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Sameer J Khandhar,
Hirosada Yamamoto,
Jeffrey J Teuteberg,
Michael A Shullo,
Hiram G Bezerra,
Marco A Costa,
Faith Selzer,
Joon S Lee,
Oscar C Marroquin, Dennis M McNamara,
Suresh R Mulukutla,
Catalin Toma
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ABSTRACT: BACKGROUND: Optical coherence tomography (OCT) is a novel intravascular imaging modality with excellent spatial resolution. This study explored the utility of OCT in cardiac transplantation for the detection and characterization of early changes associated with coronary allograft vasculopathy (CAV). METHODS: Fifteen consecutive patients, 1 to 4 years after transplant with no angiographic evidence of CAV, underwent successful OCT imaging using the Fourier-domain OCT system (C7-XR, St. Jude Medical, St. Paul, MN) in the left anterior descending artery. Analysis included measurements of the lumen, intima, and media layers, and characterization of atherosclerotic plaques. Patients were stratified by intima-to-media (I/M) ratio and classified as normal (≤1) or abnormal (>1). RESULTS: Patients were a mean of 2.8 years after transplant, 58 years old, and 92% were men. OCT imaging revealed 8 of 15 patients had intimal hyperplasia with an I/M ratio >1. Comparing those with I/M ratio of ≤1 and >1, the median (interquartile range) intimal thickness was greater (75 [70-101] vs 206 [97-269]μm, p = 0.03), whereas the media thickness was no different (72 [70-103] vs 94 [73-113]μm, p = 0.53). In addition, 7 of 15 patients had lipid-rich or calcified atherosclerotic plaques. CONCLUSIONS: OCT provides high-resolution quantitative imaging of the coronary arteries and its use allows for detailed assessment of the coronary artery wall and early morphologic changes that occur after cardiac transplantation. The clinical predictive value of these OCT-derived measurements remains to be determined.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 03/2013; · 3.54 Impact Factor
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ABSTRACT: BACKGROUND: Heart transplantation in adults with congenital heart disease (CHD) has historically been associated with sub-optimal survival compared with other indications for transplantation. The purpose of this study was to evaluate survival outcomes after heart transplantation in a contemporary cohort of adults with CHD and to identify risk factors for mortality that may help guide recipient and donor selection. METHODS: We performed a retrospective analysis of our adult heart transplant database, from January 2001 to February 2011, identifying 19 patients who underwent transplantation for CHD. These patients were compared with a control group of 428 patients who underwent transplantation for indications other than CHD. Kaplan-Meier survival analysis and Cox regression modeling were performed. RESULTS: The mean age for the CHD group was 39.4 ± 13 years vs 54.7 ± 12 years (p < 0.001). There was no significant difference in survival (CHD vs control) at 30 days (89% vs 92%, p = 0.5567), 1 year (84% vs 86%, p = 0.6976) or 5 years (70% vs 72%, p = 0.8478). The only significant predictor of death in the CHD group was donor organ ischemic time >4 hours (HR 13.26, 95% CI 1.3 to 132.2, p = 0.028). There was no significant correlation with recipient age, history of failed Fontan surgery, pre-operative ventilator use, donor:recipient weight ratio <0.8, donor:recipient CMV mismatch, model for end-stage liver disease (MELD) score or percent reactive antibody >10%. CONCLUSIONS: In the modern era, with careful donor and recipient selection, adults with CHD have excellent early and mid-term survival after heart transplantation, rivaling that of recipients with other indications for transplantation.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 03/2013; · 3.54 Impact Factor
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John P Boehmer,
Randall C Starling,
Leslie T Cooper,
Guillermo Torre-Amione,
Ilan Wittstein,
G William Dec,
David W Markham,
Mark J Zucker,
John Gorcsan,
Charles McTiernan,
Kevin Kip, Dennis M McNamara
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ABSTRACT: Left ventricular assist device (LVAD) support as bridge to recovery (BTR) is uncommon for subjects with chronic heart failure. Myocardial recovery is more evident in recent onset nonischemic cardiomyopathy (ROCM); however, the prevalence of BTR in this subset has not been addressed.
We examined the use of LVAD support for subjects with ROCM in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) study. The overall cohort (n = 373) was 38% female, 21% black, with a mean age of 45 ± 14 years. LVAD support was used in 3.8% (n = 14, 43% female, age 32 ± 10). Of LVAD subjects, 57% (8/14) were BTR, including 73% (8/11) of subjects with symptoms ≤4 months at the time of support. Left ventricular end-diastolic diameter (LVEDD) was smaller in BTR than nonrecovered (NR) subjects (P = .04). Myocardial inflammation was more common in BTR (75% versus 0%, P = .005), whereas fibrosis was less evident (25% versus 100%, P = .005). Of BTR subjects, 7/8 (87.5%) were alive and free of transplant with median follow-up of 19 months.
In a multicenter registry of ROCM, BTR was common and occurred in the majority of subjects requiring LVAD support. Histology and LVEDD may assist in predicting potential for BTR in ROCM.
Journal of cardiac failure 10/2012; 18(10):755-61. · 3.25 Impact Factor
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Richard Sheppard,
Paul J Mather,
Jeffrey D Alexis,
Randall C Starling,
John P Boehmer,
Vinay Thohan,
Daniel F Pauly,
David W Markham,
Mark Zucker,
Kevin E Kip, Dennis M McNamara
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ABSTRACT: Given the potential for recovery in recent onset nonischemic cardiomyopathy (ROCM), the timing and need for implantable cardioverter-defibrillator (ICDs) remains controversial. We examined the utilization of ICDs and the impact on survival for subjects with ROCM.
An National Heart, Lung, and Blood Institute sponsored registry enrolled 373 subjects with ROCM, all with a left ventricular ejection fraction (LVEF) ≤0.40 and ≤6 months of symptoms. The mean age was 45 ± 14 years, 38% were female, 21% black, 75% New York Heart Association II/III, and the mean LVEF was 0.24 ± 0.08. Survival was comparable for subjects with an ICD within 1 month of entry (n = 43, 1/2/3 year % survival = 97/97/92) and those with no ICD at 1 month (n = 330, % survival = 98/97/95, P = .30) and between those with and without an ICD at 6 months (ICD, n = 73, 1/2/3 year % survival = 98/98/95; no ICD, n = 300, % survival = 98/96/95, P = .95). There were only 6 sudden cardiac deaths (SCD) noted (% survival free from SCD = 99/98/97) and these occurred in 1.9% of subjects without ICD and 0.9% of those with a device (P = .50).
In a multicenter cohort of ROCM the risk of SCD was low at 1% per year. Early ICD placement did not impact survival and can be deferred while assessing potential for myocardial recovery.
Journal of cardiac failure 09/2012; 18(9):675-81. · 3.25 Impact Factor
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Marwan M Refaat,
Steven A Lubitz,
Seiko Makino,
Zahid Islam,
J Michael Frangiskakis,
Haider Mehdi,
Rebecca Gutmann,
Michael L Zhang,
Heather L Bloom,
Calum A MacRae,
Samuel C Dudley,
Alaa A Shalaby,
Raul Weiss, Dennis M McNamara,
Barry London,
Patrick T Ellinor
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ABSTRACT: Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. The etiology of DCM is genetically heterogeneous.
We sought to define the prevalence of mutations in the RNA splicing protein RBM20 in a large cohort with DCM and to determine whether genetic variation in RBM20 is associated with clinical outcomes.
Subjects included in the Genetic Risk Assessment of Defibrillator Events (GRADE) study were aged at least 18 years, had an ejection fraction of ≤30%, and an implantable cardioverter-defibrillator (ICD). The coding region and splice junctions of RBM20 were screened in subjects with DCM; 2 common polymorphisms in RBM20, rs942077 and rs35141404, were genotyped in all GRADE subjects.
A total of 1465 subjects were enrolled in the GRADE study, and 283 with DCM were screened for RBM20 mutations. The mean age of subjects with DCM was 58 ± 13 years, 64% were males, and the mean follow-up time was 24.2 ± 17.1 months after ICD placement. RBM20 mutations were identified in 8 subjects with DCM (2.8%). Mutation carriers had a similar survival, transplantation rate, and frequency of ICD therapy compared with nonmutation carriers. Three of 8 subjects with RBM20 mutations (37.5%) had atrial fibrillation (AF), whereas 19 subjects without mutations (7.4%) had AF (P = .02). Among all GRADE subjects, rs35141404 was associated with AF (minor allele odds ratio = 0.62; 95% confidence interval = 0.44-0.86; P = .006). In the subset of GRADE subjects with DCM, rs35141404 was associated with AF (minor allele odds ratio = 0.58; P = .047).
Mutations in RBM20 were observed in approximately 3% of subjects with DCM. There were no differences in survival, transplantation rate, and frequency of ICD therapy in mutation carriers.
Heart rhythm: the official journal of the Heart Rhythm Society 03/2012; 9(3):390-6. · 4.56 Impact Factor
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Journal of the American College of Cardiology 02/2012; 59(8):776-7. · 14.16 Impact Factor
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ABSTRACT: AimsBecause benefits of cardiac resynchronization therapy (CRT) appear to be less favourable in non-left bundle branch block (LBBB) patients, this prospective longitudinal study tested the hypothesis that QRS morphology and echocardiographic mechanical dyssynchrony were associated with long-term outcome after CRT.Methods and resultsTwo-hundred and seventy-eight consecutive New York Heart Association class III and IV CRT patients with QRS ≥120 ms and ejection fraction ≤35% were studied. The pre-specified primary endpoint was death, heart transplant, or left ventricular assist device over 4 years. Dyssynchrony assessed before CRT included interventricular mechanical delay (IVMD) and speckle-tracking radial strain using pre-specified cut-offs for each. Of 254 with baseline quantitative echocardiographic data available, 128 had LBBB, 81 had intraventricular conduction delay (IVCD), and 45 had right bundle branch block (RBBB). Radial dyssynchrony was observed in 85% of the patients with LBBB, 59% with IVCD*, and 40% with RBBB* (*P < 0.01 vs. LBBB). Of 248 (98%) with follow-up, LBBB patients had a significantly more favourable long-term survival than non-LBBB patients. However, non-LBBB patients with dyssynchrony had a more favourable event-free survival than those without dyssynchrony: radial dyssynchrony hazard ratio 2.6, 95% confidence interval (CI) 1.47-4.53 (P = 0.0008) and IVMD hazard ratio 4.9, 95% CI 2.60-9.16 (P = 0.0007). Right bundle branch block patients who lacked dyssynchrony had the least favourable outcome.ConclusionNon-LBBB patients with dyssynchrony had a more favourable long-term survival than non-LBBB patients who lacked dyssynchrony. Mechanical dyssynchrony and QRS morphology are associated with outcome following CRT.
European Heart Journal 02/2012; · 10.48 Impact Factor
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Leslie T Cooper,
Paul J Mather,
Jeffrey D Alexis,
Daniel F Pauly,
Guillermo Torre-Amione,
Ilan S Wittstein,
G William Dec,
Mark Zucker,
Jagat Narula,
Kevin Kip, Dennis M McNamara
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ABSTRACT: Whether myocardial recovery occurs more frequently in peripartum cardiomyopathy (PPCM) than in recent onset cardiomyopathies in men and nonperipartum women has not been prospectively evaluated. This was examined through an analysis of outcomes in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) registry.
IMAC2 enrolled 373 subjects with recent onset nonischemic dilated cardiomyopathy. Left ventricular ejection fraction (LVEF) was assessed at entry and 6 months, and subjects followed for up to 4 years. Myocardial recovery was compared between men (group 1), nonperipartum women (group 2) and subjects with PPCM (group 3). The cohort included 230 subjects in group 1, 104 in group 2, and 39 in group 3. The mean LVEF at baseline in groups 1, 2, and 3 was 0.23 ± 0.08, 0.24 ± 0.08, and 0.27 ± 0.07 (P = .04), and at 6 months was 0.39 ± 0.12, 0.42 ± 0.11, and 0.45 ± 0.14 (P = .007). Subjects in group 3 had a much greater likelihood of achieving an LVEF >0.50 at 6 months than groups 1 or 2 (19 %, 34%, and 48% respectively, P = .002).
Prospective evaluation confirms myocardial recovery is greatest in women with PPCM, poorest in men, and intermediate in nonperipartum women. On contemporary therapy, nearly half of women with PPCM normalize cardiac function by 6 months.
Journal of cardiac failure 01/2012; 18(1):28-33. · 3.25 Impact Factor
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ABSTRACT: Hyperhomocysteinaemia is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial dysfunction. Homocysteine modulates cellular methylation reactions. P66shc is a protein that promotes oxidative stress whose expression is governed by promoter methylation. We asked if homocysteine induces endothelial p66shc expression via hypomethylation of CpG dinucleotides in the p66shc promoter, and whether p66shc mediates homocysteine-stimulated endothelial cell dysfunction.
Homocysteine stimulates p66shc transcription in human endothelial cells and hypomethylates specific CpG dinucleotides in the human p66shc promoter. Knockdown of p66shc inhibits the increase in reactive oxygen species, and decrease in nitric oxide, elicited by homocysteine in endothelial cells and prevents homocysteine-induced up-regulation of endothelial intercellular adhesion molecule-1. In addition, knockdown of p66shc mitigates homocysteine-induced adhesion of monocytes to endothelial cells. Inhibition of DNA methyltransferase activity or knockdown of DNA methyltransferase 3b abrogates homocysteine-induced up-regulation of p66shc. Comparison of plasma homocysteine in humans with coronary artery disease shows a significant difference between those with highest and lowest p66shc promoter CpG methylation in peripheral blood leucocytes.
Homocysteine up-regulates human p66shc expression via hypomethylation of specific CpG dinucleotides in the p66shc promoter, and this mechanism is important in homocysteine-induced endothelial cell dysfunction.
Cardiovascular research 09/2011; 92(3):466-75. · 5.80 Impact Factor
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ABSTRACT: We sought to determine clinical and demographic predictors of recovery of left ventricular function for subjects with recent onset cardiomyopathy (ROCM).
Although ROCM is a frequent reason for consultation and transplantation referral, its prognosis and natural history on contemporary therapy are unknown.
In the multicenter IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study, subjects with a left ventricular ejection fraction (LVEF) of ≤0.40, fewer than 6 months of symptom duration, and an evaluation consistent with idiopathic dilated cardiomyopathy or myocarditis were enrolled. LVEF was reassessed at 6 months, and subjects were followed up for 4 years. LVEF and event-free survival were compared by race, sex, and clinical phenotype.
The cohort of 373 persons was 38% female and 21% black, with a mean age of 45 ± 14 years. At entry, 91% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and 82% were receiving beta-blockers, which increased to 92% and 94% at 6 months. LVEF was 0.24 ± 0.08 at entry and 0.40 ± 0.12 at 6 months (mean increase: 17 ± 13 ejection fraction units). Transplant-free survival at 1, 2, and 4 years was 94%, 92%, and 88%, respectively; survival free of heart failure hospitalization was 88%, 82%, and 78%, respectively. In analyses adjusted for sex, baseline LVEF, and blood pressure, LVEF at 6 months was significantly lower in blacks than in nonblacks (p = 0.02). Left ventricular end-diastolic diameter at presentation was the strongest predictor of LVEF at 6 months (p < 0.0001).
Outcomes in ROCM are favorable but differ by race. Left ventricular end-diastolic diameter by transthoracic echo at presentation was most predictive of subsequent myocardial recovery. (Genetic Modulation of Left Ventricular Recovery in Recent Onset Cardiomyopathy; NCT00575211).
Journal of the American College of Cardiology 09/2011; 58(11):1112-8. · 14.16 Impact Factor
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ABSTRACT: The purpose of this study was to evaluate mechanical dyssynchrony in patients with acute onset cardiomyopathy with narrow QRS interval, and its association with improvements in left ventricular (LV) function.
LV dyssynchrony has been usually studied in patients with chronic heart failure and wide QRS in the context of cardiac resynchronization therapy.
We studied 201 patients enrolled in the IMAC-2 (Inflammatory Mediators in Acute Cardiomyopathy) trial with recent onset nonischemic cardiomyopathy and ejection fraction <40%. Dyssynchrony was assessed using speckle-tracking velocity vector imaging. Diastolic function was assessed by mitral inflow E and mitral E' annular velocities (E/E'). A normal control group of 15 normal volunteers was studied for comparison.
Although mean QRS was narrow (98 ± 21 ms), 108 (54%) acute cardiomyopathy patients had significant LV dyssynchrony at presentation: opposing wall delay 89 ± 51 ms, versus 35 ± 11 ms in controls, and 12-site standard deviation 43 ± 23, versus 24 ± 8 ms in controls (p < 0.001). Patients with dyssynchrony had greater degrees of diastolic dysfunction: E/E' 15 ± 8 versus 12 ± 6 (p < 0.05). At 6 months, group mean ejection fraction improved from 23 ± 8% to 40 ± 12% and E/E' improved from 14 ± 7 to 9 ± 5 (both p < 0.001). Dyssynchrony improved from 89 ± 51 ms to 52 ± 35 ms in maximum opposing wall delay, and 43 ± 23 ms to 32 ± 19 ms in 12-site standard deviation, and the prevalence of dyssynchrony decreased to 12% after 6 months (p < 0.001 vs. baseline).
Mechanical dyssynchrony was observed in a significant number of patients with acute onset cardiomyopathy, despite having a narrow QRS interval. Resolution of dyssynchrony associated with improvements in LV function occurred in the large majority of these patients.
JACC. Cardiovascular imaging 05/2011; 4(5):445-56. · 14.29 Impact Factor
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ABSTRACT: Calcineurin inhibitor (CNI)-associated renal insufficiency is common after cardiac transplantation (CTX); however, the addition of sirolimus allows for CNI dose reduction and this strategy may limit CNI renal toxicity. This study examines the long-term effects of such a strategy. METHODS: Patients from a single center who had CTX from 1990 to 2007 and who were converted to sirolimus and a dose-reduced CNI were compared to group-matched controls maintained on CNI and an antiproliferative agent. RESULTS: One hundred and fifty-five patients (79 sirolimus and 76 controls) were included and had similar baseline characteristics. Sirolimus was started a mean of 1429 d post-CTX and maintained for a mean of 823 d. Reason for conversion to sirolimus was renal insufficiency (34%), vasculopathy (29%), recurrent rejection (19%), and other (18%). The eGFR was not different between groups at baseline (44.7 mL/min/1.73 m(2) vs. 46.0, p = 0.64) or at any point during follow-up: 90 d, 180 d, 1 yr, 2 yr, and 3 yr. conclusion: Patients converted to a regimen of sirolimus and a dosed-reduced CNI have stable renal function over the following three yr, but do not have an improvement in renal outcomes compared to patients maintained on full dose CNI.
Clinical Transplantation 02/2011; 26(1):42-9. · 1.67 Impact Factor
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Qi Chen,
Steven E Reis,
Candace Kammerer,
Wendy Craig, Dennis M McNamara,
Richard Holubkov,
Barry L Sharaf,
George Sopko,
Daniel F Pauly,
C Noel Bairey Merz,
M Ilyas Kamboh
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ABSTRACT: Atherosclerosis is the major cause of coronary artery disease (CAD), and oxidized LDL (oxLDL) is believed to play a key role in the initiation of the atherosclerotic process. Recent studies show that inflammation and autoimmune reactions are also relevant in atherosclerosis. In this study, we examined the association of antibodies against oxLDL (anti-oxLDL) with the severity of CAD in 558 Women's Ischemia Syndrome Evaluation (WISE) study samples (465 whites; 93 blacks) determined by coronary stenosis (< 20%, 20%-49%, > 50% stenosis). We also examined the relationship of anti-oxLDL with serum lipid levels and nine candidate genes including APOE, APOH, APOA5, LPL, LRP1, HL, CETP, PON1, and OLR1. IgM anti-oxLDL levels were significantly higher in the >20% stenosis group than in the ≥ 20% stenosis group in whites (0.69 ± 0.02 vs. 0.64 ± 0.01, respectively; P = 0.02). IgM anti-oxLDL levels correlated significantly with total cholesterol (r² = 0.01; P = 0.03) and LDL cholesterol (r² = 0.017; P = 0.004) in whites. Multiple regression analysis revealed a suggestive association of LPL/S447X single-nucleotide polymorphism (SNP) with both IgG anti-oxLDL (P = 0.02) and IgM anti-oxLDL (P = 0.07), as well as between IgM anti-oxLDL and the OLR1/3'UTR SNP (P = 0.020). Our data suggest that higher IgM anti-oxLDL levels may provide protection against coronary stenosis and that genetic variation in some candidate genes are determinants of anti-oxLDL levels.
The Journal of Lipid Research 01/2011; 52(4):801-7. · 5.56 Impact Factor
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ABSTRACT: The ability of echocardiographic dyssynchrony to predict response to cardiac resynchronization therapy (CRT) has been unclear.
A prospective, longitudinal study was designed with predefined dyssynchrony indexes and outcome variables to test the hypothesis that baseline dyssynchrony is associated with long-term survival after CRT. We studied 229 consecutive class III to IV heart failure patients with ejection fraction ≤35 and QRS duration ≥120 milliseconds for CRT. Dyssynchrony before CRT was defined as tissue Doppler velocity opposing-wall delay ≥65 milliseconds, 12-site SD (Yu Index) ≥32 milliseconds, speckle tracking radial strain anteroseptal-to-posterior wall delay ≥130 milliseconds, or pulsed Doppler interventricular mechanical delay ≥40 milliseconds. Outcome was defined as freedom from death, heart transplantation, or left ventricular assist device implantation. Of 210 patients (89) with dyssynchrony data available, there were 62 events: 47 deaths, 9 transplantations, and 6 left ventricular assist device implantations over 4 years. Event-free survival was associated with Yu Index (P=0.003), speckle tracking radial strain (P=0.003), and interventricular mechanical delay (P=0.019). When adjusted for confounding baseline variables of ischemic origin and QRS duration, Yu Index and radial strain dyssynchrony remained independently associated with outcome (P<0.05). Lack of radial dyssynchrony was particularly associated with unfavorable outcome in those with QRS duration of 120 to 150 milliseconds (P=0.002).
The absence of echocardiographic dyssynchrony was associated with significantly less favorable event-free survival after CRT. Patients with narrower QRS duration who lacked dyssynchrony had the least favorable long-term outcome. These observations support the relationship of dyssynchrony and CRT response.
Circulation 10/2010; 122(19):1910-8. · 14.74 Impact Factor
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Circulation Cardiovascular Genetics 06/2010; 3(3):226-8. · 6.11 Impact Factor
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ABSTRACT: Myocardial recovery after ventricular assist devices (VAD) is rare but appears more common in nonischemic cardiomyopathies (NICM). We sought to evaluate left ventricular (LV) end diastolic diameter (LVEDD) for predicting recovery after VAD.
NICM patients receiving long-term mechanical support between 1996 and 2008 were reviewed. Subjects were divided into 3 groups: mild, moderate, and severe dilation (Group A: LVEDD <6.0 cm [n = 22]; Group B: 6.0-7.0 cm [n = 32]; Group C: >7.0 cm [n = 48], respectively). Overall, recovery (successful explant without transplantation) occurred in 14 of 102 subjects (14%). Of these, 2 died and 2 required transplantation within 1 year. Recovery was more common in patients without LV dilation (Groups A/B/C = 32%/22%/0%, P < .001), as was sustained recovery (alive and transplant free 1 year after explant; A/B/C = 27%/10%/0%, P = .001). Of the recovery patients in Group A, 6/7 (86%) had sustained recovery versus 3/6 (50%) in Group B.
Recovery occurred in 32% of NICM patients without significant LV dilation at time of VAD, the majority of whom experienced significant sustained recovery. Recovery was not evident in those with severe LV dilation. Routine echocardiography at the time of implant may assist in targeting patients for recovery after VAD.
Journal of cardiac failure 02/2010; 16(2):99-105. · 3.25 Impact Factor
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Dennis M McNamara
Heart Failure Clinics 01/2010; 6(1):xv-xvi.
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Dennis M McNamara
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ABSTRACT: Neurohormonal activation is an important driver of heart-failure progression, and all pharmacologic interventions that improve heart-failure survival inhibit this systemic response to myocardial injury. Adrenergic stimulation of beta(1) receptors in the kidney results in the release of plasma renin, the conversion of peptide precursors to angiotensin II (a2), and ultimately the production of aldosterone. beta(1)-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone receptor antagonists all act by inhibiting the activity of critical protein of this core pathway: the beta(1) receptor, ACE, the a2 receptor, and aldosterone synthase. Investigation of the pharmacogenetic interactions of the ACE D/I polymorphism and heart-failure therapy demonstrates the power of genomics to target therapeutics. This review explores how genetic variation in genes involved in neurohormonal activation influences heart-failure outcomes and the impact of pharmacotherapy.
Heart Failure Clinics 01/2010; 6(1):35-43.
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Dennis M McNamara,
S William Tam,
Michael L Sabolinski,
Page Tobelmann,
Karen Janosko,
Lakshmi Venkitachalam,
Elizabeth Ofili,
Clyde Yancy,
Arthur M Feldman,
Jalal K Ghali,
Anne L Taylor,
Jay N Cohn,
Manuel Worcel
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ABSTRACT: Genetic heterogeneity at the endothelial nitric oxide synthase (NOS3) locus influences heart failure outcomes. The prevalence of NOS3 variants differs in black and white cohorts, but the impact of these differences is unknown.
Subjects (n = 352) in the Genetic Risk Assessment of Heart Failure (GRAHF) substudy of the African-American Heart Failure Trial were genotyped for NOS3 polymorphisms: -786 T/C promoter, intron 4a/4b, and Glu298Asp and allele frequencies and compared with a white heart failure cohort. The effect of treatment with fixed-dose combination of isosorbide dinitrates and hydralazine (FDC I/H) on event-free survival and composite score (CS) of survival, hospitalization, and quality of life (QoL) was analyzed within genotype subsets. In GRAHF, NOS3 genotype frequencies differed from the white cohort (P < .001). The -786 T allele was associated with lower left ventricular ejection fraction (LVEF) (P = .01), whereas the intron 4a allele was linked to lower diastolic blood pressure and higher LVEF (P = .03). Only the Glu298Asp polymorphism influenced treatment outcome; therapy with FDC I/H improved CS (P = .046) and QoL (P = .03) in the Glu298Glu subset only.
In black subjects with heart failure, NOS3 genotype influences blood pressure and left ventricular remodeling. The impact of genetic heterogeneity on treatment with FDC I/H requires further study.
Journal of cardiac failure 05/2009; 15(3):191-8. · 3.25 Impact Factor
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ABSTRACT: Left ventricular assist device (LVAD) support may facilitate myocardial recovery. We evaluated the impact of LVAD support on Fas expression in a cohort with end-stage heart failure. Myocardial gene expression was assessed pre- and post-LVAD by RNase protection assay and compared to control donor hearts. The expression of Fas is markedly elevated at the time of LVAD support and is tightly correlated with TNF expression. While interleukin (IL)-6 was significantly reduced by LVAD support, the impact of support on Fas was highly variable and tightly linked to tumor necrosis factor (TNF). The role of Fas in predicting recovery after LVAD support requires further investigation.
Clinical and Translational Science 12/2008; 1(3):245-8. · 1.13 Impact Factor
