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Clinico-pathological mismatch of etiological classification in heart failure: preponderance and clinical implications
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Journal of Cardiac Failure Vol. 10 No. 4 Suppl. 2004
Cardiovascular Structure 080
082
Atrial Natriuretic Peptide Gene Load Modulates Pressure Overload-induced Cardiac Remodeling Veronica Franco, Yiu Fai Chen, Ji An Feng, Fadi Hage, Dajun Wang, Suzanne Oparil, Gilbert Perry; Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
Association of Renal Insufficiency with Eccentric Left Ventricular Hypertrophy in Patients with Renal Artery Stenosis George T. Maly,1 Samer J. Khouri,1 Hari B. Nair,1 David J. Kennedy,1 Mark W. Burket,1 William J. Thomas,1 Joseph I. Shapiro,1 Christopher J. Cooper1; 1Division of Cardiology, Medical College of Ohio, Toledo, OH
Background: We have previously shown that mice with homozygous deletion of the pro-atrial natriuretic peptide (ANP, Nppa⫺/⫺) gene exhibit left ventricular (LV) hypertrophy at baseline and exaggerated hypertrophy after pressure overload induced by transverse aortic constriction (TAC). Nppa⫺/⫺ mice have increased expression of extracellular matrix molecules, metalloproteinase-2, tissue inhibitor of metalloproteinase-3 and exaggerated cardiac remodeling after TAC. Hypothesis: A single copy of the pro-ANP (Nppa⫹/⫺) gene will not be adequate to protect heterozygous mice against exaggerated LV hypertrophy resulting from pressure overload stress. Therefore, Nppa⫹/⫺ mice will have exaggerated cardiac remodeling compared to wild type Nppa⫹/⫹ mice after TAC. Cardiac remodeling in Nppa⫹/⫺ mice will be less marked than in Nppa⫺/⫺ animals. Methods: Nppa⫹/⫹, Nppa⫹/⫺ and Nppa⫺/⫺ mice were subjected to TAC. Mice were fed a basal salt diet. One week after TAC, echocardiogram was performed. Subsequently, blood was collected for plasma ANP quantification, and hearts were removed and weighted. Heart and echocardiographic measurements were normalized by ANCOVA, using the body weight as a covariate. The LV was divided in 2 sections, one for collagen volume evaluation by picrosirious red stain and the second one for LV ANP, collagen I and collagen III mRNA expression. Results were analyzed by 2-way ANOVA. Results: Nppa⫹/⫺ mice exhibit exaggerated LV hypertrophy compared to Nppa⫹/⫹ mice, but less than the Nppa⫺/⫺ mice. There was a significant interaction (p⬍0.05) between genotype x TAC on LV weight, LV end-diastolic dimension (EDD), LV ejection fraction (LVEF), LV collagen volume, and LV collagen I and III mRNA expression. Conclusion: Cardiac remodeling
Introduction: Observational studies have consistently demonstrated high cardiovascular event rates in patients with renal artery stenosis (RAS) that present with renal insufficiency. However, no study has yet established in this population a clear linkage between renal insufficiency and changes in cardiac structure. Hypothesis: Left ventricle hypertrophy (LVH) is an independent risk factor for increased cardiac morbidity and mortality. Thus, the current study was undertaken to 1) evaluate the prevalence of LVH in this population and describe the patterns of hypertrophy, and 2) determine whether renal insufficiency or other baseline factors influence the frequency or pattern of LVH. Methods: The population is a cohort of 78 patients out of 244 patients undergoing stenting for renal artery stenosis, who had an echocardiogram prior to the intervention. LVH was determined in all the patients and categorized into normal, concentric hypertrophy and eccentric hypertrophy using left ventricular mass index (LVMI) using the criteria of Devereux (LVMI ⬎134 g/m2 for men and ⬎110g/m2 for women), and relative wall thickness (RWT) was calculated as the 2 X posterior to end diastolic diameter ratio (a value of 0.44 was taken as the partition value to distinguish between LVH phenotypes). Baseline clinical characteristics and the indications for renal stenting were compared to the left ventricular geometry. Results: The baseline clinical characteristics of the patients who had echocardiogram (n ⫽ 78) were similar (p ⫽ NS) to the patients who did not have an echocardiogram (n ⫽ 166). The mean left ventricular mass index (LVMI) in the 78 patients was 117 ⫾ 40 g/m2 and 38% of the patients had LVH. Among the 30 patients with LVH, 13 (43%) had concentric hypertrophy and 17 (57%) had eccentric hypertrophy. Patients with eccentric hypertrophy were more likely to have renal insufficiency (53% vs 19%, 23%, p ⫽ 0.02) and heart failure as the indication for renal artery stenting (47% vs 16%, 23%, p ⫽ 0.04). Conclusions: In patients with renal artery stenosis undergoing stenting, there is a high prevalence of LVH (38%), which is consistent with previously published studies. The current study demonstrating a strong association of chronic renal insufficiency with eccentric hypertrophy might be a major factor that contributes to the increased morbidity and mortality in patients with renal artery stenosis presenting with renal insufficiency.
083
after pressure overload is negatively associated with ANP gene load. The heterozygous Nppa⫹/⫺ mouse is a novel model for studying LV hypertrophy and the transition to failure during pressure overload stress. It is less abnormal than Nppa⫺/⫺ at baseline and may more closely resemble the human condition.
081 Clinico-Pathological Mismatch of Etiological Classification in Heart Failure: Preponderance and Clinical Implications Patricia A. Uber,1 Zola M. N’Dandu,1 Robert L. Scott,1 Myung H. Park,1 Hector O. Ventura,1 Mandeep R. Mehra1; 1Department Of Cardiovascular Medicine, Ochsner Clinic Foundation, New Orleans, LA Background: The clinical classification of heart failure that demarcates etiology into ischemic and non-ischemic cardiomyopathy is suggested to guide therapy. Typically, those with an ischemic substrate demonstrate a worse prognosis and are considered candidates for treatment strategies targeted towards modification of the ischemic substrate. Since considerable overlap in these diagnostic strata exists and the extent of clincial misclassification remains unknown, we sought to review the preponderance and implications of such misclassification by reviewing the final pathological diagnosis. Methods: Between 1/1992-8/2003, 112 patients with the clinical etiological diagnosis of non-ischemic cardiomyopathy (confirmed by a heart failure specialist) underwent heart transplantation. Patients were excluded if they were ⬍35 years old, had congenital heart disease, myocarditis, peripartum cardiomyopathy, primary valvular heart disease or infiltrative disease. The recipient heart was examined histopathologically and a pathologist blinded to clinical information classified the etiology of heart failure. Ischemic cardiomyopathy was defined as the presence of severe 3-vessel coronary disease (CAD) with myocardial scar (definition derived from analysis of 51 control hearts with ischemic cardiomyopathy confirmed on pathological analysis). Presence of significant CAD and ante-mortem myocardial ischemia were also analyzed. Results: The study included 112 patients (age 57 ⫾ 9 years, 71%men) with severe ventricular dysfunction (LVEF 19 ⫾ 11%) and non-ischemic cardiomyopathy as the diagnosis at cardiac transplant. 21% (23/112) were reclassified pathologically as ischemic cardiomyopathy. Of those accurately classified (89/112), 33% (29/89) were found to have at least moderate-severe CAD in ⱖ 1 vessel territory with or without infarction. Additionally, 18% (16/89) explanted hearts were noted to have areas compatible with recent ischemia (occlusive thrombus or ischemic infarction). Those patients with mis-classification were older (59 ⫾ 7 versus 53 ⫾ 8 years, p0.001) and had a shorter interval from listing to transplantation (44 months versus 58 months, p0.05). Inferences: This investigation suggests a high prevalence of etiological mis-diagnosis in advanced heart failure. The diagnosis of non-ischemic cardiomyopathy greatly underestimates the potential pathological contribution of concomitant coronary arteriopathy to disease progression and might steer the clinician away from opportunities for therapeutic intervention.
Early Detection of the Cardiomyopathy of Duchenne Muscular Dystrophy is Enhanced by Tissue Doppler Imaging and Myocardial Performance Index Tayyab Mohyuddin,1 Robert S. Finkelhor,1 Irwin B. Jacobs,2 Robert C. Bahler1; 1 Heart and Vascular Center, MetroHealth Medical Center, Cleveland, OH; 2Pediatrics, MetroHealth Medical Center, Cleveland, OH Background: Two-dimensional echo is the current method for detection of LV dysfunction in Duchenne muscular dystrophy (DMD), yet complete 2-D imaging is suboptimal in most DMD patients. Tissue Doppler velocities (TDV) are abnormal in a number of cardiac conditions when standard indices of LV function are normal. Hypothesis: Detection of left ventricular dysfunction in DMD is enhanced by TDV. Methods: We report TDV data in 31 DMD patients (median age 17.5 yrs, range 1134) and 13 age-matched controls. Thirty patients were wheelchair dependent; 14 required ventilation support. Standard 2-D images were sought. LV fractional shortening (FS) was obtained from the parasternal long-axis view. LV ejection fraction (LVEF) was a visual estimate since image quality was inadequate for quantitation. TDV were recorded from the septal and lateral aspects of the mitral annulus from an apical 4chamber view. Offline measurements were obtained from digital images and reported as the average of 3 beats. Myocardial performance index (MPI) was derived from the septal recording of TDV and calculated as: [(isovolumic contraction time ⫹ isovolumic relaxation time ⫹ diastolic filling time) - ejection time]/ejection time. Abnormal TDV were defined as outside the 95% normal confidence limits reported for 131 healthy children. Results: TDV data could be recorded in 26 patients and all 13 controls. DMD patients had significantly lower TDV, particularly in early diastole, and the MPI was higher. Comparison of DMD versus Controls
Parameter
Septal S cm/s
Septal E cm/s
Lateral S cm/s
Lateral E cm/s
FS (%)
LVEF (%)
DMD 6.7 ⫾ 1.4** 8.7 ⫾ 2.0* 7.5 ⫾ 2.0* 10.9 ⫾ 3.2* 23 ⫾ 10* 47 ⫾ 13* Controls 8.3 ⫾ 1.4 12.8 ⫾ 2.6 11.1 ⫾ 2.4 17.3 ⫾ 4.4 37.3 ⫾ 3 61 ⫾ 4 Number 2/26 21/26 12/22 15/22 25/31 12/30 abnormal
MPI 0.56 ⫾ 0.22* 0.31 ⫾ 07 19/24
* p ⬍ 0.001, ** p ⬍ 0.01
All patients with abnormal FS had abnormal TDV; all patients with normal TDV had normal FS. Abnormal TDV occurred in 2/6 patients despite a normal FS. An abnormal MPI (⬎0.40) was a more sensitive indicator of global LV dysfunction than the visual estimate of ejection fraction (p⬍0.01). Only 1 patient had normal values for both TDV and MPI. In DMD patients TDV were inversely related to age (p⬍0.01) and MPI was directly related (p⬍0.01). Conclusion: Detection of abnormal LV function in DMD patients is improved by both the measurement of TDV and the calculation of MPI from the TDV recording.
Journal of Cardiac Failure Vol. 10 No. 4 Suppl. 2004
Cardiovascular Structure 080
082
Atrial Natriuretic Peptide Gene Load Modulates Pressure Overload-induced Cardiac Remodeling Veronica Franco, Yiu Fai Chen, Ji An Feng, Fadi Hage, Dajun Wang, Suzanne Oparil, Gilbert Perry; Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
Association of Renal Insufficiency with Eccentric Left Ventricular Hypertrophy in Patients with Renal Artery Stenosis George T. Maly,1 Samer J. Khouri,1 Hari B. Nair,1 David J. Kennedy,1 Mark W. Burket,1 William J. Thomas,1 Joseph I. Shapiro,1 Christopher J. Cooper1; 1Division of Cardiology, Medical College of Ohio, Toledo, OH
Background: We have previously shown that mice with homozygous deletion of the pro-atrial natriuretic peptide (ANP, Nppa⫺/⫺) gene exhibit left ventricular (LV) hypertrophy at baseline and exaggerated hypertrophy after pressure overload induced by transverse aortic constriction (TAC). Nppa⫺/⫺ mice have increased expression of extracellular matrix molecules, metalloproteinase-2, tissue inhibitor of metalloproteinase-3 and exaggerated cardiac remodeling after TAC. Hypothesis: A single copy of the pro-ANP (Nppa⫹/⫺) gene will not be adequate to protect heterozygous mice against exaggerated LV hypertrophy resulting from pressure overload stress. Therefore, Nppa⫹/⫺ mice will have exaggerated cardiac remodeling compared to wild type Nppa⫹/⫹ mice after TAC. Cardiac remodeling in Nppa⫹/⫺ mice will be less marked than in Nppa⫺/⫺ animals. Methods: Nppa⫹/⫹, Nppa⫹/⫺ and Nppa⫺/⫺ mice were subjected to TAC. Mice were fed a basal salt diet. One week after TAC, echocardiogram was performed. Subsequently, blood was collected for plasma ANP quantification, and hearts were removed and weighted. Heart and echocardiographic measurements were normalized by ANCOVA, using the body weight as a covariate. The LV was divided in 2 sections, one for collagen volume evaluation by picrosirious red stain and the second one for LV ANP, collagen I and collagen III mRNA expression. Results were analyzed by 2-way ANOVA. Results: Nppa⫹/⫺ mice exhibit exaggerated LV hypertrophy compared to Nppa⫹/⫹ mice, but less than the Nppa⫺/⫺ mice. There was a significant interaction (p⬍0.05) between genotype x TAC on LV weight, LV end-diastolic dimension (EDD), LV ejection fraction (LVEF), LV collagen volume, and LV collagen I and III mRNA expression. Conclusion: Cardiac remodeling
Introduction: Observational studies have consistently demonstrated high cardiovascular event rates in patients with renal artery stenosis (RAS) that present with renal insufficiency. However, no study has yet established in this population a clear linkage between renal insufficiency and changes in cardiac structure. Hypothesis: Left ventricle hypertrophy (LVH) is an independent risk factor for increased cardiac morbidity and mortality. Thus, the current study was undertaken to 1) evaluate the prevalence of LVH in this population and describe the patterns of hypertrophy, and 2) determine whether renal insufficiency or other baseline factors influence the frequency or pattern of LVH. Methods: The population is a cohort of 78 patients out of 244 patients undergoing stenting for renal artery stenosis, who had an echocardiogram prior to the intervention. LVH was determined in all the patients and categorized into normal, concentric hypertrophy and eccentric hypertrophy using left ventricular mass index (LVMI) using the criteria of Devereux (LVMI ⬎134 g/m2 for men and ⬎110g/m2 for women), and relative wall thickness (RWT) was calculated as the 2 X posterior to end diastolic diameter ratio (a value of 0.44 was taken as the partition value to distinguish between LVH phenotypes). Baseline clinical characteristics and the indications for renal stenting were compared to the left ventricular geometry. Results: The baseline clinical characteristics of the patients who had echocardiogram (n ⫽ 78) were similar (p ⫽ NS) to the patients who did not have an echocardiogram (n ⫽ 166). The mean left ventricular mass index (LVMI) in the 78 patients was 117 ⫾ 40 g/m2 and 38% of the patients had LVH. Among the 30 patients with LVH, 13 (43%) had concentric hypertrophy and 17 (57%) had eccentric hypertrophy. Patients with eccentric hypertrophy were more likely to have renal insufficiency (53% vs 19%, 23%, p ⫽ 0.02) and heart failure as the indication for renal artery stenting (47% vs 16%, 23%, p ⫽ 0.04). Conclusions: In patients with renal artery stenosis undergoing stenting, there is a high prevalence of LVH (38%), which is consistent with previously published studies. The current study demonstrating a strong association of chronic renal insufficiency with eccentric hypertrophy might be a major factor that contributes to the increased morbidity and mortality in patients with renal artery stenosis presenting with renal insufficiency.
083
after pressure overload is negatively associated with ANP gene load. The heterozygous Nppa⫹/⫺ mouse is a novel model for studying LV hypertrophy and the transition to failure during pressure overload stress. It is less abnormal than Nppa⫺/⫺ at baseline and may more closely resemble the human condition.
081 Clinico-Pathological Mismatch of Etiological Classification in Heart Failure: Preponderance and Clinical Implications Patricia A. Uber,1 Zola M. N’Dandu,1 Robert L. Scott,1 Myung H. Park,1 Hector O. Ventura,1 Mandeep R. Mehra1; 1Department Of Cardiovascular Medicine, Ochsner Clinic Foundation, New Orleans, LA Background: The clinical classification of heart failure that demarcates etiology into ischemic and non-ischemic cardiomyopathy is suggested to guide therapy. Typically, those with an ischemic substrate demonstrate a worse prognosis and are considered candidates for treatment strategies targeted towards modification of the ischemic substrate. Since considerable overlap in these diagnostic strata exists and the extent of clincial misclassification remains unknown, we sought to review the preponderance and implications of such misclassification by reviewing the final pathological diagnosis. Methods: Between 1/1992-8/2003, 112 patients with the clinical etiological diagnosis of non-ischemic cardiomyopathy (confirmed by a heart failure specialist) underwent heart transplantation. Patients were excluded if they were ⬍35 years old, had congenital heart disease, myocarditis, peripartum cardiomyopathy, primary valvular heart disease or infiltrative disease. The recipient heart was examined histopathologically and a pathologist blinded to clinical information classified the etiology of heart failure. Ischemic cardiomyopathy was defined as the presence of severe 3-vessel coronary disease (CAD) with myocardial scar (definition derived from analysis of 51 control hearts with ischemic cardiomyopathy confirmed on pathological analysis). Presence of significant CAD and ante-mortem myocardial ischemia were also analyzed. Results: The study included 112 patients (age 57 ⫾ 9 years, 71%men) with severe ventricular dysfunction (LVEF 19 ⫾ 11%) and non-ischemic cardiomyopathy as the diagnosis at cardiac transplant. 21% (23/112) were reclassified pathologically as ischemic cardiomyopathy. Of those accurately classified (89/112), 33% (29/89) were found to have at least moderate-severe CAD in ⱖ 1 vessel territory with or without infarction. Additionally, 18% (16/89) explanted hearts were noted to have areas compatible with recent ischemia (occlusive thrombus or ischemic infarction). Those patients with mis-classification were older (59 ⫾ 7 versus 53 ⫾ 8 years, p0.001) and had a shorter interval from listing to transplantation (44 months versus 58 months, p0.05). Inferences: This investigation suggests a high prevalence of etiological mis-diagnosis in advanced heart failure. The diagnosis of non-ischemic cardiomyopathy greatly underestimates the potential pathological contribution of concomitant coronary arteriopathy to disease progression and might steer the clinician away from opportunities for therapeutic intervention.
Early Detection of the Cardiomyopathy of Duchenne Muscular Dystrophy is Enhanced by Tissue Doppler Imaging and Myocardial Performance Index Tayyab Mohyuddin,1 Robert S. Finkelhor,1 Irwin B. Jacobs,2 Robert C. Bahler1; 1 Heart and Vascular Center, MetroHealth Medical Center, Cleveland, OH; 2Pediatrics, MetroHealth Medical Center, Cleveland, OH Background: Two-dimensional echo is the current method for detection of LV dysfunction in Duchenne muscular dystrophy (DMD), yet complete 2-D imaging is suboptimal in most DMD patients. Tissue Doppler velocities (TDV) are abnormal in a number of cardiac conditions when standard indices of LV function are normal. Hypothesis: Detection of left ventricular dysfunction in DMD is enhanced by TDV. Methods: We report TDV data in 31 DMD patients (median age 17.5 yrs, range 1134) and 13 age-matched controls. Thirty patients were wheelchair dependent; 14 required ventilation support. Standard 2-D images were sought. LV fractional shortening (FS) was obtained from the parasternal long-axis view. LV ejection fraction (LVEF) was a visual estimate since image quality was inadequate for quantitation. TDV were recorded from the septal and lateral aspects of the mitral annulus from an apical 4chamber view. Offline measurements were obtained from digital images and reported as the average of 3 beats. Myocardial performance index (MPI) was derived from the septal recording of TDV and calculated as: [(isovolumic contraction time ⫹ isovolumic relaxation time ⫹ diastolic filling time) - ejection time]/ejection time. Abnormal TDV were defined as outside the 95% normal confidence limits reported for 131 healthy children. Results: TDV data could be recorded in 26 patients and all 13 controls. DMD patients had significantly lower TDV, particularly in early diastole, and the MPI was higher. Comparison of DMD versus Controls
Parameter
Septal S cm/s
Septal E cm/s
Lateral S cm/s
Lateral E cm/s
FS (%)
LVEF (%)
DMD 6.7 ⫾ 1.4** 8.7 ⫾ 2.0* 7.5 ⫾ 2.0* 10.9 ⫾ 3.2* 23 ⫾ 10* 47 ⫾ 13* Controls 8.3 ⫾ 1.4 12.8 ⫾ 2.6 11.1 ⫾ 2.4 17.3 ⫾ 4.4 37.3 ⫾ 3 61 ⫾ 4 Number 2/26 21/26 12/22 15/22 25/31 12/30 abnormal
MPI 0.56 ⫾ 0.22* 0.31 ⫾ 07 19/24
* p ⬍ 0.001, ** p ⬍ 0.01
All patients with abnormal FS had abnormal TDV; all patients with normal TDV had normal FS. Abnormal TDV occurred in 2/6 patients despite a normal FS. An abnormal MPI (⬎0.40) was a more sensitive indicator of global LV dysfunction than the visual estimate of ejection fraction (p⬍0.01). Only 1 patient had normal values for both TDV and MPI. In DMD patients TDV were inversely related to age (p⬍0.01) and MPI was directly related (p⬍0.01). Conclusion: Detection of abnormal LV function in DMD patients is improved by both the measurement of TDV and the calculation of MPI from the TDV recording.