed; Treatment Outcome

It is accepted practice to prescribe beta-blockers in order to retard aortic dilatation and prevent aortic dissection and rupture in patients with Marfan syndrome. A critical review of the published pharmacological studies shows this practice to be based on limited evidence. The data from small clinical and experimental studies with surrogate end points suggest greater potential benefit from alternative drug regimens, and a recent experimental study showed that losartan may interrupt the mechanism of disease as well as deal with its functional consequences. It is now essential to perform large, collaborative, randomised controlled trials with clinical end points of new treatments in Marfan syndrome.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiovascular Agents; Humans; Losartan; Marfan Syndrome

The cardiovascular complications of Marfan syndrome (MFS) remain the primary source of morbidity and mortality in affected patients. Over the last decade, the underlying pathogenesis of these cardiovascular abnormalities has been the focus of much research. Such research has shed light on the potential role of several novel medical therapies and their ability to prevent cardiovascular disease progression. This paper summarizes the research underlying new medical therapies and provides a review of the scientific foundation underlying all current medical therapies used for prevention of cardiovascular disease in patients with MFS, including beta-adrenoceptor antagonists, calcium channel antagonists, ACE inhibitors, and angiotensin receptor antagonists.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Aortic Diseases; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Humans; Marfan Syndrome

Topics: Athletic Injuries; Cardiovascular Agents; Cardiovascular Diseases; Clinical Laboratory Techniques; Diagnosis, Differential; Female; Humans; Magnetic Resonance Angiography; Marfan Syndrome; Pregnancy; Pregnancy Complications; Risk Factors

Marfan syndrome (MFS) is associated with mutations in fibrillin-1 that predispose afflicted individuals to progressive thoracic aortic aneurysm (TAA) leading to dissection and rupture of the vessel wall. Here we combined computational and experimental approaches to identify and test FDA-approved drugs that may slow or even halt aneurysm progression. Computational analyses of transcriptomic data derived from the aortas of MFS patients and MFS mice (Fbn1mgR/mgR mice) predicted that subcellular pathways associated with reduced muscle contractility are key TAA determinants that could be targeted with the GABAB receptor agonist baclofen. Systemic administration of baclofen to Fbn1mgR/mgR mice validated our computational prediction by mitigating arterial disease progression at the cellular and physiological levels. Interestingly, baclofen improved muscle contraction-related subcellular pathways by upregulating a different set of genes than those downregulated in the aorta of vehicle-treated Fbn1mgR/mgR mice. Distinct transcriptomic profiles were also associated with drug-treated MFS and wild-type mice. Thus, systems pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.

Topics: Animals; Aortic Aneurysm, Thoracic; Cardiovascular Agents; Disease Models, Animal; Drug Repositioning; Gene Expression Profiling; Humans; Marfan Syndrome; Mice; Mice, Transgenic; Transcriptome

Topics: Aneurysm; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Combined Modality Therapy; Continuous Positive Airway Pressure; Echocardiography, Transesophageal; Enterobacteriaceae Infections; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Marfan Syndrome; Middle Aged; Mitral Valve Insufficiency; Oxygen Inhalation Therapy; Postoperative Complications; Pulmonary Artery; Pulmonary Valve Insufficiency; Respiratory Insufficiency

The clinical profiles and outcomes of patients treated surgically for acute type B aortic dissection (ABAD) are often reported for those in small series or for those cared for at a single institution over a long time period, during which a continuous evolution in techniques has occurred. Accordingly, we sought to evaluate the clinical features and surgical results of patients enrolled in the International Registry of Acute Aortic Dissection by identifying primary factors that influenced surgical outcome and estimating average surgical mortality for ABAD in the current era.. A comprehensive analysis of 290 clinical variables and their relation to surgical outcomes for 82 patients who required surgery for ABAD (from a population of 1256 patients; mean+/-SD age, 60.6+/-15.0 years; 82.9% male) and who were enrolled in the International Registry of Acute Aortic Dissection was performed. The overall in-hospital mortality was 29.3%. Factors associated with increased surgical mortality based on univariate analysis were preoperative coma or altered consciousness, partial thrombosis of the false lumen, evidence of periaortic hematoma on diagnostic imaging, descending aortic diameter >6 cm, right ventricle dysfunction at surgery, and shorter time from the onset of symptoms to surgery. Factors associated with favorable outcomes included radiating pain, normotension at surgery (systolic blood pressure 100 to 149 mm Hg), and reduced hypothermic circulatory arrest time. The 2 independent predictors of surgical mortality were age >70 years (odds ratio, 4.32; 95% confidence interval, 1.30 to 14.34) and preoperative shock/hypotension (odds ratio, 6.05; 95% confidence interval, 1.12 to 32.49).. The present study provides insights into current-day clinical profiles and surgical outcomes of ABAD. Knowledge about different preoperative clinical conditions may help surgeons in making treatment decisions among these high-risk patients.

Topics: Acute Disease; Aged; Anastomosis, Surgical; Antihypertensive Agents; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Atherosclerosis; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Comorbidity; Disease Susceptibility; Europe; Female; Follow-Up Studies; Heart Diseases; Hemodynamics; Hospital Mortality; Humans; Hypertension; Japan; Male; Marfan Syndrome; Middle Aged; Paraplegia; Postoperative Complications; Registries; Spinal Cord Ischemia; Stents; Survival Analysis; Treatment Outcome; United States