[Show abstract][Hide abstract] ABSTRACT: Federally funded research on the ethical, legal, and social implications (ELSI) of genomics includes a programmatic charge to consider policy-relevant questions and to communicate findings in venues that help inform the policy-making process. In addressing this goal, investigators must consider the range of policies that are relevant to human genetics; how foundational research in bioethics, law, and the social sciences might inform those policies; and the potential professional issues that this translational imperative raises for ELSI investigators. We review these questions in light of experiences from a consortium of federally funded Centers of Excellence in ELSI Research, and offer a set of policy recommendations for program design and evaluation of ELSI research. We conclude that it would be a mistake to require that ELSI research programs demonstrate a direct impact on science or health policy; however, ELSI researchers can take steps to increase the relevance of their work to policy makers. Similarly, funders of ELSI research who are concerned with facilitating policy development can help by building cross-disciplinary translational research capacities, and universities can take steps to make policy-relevant research more rewarding for scholars in the humanities, social sciences, and law.Genet Med advance online publication 19 June 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.74.
Genetics in medicine: official journal of the American College of Medical Genetics 06/2014; · 3.92 Impact Factor
[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.
Journal of Clinical Investigation 02/2014; · 12.81 Impact Factor
[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.
The American journal of cardiology 01/2014; · 3.58 Impact Factor
[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.
Current opinion in cardiology 11/2013; · 2.66 Impact Factor
[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.
Personalized Medicine 11/2013; 10(8). · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The utilization of genome-wide chromosomal microarray analysis (CMA) in pediatric clinical practice provides an opportunity to consider how genetic diagnostics is evolving, and to prepare for the clinical integration of genome-wide sequencing technologies. We conducted semi-structured interviews with 15 healthcare providers (7 genetic counselors, 4 medical geneticists, and 4 non-genetics providers) to investigate the impact of CMA on clinical practice, and implications for providers, patients and families. Interviews were analyzed qualitatively using content analysis. Most providers reported that genomic testing enhanced their professional experience and was beneficial to patients, primarily due to the improved diagnostic rate compared with earlier chromosomal studies. Other effects on practice included moving towards genotype-first diagnosis and broadening indications for chromosomal testing. Opinions varied concerning informed consent and disclosure of results. The duty to disclose incidental findings (IFs) was noted; however concerns were raised about potential psychosocial harms of disclosing pre-symptomatic findings. Tensions were revealed between the need for comprehensive informed consent for all families and the challenges of communicating time-consuming and potentially anxiety-provoking information regarding uncertain and incidental findings that may be relevant only in rare cases. Genetic counselors can play an important role in liaising with families, health professionals and testing laboratories, providing education and guidance to non-genetics providers, and enabling families to receive adequate pre-and post-test information and follow-up care.
Journal of Genetic Counseling 09/2013; · 1.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Few data exist on race-related differences in acute aortic dissection patients.
We evaluated black (n = 189, 14%) or white (n = 1165, 86%) patients (mean age 62.8 ± 15.3 years; 36.4% women) enrolled in 13 US centers participating in the International Registry of Acute Aortic Dissection. We excluded patients of other racial descent.
Type B acute aortic dissection was more frequent in the black cohort (52.4% vs 39.3%, P = .001). Black patients were younger (mean age 54.6 ± 12.8 years vs 64.2 ± 15.2 years, P <.001) and more likely to have a history of cocaine abuse (12% vs 1.6%, P <.001), hypertension (89.7% vs 73.9%, P <.001), and diabetes (13.2% vs 6.4%, P = .001). Conversely, they were less likely to have bicuspid aortic valve (1.8% vs 5.8%, P = .029), iatrogenic dissection (0.5% vs 4.5%, P = .010), and prior aortic dissection repair (7.7% vs 12.8%, P = .047). Presenting features were similar except for more abdominal pain (44.6% vs 30.6%, P <.001) and left ventricular hypertrophy on echocardiogram (44.2% vs 20.1%, P <.001) in blacks. Management was similar. Hypotension/shock/tamponade was less common (7.6% vs 20.1%, P <.001), whereas acute kidney failure was more common (41.0% vs 21.7%, P <.001) in blacks. Mortality was similar in-hospital (14.3% vs 19.1%, P = .110, odds ratio 0.704, 95% confidence interval 0.457-1.085) and at 3 years postdischarge, as evaluated by Kaplan-Meier survival analysis (22.0% vs 14.3%, P = .224, SE = 0.062 and 0.018).
Our study shows differences in type, etiology, and presentation of blacks and whites with acute aortic dissection, yet similar mortality for these cohorts.
The American journal of medicine 08/2013; · 5.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The classification of aortic dissection into acute (<14 days from symptom onset) versus chronic (≥14 days) is based on survival estimates of patients treated decades before modern diagnostic and treatment modalities were available. A new classification of aortic dissection in the current era may provide clinicians with a more precise method of characterizing the interaction of time, dissection location, and treatment type with survival.
We developed separate Kaplan-Meier survival curves for Type A and Type B aortic dissection using data from the International Registry of Aortic Dissection (IRAD). Daily survival was stratified based on type of therapy provided: medical therapy alone (medical), nonsurgical intervention plus medical therapy (endovascular), and open surgery plus medical therapy (surgical). The log-rank statistic was used to compare the survival curves of each management type within Type A and Type B aortic dissection.
There were 1815 patients included, 67.3% male with mean age 62.0 ± 14.2 years. When survival curves were constructed, 4 distinct time periods were noted: hyperacute (symptom onset to 24 hours), acute (2-7 days), subacute (8-30 days), and chronic (>30 days). Overall survival was progressively lower through the 4 time periods.
This IRAD classification system can provide clinicians with a more robust method of characterizing survival after aortic dissection over time than previous methods. This system will be useful for treating patients, counseling patients and families, and studying new diagnostic and treatment methods.
The American journal of medicine 08/2013; 126(8):730.e19-24. · 5.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by vascular malformations, and many clinical complications are related to pulmonary arteriovenous malformations (PAVMs) because they provide direct right-to-left shunts. Paradoxical emboli through these shunts are a well-recognized cause of transient ischemic attack, stroke, and cerebral abscess. The aim of this study was to determine whether paradoxical emboli through PAVMs could manifest as cardiac ischemic events. The study included a single-center population of 98 patients with PAVMs. Eighty-four had undergone PAVM embolotherapy, and the remaining 14 patients had PAVMs too small to require embolization. Patients were interviewed by telephone and surveyed regarding their cardiopulmonary symptoms and histories of cardiac diagnoses. We found that 6 patients (which is 18% of patients with symptomatic PAVMs, n = 33, and 6% of the total cohort, n = 98) reported that they had experienced typical angina pectoris-like chest pain or had a myocardial infarction before PAVM embolotherapy. Five patients had had a cardiac catheterization, 4 had normal coronary arteries, and 1 had a single artery occlusion. In conclusion, we suggest that in patients with untreated PAVMs, cardiac ischemia can occur because of a paradoxical embolus through PAVMs to a coronary artery.
The American journal of cardiology 05/2013; · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetic testing has been utilized to determine the etiology of some pediatric cardiac conditions for decades. However, new techniques, such as clinical whole exome sequencing, raise ethical challenges that must be addressed for the successful integration of these techniques into routine clinical care. One major ethical concern is the ability of patients to provide meaningful informed consent for this type of complex testing. A case of familial dilated cardiomyopathy with pediatric onset of unknown genetic etiology was utilized to facilitate the discussion of these issues by a panel including cardiologists, a geneticist, and a genetic counselor. Cardiologists and their medical genetics colleagues need to continue to discuss and investigate how to ethically integrate rapidly advancing genetic testing technologies into patient care to optimize potential benefits and minimize potential harms.
World journal for pediatric & congenital heart surgery. 01/2013; 4(1):58-61.
[Show abstract][Hide abstract] ABSTRACT: Acute aortic intramural hematoma (IMH) is an important subgroup of aortic dissection, and controversy surrounds appropriate management.
Patients with acute aortic syndromes in the International Registry of Acute Aortic Dissection (1996-2011) were evaluated to examine differences between patients (based on the initial imaging test) with IMH or classic dissection (AD). Of 2830 patients, 178 had IMH (64 type A [42%], 90 type B [58%], and 24 arch). Patients with IMH were older and presented with similar symptoms, such as severe pain. Patients with type A IMH were less likely to present with aortic regurgitation or pulse deficits and were more likely to have periaortic hematoma and pericardial effusion. Although type A IMH and AD were managed medically infrequently, type B IMH were more frequently treated medically. Overall in-hospital mortality was not statistically different for type A IMH compared to AD (26.6% versus 26.5%; P=0.998); type A IMH managed medically had significant mortality (40.0%), although less than classic AD (61.8%; P=0.195). Patients with type B IMH had a hospital mortality that was less but did not differ significantly (4.4% versus 11.1%; P=0.062) from classic AD. One-year mortality was not significantly different between AD and IMH.
Acute IMH has similar presentation to classic AD but is more frequently complicated with pericardial effusions and periaortic hematoma. Patients with IMH have a mortality that does not differ statistically from those with classic AD. A small subgroup of type A IMH patients are managed medically and have a significant in-hospital mortality.
[Show abstract][Hide abstract] ABSTRACT: Despite predictions of increased clinical applications, little is known about primary care providers' (PCPs') readiness to apply genomics to patient care. The aim was to assess PCPs' current experience with genetic testing, their assessment of the understandability and clinical utility of information in sample direct-to-consumer reports for genomic assessment of disease risk and warfarin dosing and attitudes toward genomic medicine.
A web-based survey of PCPs who are members of Knowledge Networks' Physician Consulting Network was conducted.
Of the 502 respondents (23.3% response rate), most ordered genetic tests infrequently. When presented with the direct-to-consumer genomic testing reports, most believed the reports were understandable, and would be willing to review results with a patient, and many believed the results would be helpful in patient management.
Despite limited experience with genetic tests, PCPs are open to helping patients understand genomic information. However, additional physician education is needed.
Personalized Medicine 09/2012; 9(7):683-692. · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chromosomal microarray analysis (CMA) has improved the diagnostic rate of genomic disorders in pediatric populations, but can produce uncertain and unexpected findings. This paper explores clinicians' perspectives and identifies challenges in effectively interpreting results and communicating with families about CMA. Responses to an online survey were obtained from 40 clinicians who had ordered CMA. Content included practice characteristics and perceptions, and queries about a hypothetical case involving uncertain and incidental findings. Data were analyzed using non-parametric statistical tests. Clinicians' comfort levels differed significantly for explaining uncertain, abnormal, and normal CMA results, with lowest levels for uncertain results. Despite clinical guidelines recommending informed consent, many clinicians did not consider it pertinent to discuss the potential for CMA to reveal information concerning biological parentage or predisposition to late-onset disease, in a hypothetical case. Many non-genetics professionals ordering CMA did not feel equipped to interpret the results for patients, and articulated needs for education and access to genetics professionals. This exploratory study highlights key challenges in the practice of genomic medicine, and identifies needs for education, disseminated practice guidelines, and access to genetics professionals, especially when dealing with uncertain or unexpected findings.
[Show abstract][Hide abstract] ABSTRACT: A considerable number of patients with acute type B aortic dissection (ABAD) treated with medical management alone will exhibit aortic enlargement during follow-up, which could lead to aortic aneurysm and rupture. The purpose of this study was to investigate predictors of aortic expansion among ABAD patients enrolled in the International Registry of Acute Aortic Dissection.
We analyzed 191 ABAD patients treated with medical therapy alone enrolled in the registry between 1996 and 2010, with available descending aortic diameter measurements at admission and during follow-up. The annual aortic expansion rate was calculated for all patients, and multivariate regression analysis was used to investigate factors affecting the expansion rate.
Aortic expansion was observed in 59% of ABAD patients; mean expansion rate was 1.7 ± 7 mm/y. In multivariate analysis, white race (regression coefficient [RC], 4.6; 95% confidence interval [CI], 1.4 to 7.7) and an initial aortic diameter less than 4.0 cm (RC, 6.3; 95% CI, 4.0 to 8.6) were associated with increased aortic expansion. Female sex (RC, -3.8; 95% CI, -6.1 to -1.4), intramural hematoma (RC, -3.8; 95% CI, -6.5 to -1.1), and use of calcium-channel blockers (RC, -3.8; 95% CI, -6.2 to -1.3) were associated with decreased aortic expansion.
White race and a small initial aortic diameter were associated with increased aortic expansion during follow-up, and decreased aortic expansion was observed among women, patients with intramural hematoma, and those on calcium-channel blockers. These data raise the possibility that the use of calcium-channel blockers after ABAD may reduce the rate of aortic expansion, and therefore further investigation is warranted.
The Annals of thoracic surgery 07/2012; 94(4):1223-9. · 3.45 Impact Factor