Prognostic Significance of Myocardial Fibrosis Quantification by Histopathology and Magnetic Resonance Imaging in Patients With Severe Aortic Valve Disease

Objectives We sought to determine whether the quantitative assessment of myocardial fibrosis (MF), either by histopathology or by contrast-enhanced magnetic resonance imaging (ce-MRI), could help predict long-term survival after aortic valve replacement. Background Severe aortic valve disease is characterized by progressive accumulation of interstitial MF. Methods Fifty-four patients scheduled to undergo aortic valve replacement were examined by ce-MRI. Delayed-enhanced images were used for the quantitative assessment of MF. In addition, interstitial MF was quantified by histological analysis of myocardial samples obtained during open-heart surgery and stained with picrosirius red. The ce-MRI study was repeated 27 +/- 22 months after surgery to assess left ventricular functional improvement, and all patients were followed for 52 +/- 17 months to evaluate long-term survival. Results There was a good correlation between the amount of MF measured by histopathology and by ce-MRI (r = 0.69, p < 0.001). In addition, the amount of MF demonstrated a significant inverse correlation with the degree of left ventricular functional improvement after surgery (r = -0.42, p = 0.04 for histopathology; r = -0.47, p = 0.02 for ce-MRI). Kaplan-Meier analyses revealed that higher degrees of MF accumulation were associated with worse long-term survival (chi-square = 6.32, p = 0.01 for histopathology; chi-square = 5.85, p = 0.02 for ce-MRI). On multivariate Cox regression analyses, patient age and the amount of MF were found to be independent predictors of all-cause mortality. Conclusions The amount of MF, either by histopathology or by ce-MRI, is associated with the degree of left ventricular functional improvement and all-cause mortality late after aortic valve replacement in patients with severe aortic valve disease. (J Am Coll Cardiol 2010; 56: 278-87) (c) 2010 by the American College of Cardiology Foundation

Relation of Aortic Valve Calcium Detected by Cardiac Computed Tomography to All-Cause Mortality

Aortic valve calcium (AVC) can be quantified on the same computed tomographic scan as coronary artery calcium (CAC). Although CAC is an established predictor of cardiovascular events, limited evidence is available for an independent predictive value for AVC. We studied a cohort of 8,401 asymptomatic subjects (mean age 53 10 years, 69% men), who were free of known coronary heart disease and were undergoing electron beam computed tomography for assessment of subclinical atherosclerosis. The patients were followed for a median of 5 years (range 1 to 7) for the occurrence of mortality from any cause. Multivariate Cox regression models were developed to predict all-cause mortality according to the presence of AVC. A total of 517 patients (6%) had AVC on electron beam computed tomography. During follow-up, 124 patients died (1.5%), for an overall survival rate of 96.1% and 98.7% for those with and without AVC, respectively (hazard ratio 3.39, 95% confidence interval 2.09 to 5.49). After adjustment for age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking, and a family history of premature coronary heart disease, AVC remained a significant predictor of mortality (hazard ratio 1.82, 95% confidence interval 1.11 to 2.98). Likelihood ratio chi-square statistics demonstrated that the addition of AVC contributed significantly to the prediction of mortality in a model adjusted for traditional risk factors (chi-square = 5.03, p = 0.03) as well as traditional risk factors plus the presence of CAC (chi-square = 3.58, p = 0.05). In conclusion, AVC was associated with increased all-cause mortality, independent of the traditional risk factors and the presence of CAC. (C) 2010 Published by Elsevier Inc. (Am J Cardiol 2010;106:1787-1791)

Association between degenerative aortic valve disease and long-term exposure to cardiovascular risk factors: results of the longitudinal population-based KORA/MONICA survey

Degenerative aortic valve disease (DAVD), a common finding in the elderly, is associated with an increased risk of death due to cardiovascular causes. Taking advantage of its longitudinal design, this study evaluates the prevalence of DAVD and its temporal associations with long-term exposure to cardiovascular risk factors in the general population. We studied 953 subjects (aged 25-74 years) from a random sample of German residents. Risk factors had been determined at a baseline investigation in 1994/95. At a follow-up investigation, 10 years later, standardized echocardiography determined aortic valve morphology and aortic valve area (AVA) as well as left ventricular geometry and function. At the follow-up study, the overall prevalence of DAVD was 28%. In logistic regression models adjusting for traditional cardiovascular risk factors at baseline age (OR 2.0 [1.7-2.3] per 10 years, P < 0.001), active smoking (OR 1.7 [1.1-2.4], P = 0.009) and elevated total cholesterol levels (OR 1.2 [1.1-1.3] per increase of 20 mg/dL, P < 0.001) were significantly related to DAVD at follow-up. Furthermore, age, baseline status of smoking, and total cholesterol level were significant predictors of a smaller AVA at follow-up study. In contrast, hypertension and obesity had no detectable relationship with long-term changes of aortic valve structure. In the general population we observed a high prevalence of DAVD that is associated with long-term exposure to elevated cholesterol levels and active smoking. These findings strengthen the notion that smoking cessation and cholesterol lowering are promising treatment targets for prevention of DAVD.

Contrast-enhanced magnetic resonance imaging identifies focal regions of intramyocardial fibrosis, in patients with severe aortic valve disease: Correlation with quantitative histopathology

Background Chronic aortic valve disease (AVD) is characterized by progressive accumulation of interstitial myocardial fibrosis (MF). However, assessment of MF accumulation has only been possible through histologic analyses of endomyocardial biopsies. We sought to evaluate contrast-enhanced magnetic resonance imaging (ce-MRI) as a noninvasive method to identify the presence of increased MF in patients with severe AVD. Methods Seventy patients scheduled to undergo aortic valve replacement surgery were examined by cine and ce-MRI in a 1.5-T scanner. Cine images were used for the assessment of left ventricular (LV) volumes, mass, and function. Delayed-enhancement images were used to characterize the regions of MF. In addition, histologic analyses of myocardial samples obtained during aortic valve replacement surgery were used for direct quantification of interstitial MF. Ten additional subjects who died of noncardiac causes served as controls for the quantitative histologic analyses. Results Interstitial MF determined by histopathologic analysis was higher in patients with AVID than in controls (2.7% +/- 2.0% vs 0.6% +/- 0.2%, P =.001). When compared with histopathologic results, ce-MRI demonstrated a sensitivity of 74%, a specificity of 81%, and an accuracy of 76% to identify AVD patients with increased interstitial MF There was a significant inverse correlation between interstitial MF and LV ejection fraction (r = -0.67, P <.0001). Accordingly, patients with identifiable focal regions of MF by ce-MRI exhibited worse LV systolic function than those without MF (45% +/- 14% vs 65% +/- 14%, P <.0001). Conclusions Contrast-enhanced MRI allows for the noninvasive detection of focal regions of MF in patients with severe AVD. Moreover, patients with identifiable MF by ce-MRI exhibited worse LV functional parameters. (Am Heart J 2009; 157:361-8.)

Oxidant generation predominates around calcifying foci and enhances progression of aortic valve calcification

Objective - We hypothesized that reactive oxygen species ( ROS) contribute to progression of aortic valve ( AV) calcification/ stenosis. Methods and Results - We investigated ROS production and effects of antioxidants tempol and lipoic acid ( LA) in calcification progression in rabbits given 0.5% cholesterol diet +10(4) IU/d Vit.D-2 for 12 weeks. Superoxide and H2O2 microfluorotopography and 3-nitrotyrosine immunoreactivity showed increased signals not only in macrophages but preferentially around calcifying foci, in cells expressing osteoblast/ osteoclast, but not macrophage markers. Such cells also showed increased expression of NAD(P) H oxidase subunits Nox2, p22phox, and protein disulfide isomerase. Nox4, but not Nox1 mRNA, was increased. Tempol augmented whereas LA decreased H2O2 signals. Importantly, AV calcification, assessed by echocardiography and histomorphometry, decreased 43% to 70% with LA, but increased with tempol (P <= 0.05). Tempol further enhanced apoptosis and Nox4 expression. In human sclerotic or stenotic AV, we found analogous increases in ROS production and NAD(P) H oxidase expression around calcifying foci. An in vitro vascular smooth muscle cell (VSMC) calcification model also exhibited increased, catalase-inhibitable, calcium deposit with tempol, but not with LA. Conclusions - Our data provide evidence that ROS, particularly hydrogen peroxide, potentiate AV calcification progression. However, tempol exhibited a paradoxical effect, exacerbating AV/vascular calcification, likely because of its induced increase in peroxide generation.

In Vitro and In Vivo Evaluation of Lyophilized Bioprosthetic Valve

Freeze-drying of biological tissues allows for dry storage and gamma ray sterilization, which may improve their use as a medical prosthesis. The objective of this study was to evaluate the rehydration characteristics and hydrodynamic performance of prosthetic valves before and after lyophilization. Two size 23 bovine pericardium aortic valve prostheses from different manufacturers were evaluated in a Shelhigh (Union, NJ, USA) pulse duplicator (80 ppm, 5 L/min) before and after lyophilization. Flow and transvalvular pressure gradient were registered in vitro and in vivo, and images of opening and closing of the prosthesis were obtained in the pulse duplicator in a digital camera. Rehydration was evaluated by comparison of dry valve weight with valve weight after 15 min, and 1, 24, 48, and 72 h in saline solution, inside the pulse duplicator. In vivo performance was assessed by surgical implantation in Santa Ines young male sheep in the pulmonary position after 30 min rehydration with 0.9% saline. Transvalvular pressure gradient and flow measurements were obtained immediately after implantation and 3 months after surgery when valves were explanted. Captured images showed a change in the profile opening and closing of valve prosthesis after lyophilization. The gradient measured (in vitro) in two valves was 17.08 +/- 0.57 and 18.76 +/- 0.70 mm Hg before lyophilization, and 34.24 +/- 0.59 and 30.40 +/- 0.97 mm Hg after lyophilization. Rehydration of both lyophilized valves was approximately 82%. Drying changed the profile of the opening and closing of valve prostheses, and increased on average by 83% the gradient in vitro tests. The result of the in vivo tests suggests maintaining pressure levels of the animal with the lyophilized prostheses within acceptable levels.

Exercise Echocardiography in Cryopreserved Aortic Homografts: Comparison of a Prototype Stentless, a Stented Bioprosthesis, and Native Aortic Valves

Background: Aortic valve replacement with a cryopreserved aortic homograft (CH) is an attractive alternative to bioprosthesis implantation. The aim of the study was to compare the hemodynamic performance of CH implanted with aortic root inclusion compared to prototype stentless (SS) bioprosthesis, standard stented (SD) bioprosthesis, and a native aortic valve. Methods: Hemodynamics and Doppler echocardiographic measurements such as left ventricular ejection fraction, aortic valve orifice area index (AVOAI), mean and maximal transvalvular gradients, were obtained at rest and immediately after exercise in 28 patients after aortic valve replacement with CH (n = 10), SS (n = 9), or SD (n = 9), and in a control group (CG) of 15 normal volunteers. Results: Rest and peak exercise heart rate and workload achieved were not different among the groups. Baseline AVOAI was larger for CH and CG compared to SS and SD groups (P < 0.05). Maximal and mean transvalvular pressure gradients at rest were lower for CH compared to SS and SD groups (P < 0.05), but higher than CG (P < 0,05). Conclusion: Implanted aortic CH had better hemodynamic performance than SS and SD bioprosthesis and similar to native normal aortic valves, both at rest and immediately after exercise. (ECHOCARDIOGRAPHY, Volume 26, November 2009).

Outcome of adults with asymptomatic severe aortic stenosis

Objectives: To evaluate clinical and echocardiographic variables that could be used to predict outcomes in patients with asymptomatic severe aortic valve stenosis. Management of asymptomatic severe aortic stenosis is controversial. Because prophylactic surgery may be protective, independent predictors of events that could justify early surgery have been sought. Methods: Outpatients (n= 133; mean [+/- SD] age, 66.2 +/- 13.6 years) with isolated severe asymptomatic aortic stenosis but normal left ventricular function and no previous myocardial infarction were followed up prospectively at a tertiary care hospital. Interventions: We use a ""wait-for-events"" strategy. Clinical and echocardiographic variables were analyzed. Results: Nineteen patients developed angina; 40, dyspnea; 5, syncope; and 7, sudden death during a mean follow-up period of 3.30 +/- 1.87 years. Event-free survival was 90.2 +/- 2.6% at 1 year, 73.4 +/-.9% at 2 years, 70.7 +/- 4.3% at 3 years, 57.8 +/- 4.7% at 4 years, 40.3 +/- 5.0% at 5 years, and 33.3 +/- 5.2% at 6 years. The mean follow-up period until sudden death (1.32 +/- 1.11 years) was shorter than that for dyspnea (2.44 +/- 1.84 years), syncope (2.87 +/- 1.26 years) and angina (3.03 +/- 1.68 years). Cox regression analysis disclosed only reduced but within normal limits ejection fraction as independent predictor of total events. Conclusions: Management on ""wait-for-events"" strategy is generally safe. Progressive left ventricular ejection fraction reduction even within normal limits identified patients at high risk for events in whom valve replacement surgery should be considered. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Non-invasive detection of aortic and coronary atherosclerosis in homozygous familial hypercholesterolemia by 64 slice multi-detector row computed tomography angiography

Homozygous familial hypercholesterolemia (HoFH) is a rare disorder characterized by the early onset of atherosclerosis, often at the ostia of coronary arteries. In this study we document for the first time that aortic and coronary atherosclerosis can be detected using 64 slice multiple detector row computed tomographic coronary angiography (CTCA). We studied five HoFH patients (three females, two males, mean age 19.8 +/- 2.9 years, age range 15-23 years, with a mean low density lipoprotein (LDL) cholesterol 618 +/- 211 mg/dL) using 64 slice CTCA. None of the patients showed evidence of ischemia with standard exercise testing. Calcified and mixed atherosclerotic plaques adjacent to or compromising the coronary artery ostia were found in all study subjects. Coronary plaques causing significant obstruction were found in one patient, who had previously undergone coronary artery bypass surgery and aortic valve replacement. Two other patients were noted to have non-obstructive calcified, mixed and non-calcified coronary artery plaques. Our data suggest that CTCA could be a useful non-invasive method for detection of early aortic and coronary atherosclerosis specifically affecting the coronary ostia in HoFH subjects. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Echocardiographic study of paediatric patients with mucopolysaccharidosis

Principle Mucopolysaccharidosis is an inborn error of metabolism causing glucosaminoglycans tissue storage. Cardiovascular involvement is variable but contributes significantly towards the morbidity and mortality of the patients. Objective To characterise the echocardiographic abnormalities in children and adolescents with different types of mucopolysaccharidosis. Method Echocardiograms and medical records of 28 patients aged 2–14 years, seen from 2003 to 2005, were revised. At that time, the enzymatic replacement therapy was still not available in our institution.Results Echocardiographic alterations were detected in 26 patients (93 per cent), whereas 16 (57 per cent) had abnormal auscultation, and only 6 (21 per cent) presented with cardiovascular complaint. Mitral valve thickening with dysfunction (regurgitation, stenosis, or double lesion) was diagnosed in 60.8 per cent, left ventricular hypertrophy in 43 per cent and aortic valve thickening with regurgitation in 35.8 per cent of the patients. There was no systolic dysfunction and mild left diastolic dysfunction was shown in 21.5 per cent of the patients. Pulmonary hypertension was present in 36 per cent of the patients, causing the only two deaths recorded. There was a strong association between the accumulation of dermatan sulphate and the presence of mitral valve dysfunction (p = 0.0003), aortic valve dysfunction (p = 0.006), and pulmonary hypertension (p = 0.006). Among individuals with two or more examinations, 82 per cent had a worsening evolution. Conclusions Echocardiographic alterations in children with Mucopolysaccharidosis are frequent and have a progressive character Left valve lesions, ventricular hypertrophy, and pulmonary hypertension were the most common findings and there was an association between the accumulation of dermatan sulphate and cardiovascular involvement. Unlike in adults, pulmonary hypertension was the main cause of death, not left ventricle systolic dysfunction

Association of mannose-binding lectin gene polymorphism but not of mannose-binding serine protease 2 with chronic severe aortic regurgitation of rheumatic etiology

N-Acetylglucosamine (GlcNAc) is the major immunoepitope of group A streptococcal cell wall carbohydrates. Antistreptococcal antibodies cross-reactive with anti-GlcNAc and laminin are present in sera of patients with rheumatic fever. The cross-reactivity of these antibodies with human heart valvular endothelium and the underlying basement membrane has been suggested to be a possible cause of immune-mediated valve lesion. Mannose-binding lectin (MBL) encoded by the MBL2 gene, a soluble pathogen recognition receptor, has high affinity for GlcNAc. We postulated that mutations in exon 1 of the MBL2 gene associated with a deficient serum level of MBL may contribute to chronic severe aortic regurgitation (AR) of rheumatic etiology. We studied 90 patients with severe chronic AR of rheumatic etiology and 281 healthy controls (HC) for the variants of the MBL2 gene at codons 52, 54, and 57 by using a PCR-restriction fragment length polymorphism-based method. We observed a significant difference in the prevalence of defective MBL2 alleles between patients with chronic severe AR and HC. Sixteen percent of patients with chronic severe AR were homozygotes or compound heterozygotes for defective MBL alleles in contrast to 5% for HC (P = 0.0022; odds ratio, 3.5 [ 95% confidence interval, 1.6 to 7.7]). No association was detected with the variant of the MASP2 gene. Our study suggests that MBL deficiency may contribute to the development of chronic severe AR of rheumatic etiology.

FiltekTM Silorane and FiltekTM Supreme XT resins: tissue reaction after subcutaneous implantation in isogenic mice

The aim of this study was to evaluate the tissue compatibility of a silorane-based resin system (FiltekTM Silorane) and a methacrylate-based nanoparticle resin (FiltekTM Supreme XT) after implantation in the subcutaneous connective tissue of isogenic mice. One hundred and thirty five male isogenic BALB/c mice were randomly assigned to 12 experimental and 3 control groups, according to the implanted material and the experimental period of 7, 21 and 63 days. At the end of each period, the animals were killed and the tubes with the surrounding tissues were removed and processed for microscopic analysis. Samples were subjected to a descriptive and a semi-quantitative analyses using a 4-point scoring system (0-3) to evaluate the collagen fiber formation and inflammatory infiltrate. Data were statistically analyzed using the Kruskal Wallis test (?=0.05). The results showed that there was no significant difference between the experimental and control groups considering the three evaluation periods (p>0.05). The silorane-based and the methacrylate-based nanoparticle resins presented similar tissue response to that of the empty tube (control group) after subcutaneous implantation in isogenic mice.

Tissue inflammatory response to implantation of calcium hydroxide and iodoform in the back of rats

PURPOSE: This study evaluated the inflammatory reaction caused by the implantation of iodoform and calcium hydroxide in the back of rats. These drugs may be used as intracanal dressings to eliminate residual bacteria of the root canal system. METHODS: Twenty albinic rats (Rattus norvegicus, var Wistar) were divided into four groups: control group 1 (CG1) had normal skin; control group 2 (CG2) had wounded tissue without drugs; in groups 3 and 4, iodoform (IG) and calcium hydroxide (CHG) were inserted into the wounds, respectively. After 3, 5 and 11 days, slices of the implanted areas were macroscopically and microscopically observed regarding to their qualitative and quantitative aspects. RESULTS: In the macroscopical analysis, the CHG showed a large area of necrosis and swelling, which progressively decreased; in the IG the presence of iodoform surrounded by normal tissue was observed. The qualitative and quantitative histological analysis showed that IG promoted a shorter delay in the inflammatory response than the CHG. CONCLUSION: The inflammatory reaction for iodoform had a peak period five days after the drug insertion. By comparison, calcium hydroxide showed a very large area of necrosis that could only be partially eliminated after eleven days.

Cardiomyopathy, adult valve disease and heart failure in South America

Continued assessment of temporal trends in mortality and epidemiology of specific cardiovascular diseases in South America is needed to provide a scientific basis for rational allocation of the limited healthcare resources and introduction of strategies to reduce risk and predict the future burden of cardiovascular disease. The epidemiology of cardiomyopathies, adult valve disease and heart failure (HF) in South America is reviewed here. Diseases of the circulatory system are the main cause of death based on data from about 50% of the South American population. Among the cardiovascular causes of death, cerebrovascular disease is predominant followed by ischaemic heart disease, other heart diseases and hypertensive disease. Of note, cerebrovascular disease is the main cause of death in women, and race also influenced cardiovascular mortality rates. HF is the most important cardiovascular reason for admission to hospital due to cardiovascular disease of ischaemic, idiopathic dilated cardiomyopathic, valvular, hypertensive and chagasic aetiologies. Also, mortality due to HF is high, especially owing to Chagas' disease. HF and aetiologies associated with HF are responsible for 6.3% of deaths. Rheumatic fever is the leading cause of valvular heart disease. The findings have important public health implications because the allocation of healthcare resources, and strategies to reduce the risk of HF should also consider controlling Chagas' disease and rheumatic fever in South American countries.

Vascular relaxation of canine visceral arteries after ischemia by means of supraceliac aortic cross-clamping followed by reperfusion

Background: The supraceliac aortic cross-clamping can be an option to save patients with hipovolemic shock due to abdominal trauma. However, this maneuver is associated with ischemia/reperfusion (I/R) injury strongly related to oxidative stress and reduction of nitric oxide bioavailability. Moreover, several studies demonstrated impairment in relaxation after I/R, but the time course of I/R necessary to induce vascular dysfunction is still controversial. We investigated whether 60 minutes of ischemia followed by 30 minutes of reperfusion do not change the relaxation of visceral arteries nor the plasma and renal levels of malondialdehyde (MDA) and nitrite plus nitrate (NOx). Methods: Male mongrel dogs (n = 27) were randomly allocated in one of the three groups: sham (no clamping, n = 9), ischemia (supraceliac aortic cross-clamping for 60 minutes, n = 9), and I/R (60 minutes of ischemia followed by reperfusion for 30 minutes, n = 9). Relaxation of visceral arteries (celiac trunk, renal and superior mesenteric arteries) was studied in organ chambers. MDA and NOx concentrations were determined using a commercially available kit and an ozone-based chemiluminescence assay, respectively. Results: Both acetylcholine and calcium ionophore caused relaxation in endothelium-intact rings and no statistical differences were observed among the three groups. Sodium nitroprusside promoted relaxation in endothelium-denuded rings, and there were no inter-group statistical differences. Both plasma and renal concentrations of MDA and NOx showed no significant difference among the groups. Conclusion: Supraceliac aortic cross-clamping for 60 minutes alone and followed by 30 minutes of reperfusion did not impair relaxation of canine visceral arteries nor evoke biochemical alterations in plasma or renal tissue.