Person: Shah, Ravi
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Shah
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Ravi
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Shah, Ravi
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Publication Messenger RNA and MicroRNA transcriptomic signatures of cardiometabolic risk factors(BioMed Central, 2017) McManus, David D.; Rong, Jian; Huan, Tianxiao; Lacey, Sean; Tanriverdi, Kahraman; Munson, Peter J.; Larson, Martin G.; Joehanes, Roby; Murthy, Venkatesh; Shah, Ravi; Freedman, Jane E.; Levy, DanielBackground: Cardiometabolic (CM) risk factors are heritable and cluster in individuals. We hypothesized that CM risk factors are associated with multiple shared and unique mRNA and microRNA (miRNA) signatures. We examined associations of mRNA and miRNA levels with 6 CM traits: body mass index, HDL-cholesterol and triglycerides, fasting glucose, and systolic and diastolic blood pressures through cross-sectional analysis of 2812 Framingham Heart Study who had whole blood collection for RNA isolation for mRNA and miRNA expression studies and who consented to genetic research. We excluded participants taking medication for hypertension, dyslipidemia, or diabetes. We measured mRNA (n = 17,318; using the Affymetrix GeneChip Human Exon 1.0 ST Array) and miRNA (n = 315; using qRT-PCR) expression in whole blood. We used linear regression for mRNA analyses and a combination of linear and logistic regression for miRNA analyses. We conducted miRNA-mRNA coexpression and gene ontology enrichment analyses to explore relations between pleiotropic miRNAs, mRNA expression, and CM trait clustering. Results: We identified hundreds of significant associations between mRNAs, miRNAs, and individual CM traits. Four mRNAs (FAM13A, CSF2RB, HIST1H2AC, WNK1) were associated with all 6 CM traits (FDR < 0.001) and four miRNAs (miR-197-3p, miR-328, miR-505-5p, miR-145-5p) were associated with four CM traits (FDR < 0.05). Twelve mRNAs, including WNK1, that were coexpressed with the four most pleiotropic miRNAs, were also miRNA targets. mRNAs coexpressed with pleiotropic miRNAs were enriched for RNA metabolism (miR-505-5p), ubiquitin-dependent protein catabolism (miR-197-3p, miR-328) and chromatin assembly (miR-328). Conclusions: We identified mRNA and miRNA signatures of individual CM traits and their clustering. Implicated transcripts may play causal roles in CM risk or be downstream consequences of CM risk factors on the transcriptome. Studies are needed to establish whether or not pleiotropic circulating transcripts illuminate causal pathways for CM risk. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3533-9) contains supplementary material, which is available to authorized users.Publication Risk Stratification by Regadenoson Stress Magnetic Resonance Imaging in Patients With Known or Suspected Coronary Artery Disease(Elsevier BV, 2014) Abbasi, Siddique Akbar; Heydari, Bobak; Shah, Ravi; Murthy, Venkatesh; Zhang, Ying-Yi; Blankstein, Ron; Steigner, Michael; Jerosch-Herold, Michael; Kwong, RaymondThe aim of this study was to investigate the association between major adverse cardiovascular events (MACEs) and inducible ischemia on regadenoson cardiac magnetic resonance (CMR) myocardial perfusion imaging (MPI) performed at 3.0 T. Regadenoson stress CMR MPI is increasingly used to assess patients with suspected ischemia; however, its value in patient prognostication and risk reclassification is only emerging. A total of 346 patients with suspected ischemia who were referred for regadenoson CMR were studied. The prognostic association of presence of inducible ischemia by CMR with MACEs was determined. In addition, we assessed the extent of net reclassification improvement by CMR beyond a clinical risk model. There were 52 MACEs during a median follow-up period of 1.9 years. Patients with inducible ischemia were fourfold more likely to experience MACEs (hazard ratio, 4.14, 95% confidence interval 2.37 to 7.24, p <0.0001). In the best overall model, presence of inducible ischemia conferred a 2.6-fold increased hazard for MACEs adjusted to known clinical risk markers (adjusted hazard ratio 2.59, 95% confidence interval 1.30 to 5.18, p = 0.0069). Patients with no inducible ischemia experienced a low rate of cardiac death and myocardial infarction (0.6% per patient-year), whereas those with inducible ischemia had an annual event rate of 3.2%. Net reclassification improvement across risk categories (low <5%, intermediate 5% to 10%, and high >10%) by CMR was 0.29 (95% confidence interval 0.15 to 0.44), and continuous net reclassification improvement was 0.58. In conclusion, in patients with clinical suspicion of myocardial ischemia, regadenoson stress CMR MPI provides robust risk stratification. CMR MPI negative for ischemia was associated with a very low annual rate of hard cardiac events. In addition, CMR MPI provides effective risk reclassification in a substantial proportion of patients.Publication Left Atrial Passive Emptying Function Determined by Cardiac Magnetic Resonance Predicts Atrial Fibrillation Recurrence After Pulmonary Vein Isolation(Ovid Technologies (Wolters Kluwer Health), 2014) Dodson, John; Neilan, Tomas; Shah, Ravi; Farhad, H.; Blankstein, Ron; Steigner, Michael; Michaud, Gregory F.; John, Roy M.; Abbasi, Siddique Akbar; Jerosch-Herold, Michael; Kwong, RaymondBackground While pulmonary vein isolation (PVI) has become a mainstream therapy for selected patients with atrial fibrillation (AF), late recurrent AF is common and its risk factors remain poorly defined. The purpose of our study was to test the hypothesis that reduced left atrial passive emptying function (LAPEF) as determined by cardiac magnetic resonance (CMR) has a strong association with late recurrent AF following PVI. Methods and Results 346 AF patients referred for CMR PV mapping prior to PVI were included. Maximum LA volumes (VOLmax) and volumes before atrial contraction (VOLbac) were measured; LAPEF was calculated as (VOLmax − VOLbac)/VOLmax × 100. Kaplan-Meier curves were constructed to determine late recurrent AF stratified by LAPEF quintile. Cox proportional hazards regression was used to adjust for known markers of recurrence. Over a median follow-up of 27 months, 124 patients (35.8%) experienced late recurrent AF. Patients with recurrence were more likely to have non-paroxysmal AF (75.8% vs. 51.4%, P<0.01), higher mean VOLmax (60.2 ml/m2 vs. 52.8 ml/m2, P<0.01), and lower mean LAPEF (19.1% vs. 26.0%, P<0.01). Patients in the lowest LAPEF quintile were at highest risk of developing recurrent AF (two-year recurrence lowest vs. highest: 60.5% vs. 17.3%, P<0.01). After adjusting for known predictors of recurrence, patients with low LAPEF remained significantly more likely to recur (HR lowest vs. highest quintile = 3.92, 95% CI 2.01–7.65). Conclusion We found a strong association between LAPEF and recurrent AF after PVI that persisted after multivariable adjustment.Publication Vasodilator Stress Perfusion CMR Imaging Is Feasible and Prognostic in Obese Patients(Elsevier BV, 2014) Shah, Ravi; Heydari, Bobak; Coelho-Filho, Otavio; Abbasi, Siddique Akbar; Feng, Jiazhuo H.; Neilan, Tomas; Francis, Sanjeev A.; Blankstein, Ron; Steigner, Michael; Jerosch-Herold, Michael; Kwong, RaymondObjectives This study sought to determine feasibility and prognostic performance of stress cardiac magnetic resonance (CMR) in obese patients (body mass index [BMI] ≥30 kg/m2). Background Current stress imaging methods remain limited in obese patients. Given the impact of the obesity epidemic on cardiovascular disease, alternative methods to effectively risk stratify obese patients are needed. Methods Consecutive patients with a BMI ≥30 kg/m2 referred for vasodilating stress CMR were followed for major adverse cardiovascular events (MACE), defined as cardiac death or nonfatal myocardial infarction. Univariable and multivariable Cox regressions for MACE were performed to determine the prognostic association of inducible ischemia or late gadolinium enhancement (LGE) by CMR beyond traditional clinical risk indexes. Results Of 285 obese patients, 272 (95%) completed the CMR protocol, and among these, 255 (94%) achieved diagnostic imaging quality. Mean BMI was 35.4 ± 4.8 kg/m2, with a maximum weight of 200 kg. Reasons for failure to complete CMR included claustrophobia (n = 4), intolerance to stress agent (n = 4), poor gating (n = 4), and declining participation (n = 1). Sedation was required in 19 patients (7%; 2 patients with intravenous sedation). Sixteen patients required scanning by a 70-cm-bore system (6%). Patients without inducible ischemia or LGE experienced a substantially lower annual rate of MACE (0.3% vs. 6.3% for those with ischemia and 6.7% for those with ischemia and LGE). Median follow-up of the cohort was 2.1 years. In a multivariable stepwise Cox regression including clinical characteristics and CMR indexes, inducible ischemia (hazard ratio 7.5; 95% confidence interval: 2.0 to 28.0; p = 0.002) remained independently associated with MACE. When patients with early coronary revascularization (within 90 days of CMR) were censored on the day of revascularization, both presence of inducible ischemia and ischemia extent per segment maintained a strong association with MACE. Conclusions Stress CMR is feasible and effective in prognosticating obese patients, with a very low negative event rate in patients without ischemia or infarction.Publication The Incidence, Pattern, and Prognostic Value of Left Ventricular Myocardial Scar by Late Gadolinium Enhancement in Patients With Atrial Fibrillation(Elsevier BV, 2013) Neilan, Tomas; Shah, Ravi; Abbasi, Siddique Akbar; Farhad, Hoshang; Groarke, John; Dodson, John; Coelho-Filho, Otavio; McMullan, Ciaran Joseph; Heydari, Bobak; Michaud, Gregory F.; John, Roy M.; van der Geest, Rob; Steigner, Michael; Blankstein, Ron; Jerosch-Herold, Michael; Kwong, RaymondObjectives We aimed to identify the frequency, pattern, and prognostic significance of left ventricular (LV) late gadolinium enhancement (LGE) in patients with atrial fibrillation (AF). Background There are limited data on the presence, pattern, and prognostic significance of LV myocardial fibrosis in patients with AF. Late gadolinium enhancement during cardiac magnetic resonance (CMR) is a marker for myocardial fibrosis. Methods We studied a consecutive group of 664 patients without known prior myocardial infarction being referred for radiofrequency ablation of AF. CMR was requested to assess pulmonary venous anatomy. Results Overall, 73% were male, with an average age of 56 years, and an ejection fraction of 55±10%. Left ventricular LGE was found in 88 patients (13%). The endpoint was all-cause mortality, and in this cohort we observed 68 deaths over a median follow-up period of 42 months. On univariable analysis, age (HR 1.05, CI 1.03–1.08, LRχ2 15.2, p=0.0001), diabetes (HR 2.39, CI 1.41–4.09, LRχ210.3, p=0.001), a history of heart failure (HR 1.78, CI 1.09–2.91, LRχ2 5.37, p=0.02), left atrial dimension (HR 1.04, CI 1.01–1.08, LRχ2 6.47, p=0.01), presence of LGE (HR 5.08, CI 3.08–8.36, LRχ2 28.8, p<0.0001), and LGE extent (HR 1.15, CI 1.10–1.21, LRχ2 35.6, p<0.0001) provided the strongest association with mortality. The mortality rate was 8.1% per patient-years in patients with LGE vs. 2.3% patients without LGE. In the best overall multivariable model for mortality, age and the extent of LGE were independent predictors of mortality. Indeed, each 1% increase in LGE associated with a 15% increased risk of death. Conclusions In patients with AF, LV LGE is a frequent finding and is a powerful predictor of mortality.Publication Stress Cardiac Magnetic Resonance Imaging Provides Effective Cardiac Risk Reclassification in Patients With Known or Suspected Stable Coronary Artery Disease(Ovid Technologies (Wolters Kluwer Health), 2013) Shah, Ravi; Heydari, Bobak; Coelho-Filho, O.; Murthy, Venkatesh; Abbasi, Siddique Akbar; Feng, J. H.; Pencina, M.; Neilan, Tomas; Meadows, J. L.; Francis, Sanjeev A.; Blankstein, Ron; Steigner, Michael; Di Carli, Marcelo; Jerosch-Herold, Michael; Kwong, RaymondBackground A recent large-scale clinical trial found that an initial invasive strategy does not improve cardiac outcomes beyond optimized medical therapy in patients with stable coronary artery disease (CAD). Novel methods to stratify at-risk patients may refine therapeutic decisions to improve outcomes. Methods and Results In a cohort of 815 consecutive patients referred for evaluation of myocardial ischemia, we determined the net reclassification improvement of the risk of cardiac death or nonfatal MI (MACE) incremental to clinical risk models, using guideline–based low (<1%), moderate (1–3%), and high (>3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated strong association with MACE (hazard ratio 14.66, P<0.0001) with low negative event rates of MACE and cardiac death (0.6% and 0.4%). This prognostic robustness maintained in patients with prior CAD (hazard ratio 8.17, P<0.0001, and 1.3% and 0.6%, respectively). Adding inducible ischemia to the multivariable clinical risk model (age and prior CAD adjusted) improved discrimination of MACE (C-statistic 0.81 to 0.86, P=0.04; Adjusted hazard ratio 7.37, P<0.0001) and reclassified 91.5% of patients at moderate pre-test risk (65.7% to low risk; 25.8% to high risk) with corresponding changes in the observed event rates (0.3%/year and 4.9%/year, for low and high risk post-test, respectively). Categorical net reclassification index was 0.229 (95% CI 0.063–0.391). Continuous NRI was 1.11 (95% CI 0.81–1.39). Conclusions Stress CMR effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pre-test clinical risk and in patients with prior CAD.Publication Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes(American Diabetes Association, 2017) Shah, Ravi; Murthy, Venkatesh; Pacold, Michael; Danielson, Kirsty; Tanriverdi, Kahraman; Larson, Martin G.; Hanspers, Kristina; Pico, Alexander; Mick, Eric; Reis, Jared; de Ferranti, Sarah; Freinkman, Elizaveta; Levy, Daniel; Hoffmann, Udo; Osganian, Stavroula; Das, Saumya; Freedman, Jane E.OBJECTIVE Insulin resistance (IR) is a hallmark of obesity and metabolic disease. Circulating extracellular RNAs (ex-RNAs), stable RNA molecules in plasma, may play a role in IR, though most studies on ex-RNAs in IR are small. We sought to characterize the relationship between ex-RNAs and metabolic phenotypes in a large community-based human cohort. RESEARCH DESIGN AND METHODS We measured circulating plasma ex-RNAs in 2,317 participants without diabetes in the Framingham Heart Study (FHS) Offspring Cohort at cycle 8 and defined associations between ex-RNAs and IR (measured by circulating insulin level). We measured association between candidate ex-RNAs and markers of adiposity. Sensitivity analyses included individuals with diabetes. In a separate cohort of 90 overweight/obese youth, we measured selected ex-RNAs and metabolites. Biology of candidate microRNAs was investigated in silico. RESULTS The mean age of FHS participants was 65.8 years (56% female), with average BMI 27.7 kg/m2; participants in the youth cohort had a mean age of 15.5 years (60% female), with mean BMI 33.8 kg/m2. In age-, sex-, and BMI-adjusted models across 391 ex-RNAs in FHS, 18 ex-RNAs were associated with IR (of which 16 were microRNAs). miR-122 was associated with IR and regional adiposity in adults and IR in children (independent of metabolites). Pathway analysis revealed metabolic regulatory roles for miR-122, including regulation of IR pathways (AMPK, target of rapamycin signaling, and mitogen-activated protein kinase). CONCLUSIONS These results provide translational evidence in support of an important role of ex-RNAs as novel circulating factors implicated in IR.Publication Left atrial passive function after aortic valve replacement in aortic stenosis(BioMed Central, 2014) Farhad, Hoshang; Neilan, Tomas; Abbasi, Siddique; Shah, Ravi; Feng, Jiazuo; Kwong, Raymond Y; Jerosch-Herold, MichaelPublication Weight loss decreases progressive left ventricular remodeling: The Multi-Ethnic Study of Atherosclerosis(BioMed Central, 2014) Abbasi, Siddique A; Shah, Ravi; Murthy, Venkatesh L; Eng, John; Wu, Colin; Ouyang, Pamela; Kwong, Raymond; Goldfine, Allison; Bluemke, David; Lima, Joao A; Jerosch-Herold, MichaelPublication Myocardial strain imaging with radial acquisitions (SIRA) reduces tag fading compared to Cartesian sampling(BioMed Central, 2014) Hulten, Edward; Shah, Ravi; Abbasi, Siddique; Neilan, Tomas; Feng, Jiazuo; Groarke, John; Waller, Alfonso H; Blankstein, Ron; Kwong, Raymond; Jerosch-Herold, Michael
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