Alfredo José Mansur

Periodic breathing during incremental exercise predicts mortality in patients with chronic heart failure evaluated for cardiac transplantation

OBJECTIVES We hypothesized that exercise-related periodic breathing (EPB) would be associated with poor prognosis in advanced chronic heart failure (CHF). BACKGROUND Patients with CHF might present instability of the ventilatory control system characterized by cyclic waxing and waning of tidal volume (periodic breathing [PB]). This condition is associated with several deleterious circulatory and neuro-endocrine responses; in fact, PB in awake and asleep patients has been identified as an independent risk factor for cardiac death. During exercise, however, the prognostic value of PB is still unknown in CHF patients awaiting heart transplantation. METHODS Eighty-four patients with established CHF (65 male, 19 female) were submitted to clinical evaluation, echocardiogram, ventricular scintigraphy, determination of resting serum norepinephrine levels, and an incremental cardiopulmonary exercise test on cycle ergometer. Patients were followed for up to 49.7 months (median = 15.3), and 26 patients (30.9%) died during this period. RESULTS Twenty-five of 84 patients presented EPB (29.7%). The following variables were related to mortality according to Kaplan-Meier and univariate Cox regression analysis: EPB (p = 0.004), New York Heart Association class (p = 0.04), serum norepinephrine (p = 0.06), peak oxygen uptake (ml.min(-1).kg(-1) and % predicted; p = 0.085 and p = 0.10, respectively), slope of the ratio of change in minute ventilation to change in carbon dioxide output during exercise (p = 0.10), and scintigraphic left ventricular ejection fraction (p = 0.10). Cox multivariate analysis identified EPB as the only independent variable for cardiac death prediction (p = 0.007). Therefore, EPB alone was associated with a 2.97-fold increase in risk of death in this population (95% confidence interval = 1.34 to 6.54). CONCLUSIONS Exercise-related periodic breathing independently predicts cardiac mortality in CHF patients considered for heart transplantation.

Circulating Dipeptidyl Peptidase IV Activity Correlates with Cardiac Dysfunction in Human and Experimental Heart Failure

Background—The present study addresses the hypothesis that the activity of dipeptidyl peptidase IV (DPPIV), an enzyme that inactivates peptides that possess cardioprotective actions, correlates with adverse outcomes in heart failure (HF). The therapeutic potential of DPPIV inhibition in preventing cardiac dysfunction is also investigated. Methods and Results—Measurements of DPPIV activity in blood samples obtained from 190 patients with HF and 42 controls demonstrated that patients with HF exhibited an increase of ≈130% in circulating DPPIV activity compared with healthy subjects. Furthermore, an inverse correlation was observed between serum DPPIV activity and left ventricular (LV) ejection fraction in patients with HF. Similarly, radiofrequency LV ablation-induced HF rats displayed higher DPPIV activity in the plasma (≈50%) and heart tissue (≈3.5-fold) compared with sham-operated rats. Moreover, positive correlations were observed between the plasma DPPIV activity and LV end-diastolic pressure and lung congestion. Two days after surgery, 1 group of LV ablation-induced HF rats was treated with the DPPIV inhibitor sitagliptin (40 mg/kg BID) for 6 weeks, whereas the remaining rats were administered water. Hemodynamic measurements demonstrated that radiofrequency LV-ablated rats treated with sitagliptin exhibited a significant attenuation of HF-related cardiac dysfunction, including LV end-diastolic pressure, systolic performance, and chamber stiffness. Sitagliptin treatment also attenuated cardiac remodeling and cardiomyocyte apoptosis and minimized pulmonary congestion. Conclusions—Collectively, the results presented herein associate circulating DPPIV activity with poorer cardiovascular outcomes in human and experimental HF. Moreover, the results demonstrate that long-term DPPIV inhibition mitigates the development and progression of HF in rats.

Repeated echocardiographic examinations of patients with suspected infective endocarditis

Objective: To study the diagnostic contribution of repeated transthoracic (TTE) and transoesophageal echocardiography (TOE) among patients with suspected infective endocarditis. Methods: 262 patients with 266 episodes of suspected infective endocarditis were referred for TTE and TOE over three years in a 423 bed university cardiology hospital. Patients were a mean (SD) of 47.6 (17.9) years old. 139 (52.3%) episodes occurred in men and 127 (47.7%) in women. The diagnostic information obtained from repeated TTE and TOE examinations was evaluated relative to the diagnosis of endocarditis. Results: TTE examinations were repeated in 192 (72.2%) and TOE examinations were repeated in 49 (18.4%) of 266 episodes. A mean of 2.4 TTE and 1.2 TOE examinations were performed for each episode of suspected endocarditis. The second and third TTEs added diagnostic information in 34 (26.7%) and the second and third TOEs added diagnostic information in 25 (19.7%) of 127 episodes with definite endocarditis. After the third TTE or TOE no additional diagnostic information was obtained. Conclusions: The diagnostic contribution of repeated TTE or TOE for the diagnosis of endocarditis decreased as the number of repetitions increased. In this setting, the data do not substantiate more than three TTE or TOE examinations as an efficient strategy to increase the diagnostic yield for all but selected patients with suspected endocarditis.

Assessment of the relationship between self-declared ethnicity, mitochondrial haplogroups and genomic ancestry in Brazilian individuals.

In populations that have a high degree of admixture, such as in Brazil, the sole use of ethnicity self-declaration information is not a good method for classifying individuals regarding their ethnicity. Here, we evaluate the relationship of self-declared ethnicities with genomic ancestry and mitochondrial haplogroups in 492 individuals from southeastern Brazil. Mitochondrial haplogroups were obtained by analyzing the hypervariable regions of the mitochondrial DNA (mtDNA), and the genomic ancestry was obtained using 48 autosomal insertion-deletion ancestry informative markers (AIM). Of the 492 individuals, 74.6% self-declared as White, 13.8% as Brown and 10.4% as Black. Classification of the mtDNA haplogroups showed that 46.3% had African mtDNA, and the genomic ancestry analysis showed that the main contribution was European (57.4%). When we looked at the distribution of mtDNA and genomic ancestry according to the self-declared ethnicities from 367 individuals who self-declared as White, 37.6% showed African mtDNA, and they had a high contribution of European genomic ancestry (63.3%) but also a significant contribution of African ancestry (22.2%). Of the 68 individuals who self-declared as Brown, 25% showed Amerindian mtDNA and similar contribution of European and African genomic ancestries. Of the 51 subjects who self-declared as black, 80.4% had African mtDNA, and the main contribution of genomic ancestry was African (55.6%), but they also had a significant proportion of European ancestry (32.1%). The Brazilian population had a uniform degree of Amerindian genomic ancestry, and it was only with the use of genetic markers (autosomal or mitochondrial) that we were able to capture Amerindian ancestry information. Additionally, it was possible to observe a high degree of heterogeneity in the ancestry for both types of genetic markers, which shows the high genetic admixture that is present in the Brazilian population. We suggest that in epidemiological studies, the use of these methods could provide complementary information.

Oxygen therapy, continuous positive airway pressure, or noninvasive bilevel positive pressure ventilation in the treatment of acute cardiogenic pulmonary edema

OBJECTIVE To compare the effects of 3 types of noninvasive respiratory support systems in the treatment of acute pulmonary edema: oxygen therapy (O2), continuous positive airway pressure, and bilevel positive pressure ventilation. METHODS We studied prospectively 26 patients with acute pulmonary edema, who were randomized into 1 of 3 types of respiratory support groups. Age was 69+/-7 years. Ten patients were treated with oxygen, 9 with continuous positive airway pressure, and 7 with noninvasive bilevel positive pressure ventilation. All patients received medicamentous therapy according to the Advanced Cardiac Life Support protocol. Our primary aim was to assess the need for orotracheal intubation. We also assessed the following: heart and respiration rates, blood pressure, PaO2, PaCO2, and pH at beginning, and at 10 and 60 minutes after starting the protocol. RESULTS At 10 minutes, the patients in the bilevel positive pressure ventilation group had the highest PaO2 and the lowest respiration rates; the patients in the O2 group had the highest PaCO2 and the lowest pH (p<0.05). Four patients in the O2 group, 3 patients in the continuous positive pressure group, and none in the bilevel positive pressure ventilation group were intubated (p<0.05). CONCLUSION Noninvasive bilevel positive pressure ventilation was effective in the treatment of acute cardiogenic pulmonary edema, accelerated the recovery of vital signs and blood gas data, and avoided intubation.

Analysis of a polymorphism in the promoter region of the tumor necrosis factor alpha gene in schizophrenia and bipolar disorder: further support for an association with schizophrenia

Sir – Activation of the inflammatory response system has been observed in the schizophrenia and affective disorders.1,2 Investigations of the role of the inflammatory response in these psychiatric disorders include analysis of the immune mediators at the gene level, so the genetic polymorphism of specific cytokine loci has been investigated in psychiatric disorders.3,4 Recently, Boin et al5 investigated a biallelic variant (-G308A) of the TNF- gene directly related to increased production of these cytokines, and found a significant association with schizophrenia. Interestingly, the TNF- gene is located in the region 6p21.1–21.3, near the HLA region, where linkage and association studies have suggested a locus of susceptibility to schizophrenia.6

Comparison between clinical and autopsy diagnoses in a cardiology hospital

Background: A few recent studies have evaluated diagnostic accuracy by comparison between clinical and autopsy diagnoses in a hospital specialising in cardiology. Methods: 406 consecutive autopsy cases during 2 years were studied. Patients were aged 47.4±28.4 years; 236 (58.1%) were men and 170 (41.9%) women. Diagnostic comparison was categorised in classes I to V (I, II, III and IV: discrepancy in decreasing order of importance regarding therapy and prognosis; V: concordance). Categorisation was ranked on the basis of the highest degree of discrepancy. Statistical analysis was performed with the Χ2 test and stepwise logistic regression. Results: Each age increase of 10 years added 16.2% to the risk of the diagnostic comparison to be categorised in classes I and II (major discrepancy) in comparison to classes III, IV and V (OR 1.16, 95% CI 1.07 to 1.27, p<0.001). By contrast, admission to intensive care units decreased the risk of categorisation in classes I and II by 47% (OR 0.53, 95% CI 0.32 to 0.85, p = 0.009). The most frequent diagnostic discrepancy occurred for pulmonary embolism: 30 out of 88 (34.1%) diagnoses in classes I and II. The concordance rate was 71.1% for acute myocardial infarction, 75% for aorta dissection, 73.1% for infective endocarditis and 35.2% for pulmonary embolism. Conclusion: Age and hospital ward influenced the distribution of diagnostic discrepancy or concordance between clinical and autopsy diagnoses. The lower discrepancy rate for myocardial infarction and infective endocarditis may be related to the fact that the study was carried out in a specialist hospital.

Mutations in the human phospholamban gene in patients with heart failure

BACKGROUND Phospholamban (PLN) is a crucial Ca(2+) cycling protein and a primary mediator of the β-adrenergic effects resulting in enhanced cardiac output. Mutations in the gene encoding PLN have been associated with idiopathic dilated cardiomyopathy; however, no systematic search for PLN mutations in heart failure has been conducted. METHODS We screened a cohort of 1,014 Brazilian patients with heart failure for mutations in the PLN gene. Molecular modeling studies of the mutations found were developed. Different disease etiologies were present in our sample: idiopathic, ischemic, Chagas, valvular, hypertensive, and others. RESULTS We identified 4 unrelated patients with PLN mutations (prevalence of 0.4%), 3 of them in the same amino acid residue (R9). Two patients presented a G-T missense mutation at the G26 nucleotide, which encodes an Arg-Leu substitution at codon 9 (R9L). One patient presented a G-A missense mutation at the same nucleotide, which encodes an Arg-His substitution at codon 9 (R9H). The fourth affected patient presented a T-G nonsense mutation at the nucleotide 116, substituting a termination codon for Leu-39 (L39stop). Molecular modeling studies suggested that R9L and R9H mutations might affect the region involved in protein kinase A docking and probably affect the mechanism modulating the release of phosphorylated PLN from the substrate binding site of protein kinase A. CONCLUSIONS Mutations in the PLN gene are a rare cause of heart failure, present almost exclusively in patients with dilated cardiomyopathy etiology. The Arg9 and Leu39 residues are the leading location of mutations described at this locus to date. Despite the few mutated residues described to date, the clinical spectrum of presentation appears to vary considerably.

Nuclear Factor (NF) κB polymorphism is associated with heart function in patients with heart failure

BackgroundCardiac remodeling is generally an adverse sign and is associated with heart failure (HF) progression. NFkB, an important transcription factor involved in many cell survival pathways, has been implicated in the remodeling process, but its role in the heart is still controversial. Recently, a promoter polymorphism associated with a lesser activation of the NFKB1 gene was also associated with Dilated Cardiomyopathy. The purpose of this study was to evaluate the association of this polymorphism with clinical and functional characteristics of heart failure patients of different etiologies.MethodsA total of 493 patients with HF and 916 individuals from a cohort of individuals from the general population were investigated. The NFKB1 -94 insertion/deletion ATTG polymorphism was genotyped by High Resolution Melt discrimination. Allele and genotype frequencies were compared between groups. In addition, frequencies or mean values of different phenotypes associated with cardiovascular disease were compared between genotype groups. Finally, patients were prospectively followed-up for death incidence and genotypes for the polymorphism were compared regarding disease onset and mortality incidence in HF patients.ResultsWe did not find differences in genotype and allelic frequencies between cases and controls. Interestingly, we found an association between the ATTG1/ATTG1 genotype with right ventricle diameter (P = 0.001), left ventricle diastolic diameter (P = 0.04), and ejection fraction (EF) (P = 0.016), being the genotype ATTG1/ATTG1 more frequent in patients with EF lower than 50% (P = 0.01). Finally, we observed a significantly earlier disease onset in ATTG1/ATTG1 carriers.ConclusionThere is no genotype or allelic association between the studied polymorphism and the occurrence of HF in the tested population. However, our data suggest that a diminished activation of NFKB1, previously associated with the ATTG1/ATTG1 genotype, may act modulating on the onset of disease and, once the individual has HF, the genotype may modulate disease severity by increasing cardiac remodeling and function deterioration.

Ambulatory blood pressure monitoring of patients with heart failure: a new prognosis marker

OBJECTIVE To evaluate the relationship between 24-hour ambulatory arterial blood pressure monitoring and the prognosis of patients with advanced congestive heart failure. METHODS We studied 38 patients with NYHA functional class IV congestive heart failure, and analyzed left ventricular ejection fraction, diastolic diameter, and ambulatory blood pressure monitoring data. RESULTS Twelve deaths occurred. Left ventricular ejection fraction (35.2 +/-7.3%) and diastolic diameter (72.2 +/- 7.8mm) were not correlated with the survival. The mean 24-hour (SBP24), waking (SBPw), and sleeping (SBPs) systolic pressures of the living patients were higher than those of the deceased patients and were significant for predicting survival. Patients with mean SBP24, SBPv, and SBPs >/=105mmHg had longer survival (p=0.002, p=0.01 and p=0.0007, respectively). Patients with diastolic blood pressure sleep decrements (dip) and patients with mean blood pressure dip </= 6mmHg had longer survival (p=0.04 and p=0.01, respectively). In the multivariate analysis, SBPs was the only variable with an odds ratio of 7.61 (CI: 1.56; 3704) (p=0.01). Patients with mean SBP<105mmHg were 7.6 times more likely to die than those with SBP >/= 105 mmHg CONCLUSION Ambulatory blood pressure monitoring appears to be a useful method for evaluating patients with congestive heart failure.