Rakesh K. Mishra

Associations between Kidney Function and Subclinical Cardiac Abnormalities in CKD

Heart failure is a common consequence of CKD, and it portends high risk for mortality. However, among patients without known heart failure, the associations of different stages of estimated GFR (eGFR) with changes in cardiac structure and function are not well described. Here, we performed a cross-sectional analysis to study these associations among 3487 participants of the Chronic Renal Insufficiency Cohort Study. We estimated GFR using cystatin C. The prevalence of left ventricular hypertrophy (LVH) assessed by echocardiography was 32%, 48%, 57%, and 75% for eGFR categories ≥60, 45-59, 30-44, and <30 ml/min per 1.73 m(2), respectively. In fully adjusted multivariable analyses, subjects with eGFR levels of <30 ml/min per 1.73 m(2) had twofold higher odds of LVH (OR=2.20, 95% CI=1.40-3.40; P<0.001) relative to subjects with eGFR≥60 ml/min per 1.73 m(2). This reduction in kidney function also significantly associated with abnormal LV geometry but not diastolic or systolic dysfunction. An eGFR of 30-44 ml/min per 1.73 m(2) also significantly associated with LVH and abnormal LV geometry compared with eGFR≥60 ml/min per 1.73 m(2). In summary, in this large CKD cohort, reduced kidney function associated with abnormal cardiac structure. We did not detect significant associations between kidney function and systolic or diastolic function after adjusting for potential confounding variables.

Association of cardiac troponin T with left ventricular structure and function in CKD

BACKGROUNDnSerum cardiac troponin T (cTnT) is associated with increased risk of heart failure and cardiovascular death in several population settings. We evaluated associations of cTnT levels with cardiac structural and functional abnormalities in a cohort of patients with chronic kidney disease (CKD) without heart failure.nnnSTUDY DESIGNnCross-sectional.nnnSETTING & PARTICIPANTSnChronic Renal Insufficiency Cohort (CRIC; N=3,243).nnnPREDICTORnThe primary predictor was cTnT level. Secondary predictors included demographic and clinical characteristics, hemoglobin level, high-sensitivity C-reactive protein level, and estimated glomerular filtration rate using cystatin C.nnnOUTCOMESnEchocardiography was used to determine left ventricular (LV) mass and LV systolic and diastolic function.nnnMEASUREMENTSnCirculating cTnT was measured in stored sera using the highly sensitive assay. Logistic and linear regression models were used to examine associations of cTnT level with each echocardiographic outcome.nnnRESULTSncTnT was detectable in 2,735 (84%) persons; median level was 13.3 (IQR, 7.7-23.8) pg/mL. Compared with undetectable cTnT (<3.0 pg/mL), the highest quartile (23.9-738.7 pg/mL) was approximately 2 times as likely to have LV hypertrophy (OR, 2.43; 95% CI, 1.44-4.09) in the fully adjusted model. cTnT level had a more modest association with LV systolic dysfunction; as a log-linear variable, a significant association was present in the fully adjusted model (OR of 1.4 [95% CI, 1.2-1.7] per 1-log unit; P < 0.001). There was no significant independent association between cTnT level and LV diastolic dysfunction. When evaluated as a screening test, cTnT level functioned only modestly for LV hypertrophy and concentric hypertrophy detection (area under the curve, 0.64 for both), with weaker areas under the curve for the other outcomes.nnnLIMITATIONSnThe presence of coronary artery disease was not formally assessed using either noninvasive or angiographic techniques in this study.nnnCONCLUSIONSnIn this large CKD cohort without heart failure, detectable cTnT had a strong association with LV hypertrophy, a more modest association with LV systolic dysfunction, and no association with diastolic dysfunction. These findings indicate that circulating cTnT levels in patients with CKD are predominantly an indicator of pathologic LV hypertrophy.

Association of N-terminal pro-B-type natriuretic peptide with left ventricular structure and function in chronic kidney disease (from the Chronic Renal Insufficiency Cohort [CRIC]).

We evaluated the cross-sectional associations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) with cardiac structural and functional abnormalities in a cohort of patients with chronic kidney disease without clinical heart failure, the Chronic Renal Insufficiency Cohort (n = 3,232). The associations of NT-proBNP with echocardiographically determined left ventricular (LV) mass and LV systolic and diastolic function were evaluated using multivariate logistic and linear regression models. Reclassification of participants predicted risk of LV hypertrophy (LVH), systolic and diastolic dysfunction was performed using a category-free net reclassification improvement index that compared a clinical model with and without NT-proBNP. The median NT-proBNP was 126.6 pg/ml (interquartile range 55.5 to 303.7). The greatest quartile of NT-proBNP was associated with a nearly threefold odds of LVH (odds ratio 2.7, 95% confidence interval [CI] 1.8 to 4.0) and LV systolic dysfunction (odds ratio 2.7, 95% CI 1.7 to 4.5) and a twofold odds of diastolic dysfunction (odds ratio 2.0, 95% CI 1.3 to 2.9) in the fully adjusted models. When evaluated alone as a screening test, NT-proBNP functioned modestly for the detection of LVH (area under the curve 0.66) and LV systolic dysfunction (area under the curve 0.62) and poorly for the detection of diastolic dysfunction (area under the curve 0.51). However, when added to the clinical model, NT-proBNP significantly reclassified participants likelihood of having LVH (net reclassification improvement 0.14, 95% CI 0.13-0.15; p <0.001) and LV systolic dysfunction (net reclassification improvement 0.28, 95% CI 0.27 to 0.30; p <0.001) but not diastolic dysfunction (net reclassification improvement 0.10, 95% CI 0.10 to 0.11; p = 0.07). In conclusion, in this large chronic kidney disease cohort without heart failure, NT-proBNP had strong associations with prevalent LVH and LV systolic dysfunction.

Predictors of high sensitivity cardiac troponin T in chronic kidney disease patients: a cross-sectional study in the chronic renal insufficiency cohort (CRIC).

BackgroundCardiac troponin T is independently associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). Serum levels of high sensitivity cardiac troponin T (hs-TnT) reflect subclinical myocardial injury in ambulatory patients. We sought to determine the distribution and predictors of hs-TnT in CKD patients without overt cardiovascular disease (CVD).MethodsWe studied 2464 participants within the multi-ethnic Chronic Renal Insufficiency Cohort (CRIC) who did not have self-reported CVD. We considered renal and non-renal factors as potential determinants of hs-TnT, including demographics, comorbidities, left ventricular (LV) mass, serologic factors, estimated glomerular filtration rate (eGFR) and albumin to creatinine ratio.ResultsHs-TnT was detectable in 81% of subjects, and the median (IQR) hs-TnT was 9.4 pg/ml (4.3-18.3). Analysis was performed using Tobit regression, adjusting for renal and non-renal factors. After adjustment, lower eGFR was associated with higher expected hs-TnT; participants with eGFR <u200930 ml/min/1.73u2009m2 had 3-fold higher expected hs-TnT compared to subjects with eGFR >u200960. Older age, male gender, black race, LV mass, diabetes and higher blood pressure all had strong, independent associations with higher expected hs-TnT.ConclusionsKnowledge of the determinants of hs-TnT in this cohort may guide further research on the pathology of heart disease in patients with CKD and help to stratify sub-groups of CKD patients at higher cardiovascular risk.

Patient-specific finite element based analysis of ventricular myofiber stress after Coapsys: Importance of residual stress.

BACKGROUNDnWe sought to determine regional myofiber stress after Coapsys device (Myocor, Inc, Maple Grove, MN) implantation using a finite element model of the left ventricle (LV). Chronic ischemic mitral regurgitation is caused by LV remodeling after posterolateral myocardial infarction. The Coapsys device consists of a single trans-LV chord placed below the mitral valve such that when tensioned it alters LV shape and decreases chronic ischemic mitral regurgitation.nnnMETHODSnFinite element models of the LV were based on magnetic resonance images obtained before (preoperatively) and after (postoperatively) coronary artery bypass grafting with Coapsys implantation in a single patient. To determine the effect of Coapsys and LV before stress, virtual Coapsys was performed on the preoperative model. Diastolic and systolic material variables in the preoperative, postoperative, and virtual Coapsys models were adjusted so that model LV volume agreed with magnetic resonance imaging data. Chronic ischemic mitral regurgitation was abolished in the postoperative models. In each case, myofiber stress and pump function were calculated.nnnRESULTSnBoth postoperative and virtual Coapsys models shifted end-systolic and end-diastolic pressure-volume relationships to the left. As a consequence and because chronic ischemic mitral regurgitation was reduced after Coapsys, pump function was unchanged. Coapsys decreased myofiber stress at end-diastole and end-systole in both the remote and infarct regions of the myocardium. However, knowledge of Coapsys and LV prestress was necessary for accurate calculation of LV myofiber stress, especially in the remote zone.nnnCONCLUSIONSnCoapsys decreases myofiber stress at end-diastole and end-systole. The improvement in myofiber stress may contribute to the long-term effect of Coapsys on LV remodeling.

Patient-specific finite element modeling of the Cardiokinetix Parachute® device: effects on left ventricular wall stress and function

AbstractnThe Parachute® (Cardiokinetix, Inc., Menlo Park, California) is a catheter-based device intended to reverse left ventricular (LV) remodeling after antero-apical myocardial infarction. When deployed, the device partitions the LV into upper and lower chambers. To simulate its mechanical effects, we created a finite element LV model based on computed tomography (CT) images from a patient before and 6xa0months after Parachute® implantation. Acute mechanical effects were determined by in silico device implantation (VIRTUAL-Parachute). Chronic effects of the device were determined by adjusting the diastolic and systolic material parameters to better match the 6-month post-implantation CT data and LV pressure data at end-diastole (ED) (POST-OP). Regional myofiber stress and pump function were calculated in each case. The principal finding is that VIRTUAL-Parachute was associated with a 61.2xa0% reduction in the lower chamber myofiber stress at ED. The POST-OP model was associated with a decrease in LV diastolic stiffness and a larger reduction in myofiber stress at the upper (27.1xa0%) and lower chamber (78.4xa0%) at ED. Myofiber stress at end-systole and stroke volume was little changed in the POST-OP case. These results suggest that the primary mechanism of Parachute® is a reduction in ED myofiber stress, which may reverse eccentric post-infarct LV hypertrophy.

B-type Natriuretic Peptides for the Prediction of Cardiovascular Events in Patients With Stable Coronary Heart Disease: The Heart and Soul Study

Background Brain‐type natriuretic peptide (BNP) and the amino‐terminal fragment of its prohormone (NT‐proBNP) are known predictors of cardiovascular outcomes in patients with coronary heart disease; however, the relative prognostic value of these 2 biomarkers for secondary events remains unclear. Methods and Results In 983 participants with stable coronary heart disease, we evaluated the association of BNP and NT‐proBNP with time to hospitalization for heart failure, nonfatal myocardial infarction, stroke or transient ischemic attack, cardiovascular death, and combined major adverse cardiovascular events (MACE). During an average follow‐up of 6.5±3.3 years, both BNP and NT‐proBNP were associated with increased risk of MACE in a multivariable‐adjusted model (hazard ratio per standard deviation of log BNP: 1.58; 95% CI: 1.32 to 1.89; hazard ratio per standard deviation of log NT‐proBNP: 1.84; 95% CI: 1.52 to 2.24). When added to traditional risk factors, NT‐proBNP predicted MACE better than BNP (C statistic: 0.76 versus 0.72, P<0.001). Similarly, the addition of NT‐proBNP resulted in a greater net reclassification improvement for predicting MACE than the addition of BNP (65% for NT‐proBNP, 56% for BNP). Conclusions Both BNP and NT‐proBNP were significant predictors of MACE in stable coronary heart disease; however, NT‐proBNP was superior to BNP for net risk reclassification for MACE.

A pyrene-benzthiazolium conjugate portraying aggregation induced emission, a ratiometric detection and live cell visualization of HSO3(.).

The present study deals with the photophysical property of a pyrene-benzthiazolium conjugate R1, as a strong intramolecular charge transfer (ICT) probe exhibiting long wavelength emission in the red region. Unlike traditional planar polyaromatic hydrocarbons whose aggregation generally quenches the light emission, the pyrene based R1 was found to display aggregation-induced emission (AIE) property along with simultaneous increase in its quantum yield upon increasing the water content of the medium. The R1 exhibits high specificity towards HSO3(-)/SO3(2-) by interrupting its own ICT producing there upon a large ratiometric blue shift of ∼220xa0nm in its emission spectrum. The lowest detection limit for the above measurement was found to be 8.90xa0×xa010(-8)xa0M. The fluorescent detection of HSO3(-) was also demonstrated excellently by test paper strip and silica coated TLC plate incorporating R1. The live cell imaging of HSO3(─) through R1 in HeLa cells was studied using fluorescence microscopic studies. The particle size and morphological features of R1 and R1-HSO3(-) aggregates in aqueous solution were characterized by DLS along with SEM analysis.

Mitral E Wave Deceleration Time to Peak E Velocity Ratio and Cardiovascular Outcome in Hypertensive Patients During Antihypertensive Treatment (from the LIFE Echo-Substudy)

The early mitral flow deceleration time (DTE) is a prognostically validated marker of left ventricular diastolic dysfunction. It has been reported that the DTE is influenced by the loading conditions, which can vary during antihypertensive treatment. We hypothesized that normalization of the DTE for mitral peak E-velocity (mitral deceleration index [MDI]) might better predict incident cardiovascular (CV) events in hypertensive patients during treatment compared to DTE alone or other traditional indexes of diastolic function, such as the mitral E/A ratio. We evaluated 770 hypertensive patients with electrocardiogram findings of left ventricular hypertrophy (age 66 +/- 7 years; 42% women) enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiographic substudy. Echocardiographic examinations were performed annually for 5 years during intensive antihypertensive treatment. We examined the utility of the MDI at baseline and as a time-varying predictor of incident CV events. Of the 770 patients, 70 (9%) had CV events. The baseline MDI was positively associated with age and relative wall thickness and negatively associated with gender and heart rate (all p <0.01). Unadjusted Cox regression analysis showed a positive association between the baseline MDI and CV events (hazard ratio 1.21, 95% confidence interval 1.07 to 1.37, p = 0.002). In the time-varied Cox models, a greater in-treatment MDI was associated with a greater rate of CV events (hazard ratio 1.43, 95% confidence interval 1.05 to 1.93, p = 0.022), independently of the covariates. No significant association was found for in-treatment DTE or any of the prognostically validated indexes of diastolic function. In conclusion, in our population of patients with treated hypertension with electrocardiographic findings of left ventricular hypertrophy, the MDI independently predicted future CV events. Normalization of DTE for E velocity might be preferred to other traditional diastolic function indexes in evaluating diastolic function during antihypertensive treatment.

Left Ventricular Myocardial Contractility Is Depressed in the Borderzone After Posterolateral Myocardial Infarction

BACKGROUNDnContractility in the borderzone (BZ) after anteroapical myocardial infarction (MI) is depressed. We tested the hypothesis that BZ contractility is also decreased after posterolateral MI.nnnMETHODSnFive sheep underwent posterolateral MI. Magnetic resonance imaging (MRI) was performed 2 weeks before and 16 weeks after MI, and left ventricular (LV) volume and regional strain were measured. Finite element (FE) models were constructed, and the systolic material parameter, Tmax, was calculated in the BZ and remote myocardium by minimizing the difference between experimentally measured and calculated LV strain and volume. Sheep were sacrificed 17 weeks after MI, and myocardial muscle fibers were taken from the BZ and remote myocardium. Fibers were chemically demembranated, and isometric developed force, Fmax, was measured at supramaximal [Ca(2+)]. Routine light microscopy was also performed.nnnRESULTSnThere was no difference in Tmax in the remote myocardium before and 16 weeks after MI. However, there was a large decrease (63.3%, p = 0.005) in Tmax in the BZ when compared with the remote myocardium 16 weeks after MI. In addition, there was a significant reduction of BZ Fmax for all samples (18.9%, p = 0.0067). Myocyte cross-sectional area increased by 61% (p = 0.021) in the BZ, but there was no increase in fibrosis.nnnCONCLUSIONSnContractility in the BZ is significantly depressed relative to the remote myocardium after posterolateral MI. The reduction in contractility is due at least in part to a decrease in contractile protein function.