[Show abstract][Hide abstract]ABSTRACT: Aims Shock is among the most dreaded and common complications of type A acute aortic dissection (TAAAD). However, clinical correlates, management, and short- and long-term outcomes of TAAAD patients presenting with shock in real-world clinical practice are not known. Methods and Results We evaluated 2,704 patients with TAAAD enrolled in the International Registry of Acute Aortic Dissection between January 1, 1996, and August 18, 2012. On admission, 407 (15.1%) TAAAD patients presented with shock. Most in-hospital complications (coma, myocardial or mesenteric ischemia or infarction, and cardiac tamponade) were more frequent in shock patients. In-hospital mortality was significantly higher in TAAAD patients with than without shock (30.2% vs 23.9%, P =.007), regardless of surgical or medical treatment. Most shock patients underwent surgical repair, with medically managed patients demonstrating older age and more complications at presentation. Estimates using Kaplan-Meier survival analysis indicated that most (89%) TAAAD patients with shock discharged alive from the hospital survived 5 years, a rate similar to that of TAAAD patients without shock (82%, P =.609). Conclusions Shock occurred in 1 of 7 TAAAD patients and was associated with higher rates of in-hospital adverse events and mortality. However, TAAAD survivors with or without shock showed similar long-term mortality. Successful early and aggressive management of shock in TAAAD patients has the potential for improving long-term survival in this patient population.
[Show abstract][Hide abstract]ABSTRACT: 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.
No preview · Article · Jan 2016 · Trends in cardiovascular medicine
[Show abstract][Hide abstract]ABSTRACT: More than 30 heritable conditions are associated with thoracic aortic aneurysm and dissection (TAAD). Heritable syndromic conditions, such as Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome, have somewhat overlapping systemic features, but careful clinical assessment usually enables a diagnosis that can be validated with genetic testing. Nonsyndromic FTAAD can also occur and in 20%-25% of these probands mutations exist in genes that encode elements of the extracellular matrix, signalling pathways (especially involving transforming growth factor-β), and vascular smooth muscle cytoskeletal and contractile processes. Affected individuals with either a syndromic presentation or isolated TAAD can have mutations in the same gene. In this review we focus on the genes currently known to have causal mutations for syndromic and isolated FTAAD and outline the range of associated extracardiovascular and cardiovascular manifestations with each.
No preview · Article · Nov 2015 · The Canadian journal of cardiology
[Show abstract][Hide abstract]ABSTRACT: : Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers.
METHODS : We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events.
RESULTS : From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [+/- SD] age, 11.5 +/- 6.5 years in the atenolol group and 11.0 +/- 6.2 years in the losartan group), who had an aorticroot z score greater than 3.0. The baseline-adjusted rate of change (+/- SE) in the aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139 +/- 0.013 and -0.107 +/- 0.013 standard-deviation units per year, respectively; P = 0.08). Both slopes were significantly less than zero, indicating a decrease in the degree of aortic-root dilatation relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups.
CONCLUSIONS : Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aorticroot dilatation between the two treatment groups over a 3-year period.
Full-text · Article · Nov 2014 · New England Journal of Medicine
[Show abstract][Hide abstract]ABSTRACT: Background:
Acute aortic dissection associated with cocaine use is rare and has been reported predominantly as single cases or in small patient cohorts.
Our study analyzed 3584 patients enrolled in the International Registry of Acute Aortic Dissection from 1996 to 2012. We divided the population on the basis of documented cocaine use (C+) versus non cocaine use (C-) and further stratified the cohorts into type A (33 C+/2332, 1.4%) and type B (30 C+/1252, 2.4%) dissection.
C+ patients presented at a younger age and were more likely to be male and black. Type B dissections were more common among C+ patients than in C- patients. Cocaine-related acute aortic dissection was reported more often at US sites than at European sites (86.4%, 51/63 vs 13.6%, 8/63; P < .001). Tobacco use was more prevalent in the C+ cohort. No differences were seen in history of hypertension, known atherosclerosis, or time from symptom onset to presentation. Type B C+ patients were more likely to be hypertensive at presentation. C+ patients had significantly smaller ascending aortic diameters at presentation. Acute renal failure was more common in type A C+ patients; however, mortality was significantly lower in type A C+ patients.
Cocaine use is implicated in 1.8% of patients with acute aortic dissection. The typical patient is relatively young and has the additional risk factors of hypertension and tobacco use. In-hospital mortality for those with cocaine-related type A dissection is lower than for those with non cocaine-related dissection, likely due to the younger age at presentation.
No preview · Article · May 2014 · The American Journal of Medicine
[Show abstract][Hide abstract]ABSTRACT: Patients with Marfan syndrome (MFS), a multisystem disorder caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin 1, are unusually vulnerable to stress-induced cardiac dysfunction. The prevailing view is that MFS-associated cardiac dysfunction is the result of aortic and/or valvular disease. Here, we determined that dilated cardiomyopathy (DCM) in fibrillin 1-deficient mice is a primary manifestation resulting from ECM-induced abnormal mechanosignaling by cardiomyocytes. MFS mice displayed spontaneous emergence of an enlarged and dysfunctional heart, altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including increased angiotensin II type I receptor (AT1R) signaling and abated focal adhesion kinase (FAK) activity. Partial fibrillin 1 gene inactivation in cardiomyocytes was sufficient to precipitate DCM in otherwise phenotypically normal mice. Consistent with abnormal mechanosignaling, normal cardiac size and function were restored in MFS mice treated with an AT1R antagonist and in MFS mice lacking AT1R or β-arrestin 2, but not in MFS mice treated with an angiotensin-converting enzyme inhibitor or lacking angiotensinogen. Conversely, DCM associated with abnormal AT1R and FAK signaling was the sole abnormality in mice that were haploinsufficient for both fibrillin 1 and β1 integrin. Collectively, these findings implicate fibrillin 1 in the physiological adaptation of cardiac muscle to elevated workload.
No preview · Article · Feb 2014 · Journal of Clinical Investigation
[Show abstract][Hide abstract]ABSTRACT: Little is known about the relation between type A acute aortic dissection (TAAAD) and pulse pressure (PP), defined as the difference between systolic and diastolic blood pressure. In this study, we explored the association between PP and presentation, complications, and outcomes of patients with TAAAD. PP at hospital presentation was used to divide 1,960 patients with noniatrogenic TAAAD into quartiles: narrowed (≤39 mm Hg, n = 430), normal (40 to 56 mm Hg, n = 554), mildly elevated (57 to 75 mm Hg, n = 490), and markedly elevated (≥76 mm Hg, n = 486). Variables relating to index presentation and in-hospital outcomes were analyzed. Patients with TAAAD in the narrowed PP quartiles were frequently older and Caucasian, whereas patients with markedly elevated PPs tended to be male and have a history of hypertension. Patients who demonstrated abdominal vessel involvement more commonly demonstrated elevated PPs, whereas patients with narrowed PPs were more likely to have periaortic hematoma and/or pericardial effusion. Narrowed PPs were also correlated with greater incidences of hypotension, cardiac tamponade, and mortality. Patients with TAAAD who were managed with endovascular and hybrid procedures and those with renal failure tended to have markedly elevated PPs. No difference in aortic regurgitation at presentation was noted among groups. In conclusion, patients with TAAAD in the third PP quartile had better in-hospital outcomes than patients in the lowest quartile. Patients with narrowed PPs experienced more cardiac complications, particularly cardiac tamponade, whereas those with markedly elevated PPs were more likely to have abdominal aortic involvement. Presenting PP offers a clue to different manifestations of acute aortic dissection that may facilitate initial triage and care.
No preview · Article · Jan 2014 · The American journal of cardiology
[Show abstract][Hide abstract]ABSTRACT: Genes are major determinants of human variation. Genome sequencing studies have shown that an individual genome includes 10000-11000 differences from the reference genome that changes an amino acid in a protein (non-synonymous change) and an approximately equal number of synonymous variants. Any individual is heterozygous for 50-100 variants that have been associated with genetic disorders (1000 Genomes Project Consortium et al., 2010). Genetic variation spans a range from chromosomal changes to single nucleotide changes. The impact of genetically determined characteristics likewise spans a continuum and may be nil at one extreme or lethal at the other.
[Show abstract][Hide abstract]ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant, highly penetrant and variable multisystem disorder due to maldevelopment of capillaries. The condition used to be called Osler–Weber–Rendu syndrome. The major features are epistaxis; mucocutaneous telangiectasias; and visceral arteriovenous malformations (especially in the brain, gastrointestinal tract, liver and lung). The causes defined thus far are in genes involved in signaling through the transforming growth factor β/bone morphogenetic protein pathway in endothelial cells. Early diagnosis, clinical screening and aggressive management can greatly reduce morbidity and mortality.
[Show abstract][Hide abstract]ABSTRACT: Considerable progress has been achieved in the past 5 years in defining genetic contributors to Mendelian forms of cardiac conduction disorders and dysrhythmias. To a lesser extent, the genetic factors that control electrophysiological homeostasis have been studied. Most disorders of electrophysiology are acquired, due to ischemia, inflammation, toxicities including drugs, and tissue alterations associated with age. However, the clinician must always consider whether the patient with dysrhythmia or conduction abnormalities has a primary cause of their condition. The family history remains the most important and least expensive test to perform first. This may lead to targeted genetic testing, which can facilitate directed, effective therapy and the identification of relatives at risk. Once a primary cause is eliminated, the patient must be managed empirically.
[Show abstract][Hide abstract]ABSTRACT: In this article, the emphasis is on disease. However, we stress the relationship of genetic processes to ordinary developmental mechanisms and maintenance of the healthy body, known as orthogenetics. Precise definition of a disorder, although an important question in its own right, is a luxury that we cannot afford here. For this reason, orthogenetics and pathogenetics are best seen as parts of a single continuous field of inquiry. Understanding the phenotype comes from the interactions among the insights from many disciplines.
[Show abstract][Hide abstract]ABSTRACT: Disease of the wall of the thoracic aorta has many causes: inflammation, infection and atherosclerosis are the most common 'acquired' causes, but even these have genetic predispositions. This article deals with aortic disease due to mutations in specific genes. The conditions can affect tissues and organs other than the aorta (syndromic) or be limited to the aorta (nonsyndromic).
A classification scheme based on the gene is emerging, those that affect primarily the extracellular matrix (e.g., FBN1, COL3A1), TGF-β signaling (e.g., TGFBR1, TGFB2), or vascular smooth muscle cell contractility (e.g., ACTA2, MYH11).
Understanding pathogenesis is driving the development of novel therapies, such as angiotensin receptor blockade, which is in clinical trial. However, recurrent imaging, restriction of exercise, β-adrenergic blockade, and prophylactic surgery remain effective in preventing dissection and sudden death.
No preview · Article · Nov 2013 · Current opinion in cardiology
[Show abstract][Hide abstract]ABSTRACT: To examine community pharmacists' attitudes towards pharmacogenetic (PGx) testing, including their views of the clinical utility of PGx and the ethical, social, legal and practical implications of PGx testing.
A web-based survey administered to 5600 licensed community pharmacists in the states of Ohio and Pennsylvania (USA).
Of 580 respondents, 78% had a Bachelor of Science degree in pharmacy and 58% worked in a chain drug store. Doctors of pharmacy-trained pharmacists had a significantly higher knowledge score than those with a Bachelor of Science in pharmacy (3.2 ± 0.9 vs 2.6 ± 0.6; p < 0.0001). All pharmacists had positive attitudes towards PGx and most (87%) felt it would decrease the number of adverse events, and optimize drug dosing. More than half (57%) of pharmacists felt that it was their role to counsel patients regarding PGx information. Many (65%) were concerned that PGx test results may be used to deny health insurance.
Regardless of the type of education, all pharmacists had positive attitudes towards PGx. There is still a concern among pharmacists that PGx test results may be used to deny health insurance and, thus, there is a need to educate pharmacists about legal protections prohibiting certain forms of unfair discrimination based on genotype.
Full-text · Article · Nov 2013 · Personalized Medicine
[Show abstract][Hide abstract]ABSTRACT: Background:
Stroke is a highly dreaded complication of type A acute aortic dissection (TAAAD). However, little data exist on its incidence and association with prognosis.
Methods and results:
We evaluated 2202 patients with TAAAD (mean age 62 ± 14 years, 1487 [67.5%] men) from the International Registry of Acute Aortic Dissection to determine the incidence and prognostic impact of stroke in TAAAD. Stroke was present at arrival in 132 (6.0%) patients with TAAAD. These patients were older (65 ± 12 versus 62 ± 15 years; P=0.002) and more likely to have hypertension (86% versus 71%; P=0.001) or atherosclerosis (29% versus 22%; P=0.04) than patients without stroke. Chest pain at arrival was less common in patients with stroke (70% versus 82%; P<0.001), and patients with stroke presented more often with syncope (44% versus 15%; P<0.001), shock (14% versus 7%; P=0.005), or pulse deficit (51% versus 29%; P ≤ 0.001). Arch vessel involvement was more frequent among patients with stroke (68% versus 37%; P<0.001). They had less surgical management (74% versus 85%; P<0.001). Hospital stay was significantly longer in patients with stroke (median 17.9 versus 13.3 days; P<0.001). In-hospital complications, such as hypotension, coma, and malperfusion syndromes, and in-hospital mortality (adjusted odds ratio, 1.62; 95% confidence interval, 0.99-2.65) were higher among patients with stroke. Among hospital survivors, follow-up mortality was similar between groups (adjusted hazard ratio, 1.15; 95% confidence interval, 0.46-2.89).
Stroke occurred in >1 of 20 patients with TAAAD and was associated with increased in-hospital morbidity but not long-term mortality. Whether aggressive early invasive interventions will reduce negative outcomes remains to be evaluated in future studies.