Max Grinberg

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.

Effectiveness of the Maze Procedure Using Cooled-Tip Radiofrequency Ablation in Patients With Permanent Atrial Fibrillation and Rheumatic Mitral Valve Disease

Background—Although the Cox-Maze III procedure is effective for treating permanent atrial fibrillation (AF), its high complexity limits its use. The Saline-Irrigated Cooled-tip Radiofrequency Ablation (SICTRA) System is an alternative source of energy used to ablate AF. The aim of this study was to evaluate the effectiveness of the SICTRA for the treatment of permanent AF in patients with rheumatic mitral valve (MV) disease. Methods and Results—Between February 2002 and April 2003, 70 patients with permanent AF and rheumatic MV disease were randomly assigned to undergo a modified Maze III procedure using SICTRA associated with MV surgery (group A) or MV surgery alone (group B). Groups A and B were similar in terms of baseline characteristics. The in-hospital mortality rate was 2.3% (1 death) in group A versus 0% (no deaths) in group B (P>0.99). The additional time required for the left-sided radiofrequency ablation in group A was 14.2±5.1 minutes and for right-sided ablation was 12.3±4.2 minutes. The mean postoperative follow-up periods were 13.8±3.4 and 11.5±7.3 months, respectively, in groups A and B. The overall mid-term survival rate was 95.1% in group A and 92.8% in group B (P>0.99). The cumulative rates of sinus rhythm were 79.4% in group A and 26.9% in group B (P=0.001). Doppler echocardiography documented biatrial transport function in 90.3% of group A patients in sinus rhythm. Conclusions—The SICTRA is effective for treating permanent AF associated with rheumatic MV disease.

Ten-year clinical laboratory follow-up after application of a symptom-based therapeutic strategy to patients with severe chronic aortic regurgitation of predominant rheumatic etiology.

OBJECTIVES This study was designed to assess the feasibility and the long-term results of a symptom-based strategy of aortic valve replacement in a Brazilian population with predominant rheumatic etiology. BACKGROUND Optimal criteria for valve replacement in aortic regurgitation (AR) are still not entirely clear. The appearance of symptoms is an indication for surgery, but may be associated with myocardial damage. Although cardiac imaging data have provided a safer guide for such decisions, the use of symptom-based surgical indication has not been validated and might conceivably be better in populations with predominant rheumatic etiology and younger age. METHODS Echocardiography and rest-exercise radionuclide ventriculography were performed in 75 patients with severe AR, age 28 +/- 9 years, over a period of 10 +/- 0.69 years. Thirty-seven patients developed symptoms and underwent aortic valve replacement surgery within six months. Thirty-eight patients remained asymptomatic and were managed medically. RESULTS Survival was 100% in asymptomatic patients and 82% in symptomatic. Surgical treatment caused marked ventricular remodeling, with ventricular diameter involution and an improvement of rest-exercise ejection fraction percent variation. Multivariate analysis showed that the probability of developing symptoms within 10 years was 58% for a patient with a left ventricular end-diastolic diameter > or =70 mm and 76% for a patient with left ventricular end-systolic (LVESD) > or =50 mm. Logistic regression identified LVESD and age as the most predictive and specific, but not sensitive, indicators of symptom development. CONCLUSIONS Application of a standardized therapeutic strategy to patients with severe AR and predominant rheumatic etiology resulted in 90.6% survival after 10 years of follow-up.

Association of Mannose-Binding Lectin Gene Polymorphism but Not of Mannose-Binding Serine Protease 2 with Chronic Severe Aortic Regurgitation of Rheumatic Etiology

ABSTRACT 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.

Apolipoproteins AI, B, and E polymorphisms in severe aortic valve stenosis

Hypercholesterolemia has been related to aortic valve stenosis (AS). Polymorphisms of apolipoproteins (apo) AI, B, and E are associated with variable levels of plasma lipids, but the association between these polymorphisms and AS is unknown. In a case–control study of groups matched by age, sex, comparable body mass index, hypertension, triglycerides, high‐density lipoprotein (HDL) cholesterol, and low‐density lipoprotein (LDL) cholesterol, we analyzed the distribution of apo AI A/G mutation, apo B signal peptide insertion/deletion, apo B XbaI restriction fragment length, and apo E polymorphisms in 62 non‐diabetic patients with severe aortic valve stenosis and 62 control subjects. All patients underwent echocardiographic analysis. Univariate analysis showed a higher prevalence of the XbaI X+/X+ genotype (p=0.007) of apo B and the apo E2 allele (p=0.034) in patients with severe AS. Apo polymorphisms were not associated with lipid levels, left ventricular mass, or the aortic gradient.

Effects of epinephrine in local dental anesthesia in patients with coronary artery disease

BACKGROUND The use of vasoconstrictors for local anesthesia in patients with coronary heart disease is controversial in the literature, and there is concern regarding risk of cardiac decompensation. OBJECTIVE To evaluate electrocardiographic and blood pressure parameters during restorative dental procedure under local anesthesia with and without a vasoconstrictor in patients with coronary artery disease. METHODS Sixty-two patients were included in the study, ages ranging from 39 to 80 (mean 58.7 +/- 8.8), 51 (83.2%) of whom were male. Thirty patients were randomly assigned to receive 2% lidocaine with epinephrine (epinephrine group), and the remaining patients, 2% lidocaine without epinephrine (non-epinephrine group) for local anesthesia. All patients underwent 24-hour ambulatory blood pressure monitoring and dynamic electrocardiography. Three periods were considered in the study: 1) baseline--recordings obtained during the 60 minutes prior to the procedure; 2) procedure--recordings obtained from the beginning of anesthesia to the end of the procedure and 3) 24 hours. RESULTS There was an increase in blood pressure in both groups during the procedure, compared with baseline values; but when the two groups were compared no significant difference was detected between them. Heart rate remained unchanged in both groups. No ST-segment depression > 1 mm occurred either at baseline or during the procedure. Seven patients (12.5%) experienced more than ten arrhythmia episodes per hour during the procedure, four (13.8%) in the non-epinephrine group and three (11.1%) in the epinephrine group. CONCLUSION No difference was observed in blood pressure, heart rate, or evidence of ischemia and arrhythmias in either group. The use of vasoconstrictor has proved to be safe within the range of the present study.

Protein quality control disruption by PKCβII in heart failure; rescue by the selective PKCβII inhibitor, βIIV5-3.

Myocardial remodeling and heart failure (HF) are common sequelae of many forms of cardiovascular disease and a leading cause of mortality worldwide. Accumulation of damaged cardiac proteins in heart failure has been described. However, how protein quality control (PQC) is regulated and its contribution to HF development are not known. Here, we describe a novel role for activated protein kinase C isoform βII (PKCβII) in disrupting PQC. We show that active PKCβII directly phosphorylated the proteasome and inhibited proteasomal activity in vitro and in cultured neonatal cardiomyocytes. Importantly, inhibition of PKCβII, using a selective PKCβII peptide inhibitor (βIIV5-3), improved proteasomal activity and conferred protection in cultured neonatal cardiomyocytes. We also show that sustained inhibition of PKCβII increased proteasomal activity, decreased accumulation of damaged and misfolded proteins and increased animal survival in two rat models of HF. Interestingly, βIIV5-3-mediated protection was blunted by sustained proteasomal inhibition in HF. Finally, increased cardiac PKCβII activity and accumulation of misfolded proteins associated with decreased proteasomal function were found also in remodeled and failing human hearts, indicating a potential clinical relevance of our findings. Together, our data highlights PKCβII as a novel inhibitor of proteasomal function. PQC disruption by increased PKCβII activity in vivo appears to contribute to the pathophysiology of heart failure, suggesting that PKCβII inhibition may benefit patients with heart failure. (218 words)

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 AVD 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.

Duration of symptoms in patients with infective endocarditis

Despite progress in the management of infective endocarditis, delays in diagnosis or prior antimicrobial treatment may adversely influence the symptom duration and outcome. The duration of symptoms in patients with infective endocarditis was studied in 683 cases among 653 patients with 703 episodes of the disease; patients were hospitalized within 10 days of symptom onset in 169 (24.7%) cases. Antimicrobial therapy before hospital admission was administered to 257 (36.5%) patients. Overall mortality was 25.6%. Symptom duration was longer when antimicrobials were administered before diagnosis (58.8+/-78.1 vs. 44.8+/-54.9 days), when vegetations were detected on echocardiogram (53.5+/-68.2 vs. 38.8+/-47.3) and among patients admitted before 1990 (42.3+/-67.1 vs. 54.2+/-62.4 days). Symptom duration was shorter in patients with prosthetic valve endocarditis (26.8+/-34.2 vs. 59.3+/-71.6 days). In 54 (26.5%) episodes of prosthetic valve endocarditis, patients had symptoms for more than 30 days. Staphylococcus aureus was the most frequent agent among patients with symptoms up to 10 days (41.2%) and Streptococcus among those with symptoms over 20 days (53.9%). Symptom duration did not significantly differ in regard to medical (51.3+/-69.2 days) or surgical (46.7+/-55.7 days) treatment. Mortality increased as symptom duration decreased and was highest for patients who experienced symptoms for less than 10 days (36.1%). In some patients medical care may be delivered relatively late in the course of infective endocarditis. Administration of antibiotics previous to hospital admission increased duration of symptoms, and cardiac valve prosthesis, staphylococcal infection and death were associated with more acute disease.

Pregnancy and peripartum cardiomyopathy: a comparative and prospective study

OBJECTIVE To assess pregnancy outcome in women with peripartum cardiomyopathy and to compare it with idiopathic cardiomyopathy. METHODS Twenty-six pregnant women, aged 28.4+/-6.1 years, with dilated cardiomyopathy were followed. Eighteen patients had peripartum cardiomyopathy [11 with persistent left ventricular systolic dysfunction (EF=45.2+/-2) and 7 with recovered ventricular function (EF=62.3+/-3.6)]. The 8 remaining patients had idiopathic cardiomyopathy (EF= 43.5+/-4.1). During the prenatal period, limited physical activity and a low-sodium diet were recommended, and hospitalization was recommended when complications occurred. RESULTS Of the 26 patients, 11 (42.3%) had a normal delivery; 9(35.5%) had cardiac complications, 6 (22.2%) had obstetric complications. Two patients (7.7%) died. Two preterm pregnancies occurred, with 26 health newborns (2 sets of twins). Two miscarriages took place. The cardiac complication rate during pregnancy was lower (p<0.009) in the peripartum cardiomyopathy group without ventricular dysfunction and greater (p=0.01) in the idiopathic group when compared with the peripartum group with ventricular dysfunction. Changes in left ventricular ejection fraction were not observed (p<0.05) in the postpartum period, when compared with that during pregnancy in the 3 groups. CONCLUSION Pregnancy in patients with dilated cardiomyopathy is associated with maternal morbidity. Left ventricular function is a prognostic factor and must be the most parameter when counseling patients with peripartum cardiomyopathy about a new pregnancy.