Browsing by Author "Madeira, Hugo"
Now showing 1 - 10 of 10
Results Per Page
Sort Options
- Awareness of Fabry disease in cardiology : a gap to be filledPublication . Brito, Dulce; Cardim, Nuno; Lopes, Luís Rocha; Belo, Adriana; Mimoso, Jorge; Gonçalves, Lino; Madeira, HugoIntroduction: In adults, unexplained left ventricular hypertrophy is usually due to sarcomeric hypertrophic cardiomyopathy (HCM). Fabry disease (FD) is rare but may mimic sarcomeric HCM, and has an adverse prognosis in the absence of specific treatment. We aimed to assess cardiologists’ awareness of FD based on data from the Portuguese Registry of Hypertrophic Cardiomyopathy. Methods: A total of 811 index patients, aged 55±16 years, 486 (59.9%) male, were included. Three groups were characterized: A - 128 patients, 74 (57.8%) male, with pathogenic or likely pathogenic mutation(s) in sarcomeric genes; B - 234 patients, 146 (62.4%) male, with negative genetic testing; and C - 449 patients, 266 (59.2%) male, no genetic testing performed. The groups were compared in terms of whether FD was excluded in the registry. Potential red flags for FD were also analyzed and compared between groups. Results: Patients in group A were younger and more frequently had familial HCM (A - 53.9% vs. B - 20.1% vs. C - 18.3%; p<0.001). FD was recorded as excluded in 217 (26.8%), similar in all groups; GLA gene testing was performed in only 50/217 patients (A - 48.6%, B - 25.7%, p=0.019; C - 13.4%, p=0.036 for B vs. C), mostly in women (p<0.001) in groups B and C. Alphagalactosidase A (-Gal A) activity was assessed in 39/217 (18%) patients, with no difference between groups, but more often in men (p=0.005). Among patients with potential red flags for FD, only 46.7% underwent specific tests (GLA gene testing and/or -Gal A activity). When GLA genotyping was performed no mutations were identified. Conclusions: There is a need to improve cardiologists’ alertness for the identification of FD among the Portuguese HCM population.
- Constrictive pericarditis : new methods in the diagnosis of an old disease : a case reportPublication . Silva, Doroteia; Sargento, Luís; Varela, Manuel Gato; Lopes, Mário G.; Brito, Dulce; Madeira, HugoConstrictive pericarditis is a rare clinical entity that can pose diagnostic problems. The gold standard for diagnosis is cardiac catheterization with analysis of intracavitary pressure curves, which are high and, in end-diastole, equal in all chambers. The diastolic profile in both ventricles presents the classic dip-and-plateau pattern and the difference between the diastolic pressures of both ventricles should not exceed 3-5mmHg. Unfortunately, these traditional criteria are not always present and in fact the sensitivity and specificity of equalization of diastolic pressures are relatively low and of limited value in individual patients. This highlights the need to use new cardiac imaging techniques to resolve any doubts. The case described here is a good example.
- Genetic diagnosis of hypertrophic cardiomyopathy using mass spectrometry DNA arrays and high resolution meltingPublication . Santos, Susana; Lança, Vasco; Oliveira, Helena; Branco, Patrícia; Silveira, Leonor; Marques, Vanda; Brito, Dulce; Madeira, Hugo; Bicho, Manuel; Fernandes, Alexandra R.Hypertrophic cardiomyopathy (HCM), a complex myocardial disorder with an autosomal dominant genetic pattern and prevalence of 1:500, is the most frequent cause of sudden death in apparently healthy young people. The benefits of gene-based diagnosis of HCME for both basic research and clinical medicine are limited by the considerable costs of current genetic testing due to the large number of genes and mutations involved in this pathology. However, coupling two high-throughput techniques--mass spectrometry genotyping (MSG) and high resolution melting (HRM)--is an encouraging new strategy for HCM diagnosis. Our aim was to evaluate the diagnostic efficacy of both techniques in this pathology by studying 13 individuals with a clinical phenotype of HCM. Methods: Peripheral blood samples were collected from: (i) seven subjects with a clinical diagnosis of HCM, all bearing known mutations previously identified by dideoxy sequencing and thus being used as blinded samples (sample type 1); (ii) one individual with a clinical diagnosis of HCM negative for mutations after dideoxy sequencing of the five most common HCM genes, MYH7, MYBPC3, TNNI3, TNNT2 and MYL2 (sample type 2); and (iii) five individuals individual with a clinical diagnosis of HCM who had not previously been genetically studied (sample type 3). Results: The 13 samples were analyzed by MSG for 534 known mutations in 32 genes associated with HCM phenotypes and for all coding regions and exon-intron boundaries of the same HCM genes by HRM. The 32 studied genes include the most frequent HCM-associated sarcomere genes, as well as 27 genes with lower reported HCM phenotype association. This coupled genotyping strategy enabled us to identify a c.128delC (p.A43Vfs165) frame-shift mutation in the CSRP3 gene, a gene not usually studied in current HCM genetics. The heterozygous CSRP3 mutation was found in two patients (sample types 2 and 3) aged 50 and 52 years, respectively, both with diffuse left ventricular hypertrophy. Furthermore, this coupled strategy enabled us to find a novel mutation, c.817C>T (p.Arg273Cys), in MYBPC3 in an individual from sample type 3, subsequently confirmed by dideoxy sequencing. This novel mutation in MYBPC3, not present in 200 chromosomes from 200 healthy individuals, affects a codon known to harbor an HCM-causing mutation – p.Arg253His. Conclusion: In conclusion, in the cohort used in this work coupling two technologies, MSG and HRM, with high sensitivity and low false positive results, enabled rapid, innovative and lowcost genotyping of HCM patients, which may in the short term be suitable for accurate genetic diagnosis of HCM.
- Heart rate and blood pressure in mitral valve prolapse patients : divergent effects of long-term propranolol therapy and correlations with catecholaminesPublication . da Silva, Emilia Pereira; Mendes Pedro, Mónica; Varela, Manuel Gato; Cortez-Dias, Nuno; Bicho, Manuel; Madeira, Hugo; Lopes, Mario G.Objective: There is a well known association between mitral valve prolapse (MVP) and low blood pressure (BP), although patients often have high levels of catecholamines and high heart rate (HR). The main objective of our study was to evaluate the effects of long-term adrenergic beta-blockade on these parameters. Methods: The study population consisted of 46 patients with MVP and the control group consisted of 20 normal individuals. The study had two phases: in the first phase, patients were free of medications. In the second phase, patients were under treatment with propranolol for 10 to 12 months. The tests were performed in normal individuals and patients in the first phase. Only patients underwent the same tests in the second phase. Measurement of urinary epinephrine and norepinephrine levels, by high performance liquid chromatography, was done. Rest HR was determined by electrocardiogram (ECG), and ambulatory blood pressure and HR were evaluated by 24 hours ambulatory blood pressure monitoring (ABPM) using the auscultatory method. Results: The levels of epinephrine and norepinephrine were significantly higher in patients than in normal controls and decreased under propranolol. Rest and ambulatory HR were higher in patients and decreased under propranolol. The 24 hours systolic and diastolic BPs were lower in patients, and their values increased under propranolol. Heart rate decreasing and epinephrine levels reduction were positively correlated. No correlation was found between BP increase and catecholamine levels. Conclusion: The study results show divergent effects of propranolol on blood pressure, which increased, and on heart rate, that decreased, in patients with MVP. Heart rate decrease was an expected result and depends, namely, on b1 receptors blockade. Increase in BP is an unusual response to adrenergic beta-blockade in normal conditions, and this finding supports the preponderance of b2 receptors on the BP control in patients with MVP.
- Heart rate and blood pressure in mitral valve prolapse patients : divergent effects of long-term propranolol therapy. Correlations with catecholaminesPublication . Silva, Emília Pereira da; Mendes Pedro, Mónica; Varela, Manuel Gato; Cortez-Dias, Nuno; Bicho, Manuel; Madeira, Hugo; Lopes, Mario G.Introduction: There is a well-known association between mitral valve prolapse (MVP) and low blood pressure (BP), although patients (P) often have high levels of catecholamines (CAT) and high heart rate (HR). To our knowledge, there are no studies about the effects of long-term adrenergic b-blockade on these parameters. Methods: Twenty normal individuals (N)—8 males (M) (49.9 F 12.9 years) and 12 females (F) (41.8 F 11.8 years); 46 MVP P—15 M (49.3 F 15.5 years) and 31 F (42.0 F 12.8 years). Phase1—in both N and P free of medication, determination of (1) 24H urinary epinephrine (E) and norepinephrine (NE) by HPLC; (2) rest HR by ECG; (3) 24H ambulatory HR and BP (ABM). Phase2—same tests in MVP P while taking propranolol by 10 to 12 months. Results: CAT ng/mg creatinine: E—M 5.1 F 2.5 (N), 9.1 F 3.9 (Ph1), 7.9 F 3.1 (Ph2); F 6.2 F 3.5 (N), 13.0 F 9.7 (Ph1), 10.7 F 6.7 (Ph2). Higher in P ( P b .01), lower under propranolol ( P = .002). NE—M 22.2 F 7.2 (N), 36.8 F 16.8 (Ph1), 27.4 F 10.6 (Ph2); F 28.1 F 7.3 (N), 46.2 F 18.1 (Ph1), 33.0 F 12.9 (Ph2). Higher in P ( P b .01), lower under propranolol ( P b .001). HR—M 75 F 5.4 (N), 79 F 7.2 (Ph1), 65 F 3.8 (Ph2); F 74 F 3.2 (N), 80 F 6.5 (Ph1), 69 F 6.2 (Ph2). Lower under propranolol ( P b .0001). ABM: phase1—HR higher in P. SBP and DBP lower in P. Phase2—lower HR whereas higher SBP and DBP in P under propranolol. No correlation between BP and CAT. Correlation between E levels and rest HR. Conclusions: These MVP patients had high levels of CAT, high HR, and low BP. With long-term b-blockade, HR decreased related to E, but BP raised, supporting the role of b2 receptors supercoupling on low BP in MVP.
- High resolution melting : improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohortPublication . Santos, Susana; Marques, Vanda; Pires, Marina; Silveira, Leonor; Oliveira, Helena; Lança, Vasco; Brito, Dulce; Madeira, Hugo; Esteves, J. Fonseca; Freitas, António; Carreira, Isabel M.; Gaspar, Isabel M.; Monteiro, Carolino; Fernandes, Alexandra R.Background: Hypertrophic Cardiomyopathy (HCM) is a complex myocardial disorder with a recognized genetic heterogeneity. The elevated number of genes and mutations involved in HCM limits a gene-based diagnosis that should be considered of most importance for basic research and clinical medicine. Methodology: In this report, we evaluated High Resolution Melting (HRM) robustness, regarding HCM genetic testing, by means of analyzing 28 HCM-associated genes, including the most frequent 4 HCM-associated sarcomere genes, as well as 24 genes with lower reported HCM-phenotype association. We analyzed 80 Portuguese individuals with clinical phenotype of HCM allowing simultaneously a better characterization of this disease in the Portuguese population. Results: HRM technology allowed us to identify 60 mutated alleles in 72 HCM patients: 49 missense mutations, 3 nonsense mutations, one 1-bp deletion, one 5-bp deletion, one in frame 3-bp deletion, one insertion/deletion, 3 splice mutations, one 5’UTR mutation in MYH7, MYBPC3, TNNT2, TNNI3, CSRP3, MYH6 and MYL2 genes. Significantly 22 are novel gene mutations. Conclusions: HRM was proven to be a technique with high sensitivity and a low false positive ratio allowing a rapid, innovative and low cost genotyping of HCM. In a short return, HRM as a gene scanning technique could be a cost-effective gene-based diagnosis for an accurate HCM genetic diagnosis and hopefully providing new insights into genotype/phenotype correlations.
- Portuguese study of familial dilated cardiomyopathy : the FATIMA studyPublication . Martins, Elisabete; Cardoso, José Silva; Bicho, Manuel; Bourbon, Mafalda; Ceia, Fátima; Rebocho, M. José; Moura, Brenda; Fonseca, Cândida; Correia, Maria José; Brito, Dulce; Perdigão, Carlos; Madeira, Hugo; Lima, Cassiano AbreuDilated cardiomyopathy (DCM) is a myocardial disease, characterized by ventricular dilatation and impaired systolic function, that in more than 30% of cases has a familial or genetic origin. Given its age-dependent penetrance, DCM frequently manifests in adults by signs or symptoms of heart failure, arrhythmias or sudden death. The predominant mode of inheritance is autosomal dominant, and in these cases mutations are identified in genes coding for cytoskeletal, sarcomeric or nuclear envelope proteins. To date, most studies aimed at molecular diagnosis of DCM have been in selected families, or in larger groups of patients, but screening for mutations in a limited number of genes. Consequently, the epidemiology of mutations in familial DCM remains unknown. There is thus a need for multicenter studies, involving screening for a wide range of mutations in several families and in cases of idiopathic DCM. The present article describes the methodology of a multicenter study, aimed at clinical and molecular characterization of familial DCM patients in the Portuguese population.
- Sarcomeric hypertrophic cardiomyopathy : genetic profile in a Portuguese populationPublication . Brito, Dulce; Miltenberger-Miltenyi, Gabriel; Pereira, Sónia Vale; Silva, Doroteia; Diogo, António Nunes; Madeira, HugoBackground: Sarcomeric hypertrophic cardiomyopathy has heterogeneous phenotypic expressions, of which sudden cardiac death is the most feared. A genetic diagnosis is essential to identify subjects at risk in each family. The spectrum of disease-causing mutations in the Portuguese population is unknown. Methods: Seventy-seven unrelated probands with hypertrophic cardiomyopathy were systematically screened for mutations by PCR and sequencing of five sarcomeric genes: MYBPC3, MYH7, TNNT2, TNNI3 and MYL2. Familial cosegregation analysis was performed in most patients. Results: Thirty-four different mutations were identified in 41 (53%) index patients, 71% with familial hypertrophic cardiomyopathy. The most frequently involved gene was MYBPC3 (66%) with 22 different mutations (8 novel) in 27 patients, followed by MYH7 (22%), TNNT2 (12%) and TNNI3 (2.6%). In three patients (7%), two mutations were found in MYBPC3 and/or MYH7. Additionally, 276 relatives were screened, leading to the identification of a mean of three other affected relatives for each pedigree with the familial form of the disease. Conclusions: Disease-associated mutations were identified mostly in familial hypertrophic cardiomyopathy, corroborating the idea that rarely studied genes may be implicated in sporadic forms. Private mutations are the rule, MYBPC3 being the most commonly involved gene. Mutations in MYBPC3 and MYH7 accounted for most cases of sarcomere-related disease. Multiple mutations in these genes may occur, which highlights the importance of screening both. The detection of novel mutations strongly suggests that all coding regions should be systematically screened. Genotyping in hypertrophic cardiomyopathy enables a more precise diagnosis of the disease, with implications for risk stratification and genetic counseling.
- The Portuguese Registry of Hypertrophic Cardiomyopathy : overall resultsPublication . Cardim, Nuno; Brito, Dulce; Lopes, Luís Rocha; Freitas, António; Araújo, Carla; Belo, Adriana; Gonçalves, Lino; Mimoso, Jorge; Olivotto, Iacopo; Elliott, Perry; Madeira, HugoIntroduction: We report the results of the Portuguese Registry of Hypertrophic Cardiomyopathy, an initiative that reflects the current spectrum of cardiology centers throughout the territory of Portugal. Methods: A direct invitation to participate was sent to cardiology departments. Baseline and outcome data were collected. Results: A total of 29 centers participated and 1042 patients were recruited. Four centers recruited 49% of the patients, of whom 59% were male, and mean age at diagnosis was 53±16 years. Hypertrophic cardiomyopathy (HCM) was identified as familial in 33%. The major reason for diagnosis was symptoms (53%). HCM was obstructive in 35% of cases and genetic testing was performed in 51%. Invasive septal reduction therapy was offered to 8% (23% of obstructive patients). Most patients (84%) had an estimated five-year risk of sudden death of <6%. Thirteen percent received an implantable cardioverter-defibrillator. After a median follow-up of 3.3 years (interquartile range [P25-P75] 1.3-6.5 years), 31% were asymptomatic. All-cause mortality was 1.19%/year and cardiovascular mortality 0.65%/year. The incidence of heart failure-related death was 0.25%/year, of sudden cardiac death 0.22%/year and of stroke-related death 0.04%/year. Heart failure-related death plus heart transplantation occurred in 0.27%/year and sudden cardiac death plus equivalents occurred in 0.53%/year. Conclusions: Contemporary HCM in Portugal is characterized by relatively advanced age at diagnosis, and a high proportion of invasive treatment of obstructive forms. Long-term mortality is low; heart failure is the most common cause of death followed by sudden cardiac death. However, the burden of morbidity remains considerable, emphasizing the need for diseasespecific treatments that impact the natural history of the disease.
- Tissue doppler imaging and plasma n-terminal probrain natriuretic peptide for the identification of hypertrophic cardiomyopathy mutation carriersPublication . Silva, Doroteia; Madeira, Hugo; Almeida, Augusto; Brito, DulcePrevious studies have shown that tissue Doppler imaging (TDI) is able to identify mutation carriers of hypertrophic cardiomyopathy (HC) before the development of the clinical phenotype. However, data are scarce and have sometimes been controversial. We performed a systematic study that included conventional echocardiography, TDI, and plasma NT-probrain natriuretic peptide (NT-proBNP) measurement to evaluate the parameters that could identify HC mutation carriers. A total of 138 genotyped subjects were included and divided into 3 groups: group 1, those with HC (n = 62); group 2, mutation carriers (first-degree relatives with a positive genotype but negative phenotype; n = 34); and group 3, controls (first-degree relatives with a negative genotype and phenotype; n = 42). An echocardiographic study, including TDI, was performed on all subjects, and a TDI-derived index (global function index) was also determined. The age-adjusted mean differences in the echocardiographic and TDI parameters and NT-proBNP levels were compared among the 3 groups. Compared with the HC group, the carriers had significantly higher mean E' velocities, lower mean E/E' ratio, higher mean S' velocities, and lower mean global function index and NT-proBNP values. The carriers and controls did not differ significantly either in the echocardiographic parameters studied or in the NT-proBNP levels. In conclusion, the echocardiographic and TDI parameters and NT-proBNP levels cannot be used to identify the HC mutation carrier state and therefore do not appear to be reliable for the purpose of making a preclinical diagnosis of the disease.