GABRIELA VENTURINI DA SILVA
Projetos de Pesquisa
Unidades Organizacionais
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Obstructive sleep apnoea is associated with myocardial injury in patients with refractory angina(2016) GEOVANINI, Glaucylara R.; PEREIRA, Alexandre C.; GOWDAK, Luis H. W.; DOURADO, Luciana Oliveira Cascaes; POPPI, Nilson T.; VENTURINI, Gabriela; DRAGER, Luciano F.; LORENZI-FILHO, GeraldoObjective To investigate the association between obstructive sleep apnoea (OSA) severity with markers of overnight myocardial injury in patients with refractory angina. Methods Patients with refractory angina were characterised clinically and they underwent ischaemia imaging stress tests by single-photon emission computed tomography (SPECT) and/or cardiac MRI. The patients were admitted to the hospital, remained under resting conditions for blood determination of high-sensitivity cardiac troponin T (hs-cTnT) at 14:00, 22:00 and after overnight polysomnography at 7:00. Results We studied 80 consecutive patients (age: 62 +/- 10 years; male: 66%; body mass index (BMI): 29.5 +/- 4 kg/m(2)) with well-established diagnosis of refractory angina. The mean apnoea-hypopnoea index (AHI) was 37 +/- 29 events/h and OSA (AHI >15 events/h) was present in 75% of the population. Morning detectable hs-cTnT and above 99th percentile was present in 88% and 36% of the population, respectively. Patients in the first to third quartiles of OSA severity did not have circadian variation of hs-cTnT. In contrast, patients in the fourth quartile (AHI >= 51 events/h) had a circadian variation of hs-cTnT with a morning peak of hs-cTnT that was two times higher than that in the remaining population (p = 0.02). The highest quartile of OSA severity remained associated with the highest quartile of hs-cTnT (p = 0.028) in multivariate analysis. Conclusion Very severe OSA is common and independently associated with overnight myocardial injury in patients with refractory angina.
conferenceObject Cardiac Hypertrophy and Altered Glycolytic Metabolism are Reversed in an Aortic Constriction Mice Model(2019) JENSEN, Leonardo; SILVA, Amanda; FARIA, Daniele; VENTURINI, Gabriela; PEREIRA, Alexandre; BUCHPIGUEL, Carlos Alberto; IRIGOYEN, Maria Claudia C.- Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy(2020) TOEPFER, Christopher N.; GARFINKEL, Amanda C.; VENTURINI, Gabriela; WAKIMOTO, Hiroko; REPETTI, Giuliana; ALAMO, Lorenzo; SHARMA, Arun; AGARWAL, Radhika; EWOLDT, Jourdan F.; CLOONAN, Paige; LETENDRE, Justin; LUN, Mingyue; OLIVOTTO, Iacopo; COLAN, Steve; ASHLEY, Euan; JACOBY, Daniel; MICHELS, Michelle; REDWOOD, Charles S.; WATKINS, Hugh C.; DAY, Sharlene M.; STAPLES, James F.; PADRON, Raul; CHOPRA, Anant; HO, Carolyn Y.; CHEN, Christopher S.; PEREIRA, Alexandre C.; SEIDMAN, Jonathan G.; SEIDMAN, Christine E.Background: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. Methods: We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. Results: Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. Conclusions: Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.
conferenceObject Differential IgG Repertoire in Individuals With Chagas Cardiomyopathy(2022) VENTURINI, Gabriela; BES, Taniela; KULA, Tomasz; LI, Mamie; SHROCK, Ellen; ELLEDGE, Stephen; SABINO, Ester Cerdeira; KRIEGER, Jose; PEREIRA, Alexandre; SEIDMAN, Jonathan G.; SEIDMAN, Christine E.conferenceObject Predictors of death and myocardial infarction in patients with refractory angina(2014) POPPI, N. Tavares; DOURADO, L. O. C.; VENTURINI, G.; ADAM, E. L.; LEITE, T. N. P.; CESAR, L. A. Machado; PEREIRA, A. C.; GOWDAK, L. H. W.- Variation of mechanical properties and quantitative proteomics of VSMC along the arterial tree(2014) DINARDO, Carla Luana; VENTURINI, Gabriela; ZHOU, Enhua H.; WATANABE, Ii Sei; CAMPOS, Luciene Cristina Gastalho; DARIOLLI, Rafael; MOTTA-LEAL-FILHO, Joaquim Mauricio da; CARVALHO, Valdemir Melechco; CARDOZO, Karina Helena Morais; KRIEGER, Jose Eduardo; ALENCAR, Adriano Mesquita; PEREIRA, Alexandre CostaVascular smooth muscle cells (VSMCs) are thought to assume a quiescent and homogeneous mechanical behavior after arterial tree development phase. However, VSMCs are known to be molecularly heterogeneous in other aspects and their mechanics may play a role in pathological situations. Our aim was to evaluate VSMCs from different arterial beds in terms of mechanics and proteomics, as well as investigate factors that may influence this phenotype. VSMCs obtained from seven arteries were studied using optical magnetic twisting cytometry (both in static state and after stretching) and shotgun proteomics. VSMC mechanical data were correlated with anatomical parameters and ultrastructural images of their vessels of origin. Femoral, renal, abdominal aorta, carotid, mammary, and thoracic aorta exhibited descending order of stiffness (G, P < 0.001). VSMC mechanical data correlated with the vessel percentage of elastin and amount of surrounding extracellular matrix (ECM), which decreased with the distance from the heart. After 48 h of stretching simulating regional blood flow of elastic arteries, VSMCs exhibited a reduction in basal rigidity. VSMCs from the thoracic aorta expressed a significantly higher amount of proteins related to cytoskeleton structure and organization vs. VSMCs from the femoral artery. VSMCs are heterogeneous in terms of mechanical properties and expression/organization of cytoskeleton proteins along the arterial tree. The mechanical phenotype correlates with the composition of ECM and can be modulated by cyclic stretching imposed on VSMCs by blood flow circumferential stress.
- Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients(2020) PUA, Chee Jian; THAM, Nevin; CHIN, Calvin W. L.; WALSH, Roddy; KHOR, Chiea Chuen; TOEPFER, Christopher N.; REPETTI, Giuliana G.; GARFINKEL, Amanda C.; EWOLDT, Jourdan F.; CLOONAN, Paige; CHEN, Christopher S.; LIM, Shi Qi; CAI, Jiashen; LOO, Li Yang; KONG, Siew Ching; CHIANG, Charleston W. K.; WHIFFIN, Nicola; MARVAO, Antonio de; LIO, Pei Min; HII, An An; YANG, Cheng Xi; LE, Thu Thao; BYLSTRA, Yasmin; LIM, Weng Khong; TEO, Jing Xian; PADILHA, Kallyandra; SILVA, Gabriela V.; PAN, Bangfen; GOVIND, Risha; BUCHAN, Rachel J.; BARTON, Paul J. R.; TAN, Patrick; FOO, Roger; YIP, James W. L.; WONG, Raymond C. C.; CHAN, Wan Xian; PEREIRA, Alexandre C.; TANG, Hak Chiaw; JAMUAR, Saumya Shekhar; WARE, James S.; SEIDMAN, Jonathan G.; SEIDMAN, Christine E.; COOK, Stuart A.Background: To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry. Methods: We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies. Results: Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%, P<0.0001) but an excess of variants of uncertain significance (24%, P<0.0001), as compared to Whites (pathogenic/likely pathogenic: 31%, excess of variants of uncertain significance: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency [AF]=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055, P=0.0057, genome aggregation database-East Asian AF=0.0062, P=0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, P<0.0001, genome aggregation database-East Asian AF=0.0009, P<0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared with noncarriers while its etiological fraction is limited (0.70 [95% CI, 0.35-0.86]) and thus TNNI3:p.R79C is considered variant of uncertain significance. Mutant TNNT2:p.R286H iPSC-CMs (induced pluripotent stem cells derived cardiomyocytes) show hypercontractility, increased metabolic requirements, and cellular hypertrophy and the etiological fraction (0.93 [95% CI, 0.83-0.97]) support the likely pathogenicity of TNNT2:p.R286H. Conclusions: As compared with Whites, Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-White populations.