Association between Cystatin C and MRI Measures of Left Ventricular Structure and Function: Multi-Ethnic Study of Atherosclerosis

Introduction. Reduced kidney function, approximated by elevated cystatin C, is associated with diastolic dysfunction, heart failure, and cardiovascular mortality; however, the precise mechanism(s) that account for these relationships remains unclear. Understanding the relationship between cystatin C and subclinical left ventricular (LV) remodeling, across ethnically diverse populations, may help explain the mechanisms underlying the association of kidney dysfunction with heart failure and cardiovascular mortality. Methods. Measures of cystatin C and LV parameters were obtained from the multi-ethnic study of atherosclerosis (MESA) cohort at baseline (N = 4, 970 with complete data on cystatin C and LV parameters). LV parameters; LV end-diastolic (LVEDV) and end-systolic volumes (LVESV), LV mass (LVM), concentricity (LV mass/LV end-diastolic volume), and LV ejection fraction (LVEF) were measured using magnetic resonance imaging. Nested linear models were used to examine the relationship between higher quartiles of cystatin C and LV parameters, with and without adjustment for demographics, height, and weight, and traditional cardiovascular risk factors. Similar analyses were performed stratified by ethnicity and gender. Results. A fully adjusted model demonstrated a linear relationship between higher quartiles of cystatin C and lower LVEDV, (Mean ± SE, 128 ± 0.7, 128 ± 0.7, 126 ± 0.7, 124 ± 0.8 mL; P = 0.0001). Associations were also observed between higher quartiles of cystatin C and lower LVESV (P = 0.04) and concentricity (P = 0.0001). In contrast, no association was detected between cystatin C and LVM or LVEF. In analyses stratified by race and gender, the patterns of association between cystatin C quartiles and LV parameters were qualitatively similar to the overall association. Conclusion. Cystatin C levels were inversely associated with LVEDV and LVESV with a disproportionate decrease in LVEDV compared to LVM in a multi-ethnic population. This morphometric pattern of concentric left ventricular remodeling, may in part explain the process by which kidney dysfunction leads to diastolic dysfunction, heart failure and cardiovascular mortality

Favorable Outcomes of LVAD as Bridge to Simultaneous Heart-Kidney Transplantation

Background Chronic kidney disease (CKD) is an established risk factor for incident cardiovascular disease and progression of heart failure disease state, and is associated with decreased survival after left ventricular assist device (LVAD) therapy or heart transplantation (HT). Combined heart-kidney transplantation (HKT) compared with isolated HT recently has been shown to have survival advantage among patients whose estimated glomerular filtration rate is less than 37 ml/min/m2. Data on LVAD to HKT are limited. Methods At our center, a total of 803 patients have received HT, 594 patients LVAD therapy, and 23 patients HKT from single donors; of those 23, 15 were without the use of LVAD and 8 were after support with LVAD. Results Kaplan-Meier survival analysis found LVAD-supported patients with CKD stages 4 or 5 had statistically worse 24-month survival after HT as compared with those with CKD stage 1, 2, and 3 (58% vs 88%, p=0.01). Patients who received combined HKT after LVAD had comparable 24-month survival with those who received HKT without LVAD (87% and 85%, p=NS); both groups had numerically better survival compared with those who had CKD (stage 4-5) with isolated HT (58%). Conclusions Patients supported with LVAD who demonstrate advanced CKD (stage 4-5) have worse 24-month post-HT survival compared with those with less advanced CKD (stage 1-3). Combined HKT after LVAD support is feasible and confers comparable 24-month survival compared with HKT without prior LVAD therapy. Our study supports combined HKT for select LVAD patients with advanced CKD (stage 4-5)

Right ventricular dyssynchrony in patients with pulmonary hypertension is associated with disease severity and functional class

BACKGROUND: Abnormalities in right ventricular function are known to occur in patients with pulmonary arterial hypertension. OBJECTIVE: Test the hypothesis that chronic elevation in pulmonary artery systolic pressure delays mechanical activation of the right ventricle, termed dyssynchrony, and is associated with both symptoms and right ventricular dysfunction. METHODS: Fifty-two patients (mean age 46 ± 15 years, 24 patients with chronic pulmonary hypertension) were prospectively evaluated using several echocardiographic parameters to assess right ventricular size and function. In addition, tissue Doppler imaging was also obtained to assess longitudinal strain of the right ventricular wall, interventricular septum, and lateral wall of the left ventricle and examined with regards to right ventricular size and function as well as clinical variables. RESULTS: In this study, patients with chronic pulmonary hypertension had statistically different right ventricular fractional area change (35 ± 13 percent), right ventricular end-systolic area (21 ± 10 cm(2)), right ventricular Myocardial Performance Index (0.72 ± 0.34), and Eccentricity Index (1.34 ± 0.37) than individuals without pulmonary hypertension (51 ± 5 percent, 9 ± 2 cm(2), 0.27 ± 0.09, and 0.97 ± 0.06, p < 0.005, respectively). Furthermore, peak longitudinal right ventricular wall strain in chronic pulmonary hypertension was also different -20.8 ± 9.0 percent versus -28.0 ± 4.1 percent, p < 0.01). Right ventricular dyssynchrony correlated very well with right ventricular end-systolic area (r = 0.79, p < 0.001) and Eccentricity Index (r = 0.83, p < 0.001). Furthermore, right ventricular dyssynchrony correlates with pulmonary hypertension severity index (p < 0.0001), World Health Organization class (p < 0.0001), and number of hospitalizations (p < 0.0001). CONCLUSION: Lower peak longitudinal right ventricular wall strain and significantly delayed time-to-peak strain values, consistent with right ventricular dyssynchrony, were found in a small heterogeneous group of patients with chronic pulmonary hypertension when compared to individuals without pulmonary hypertension. Furthermore, right ventricular dyssynchrony was associated with disease severity and compromised functional class

Attenuation of Salt-Induced Cardiac Remodeling and Diastolic Dysfunction by the GPER Agonist G-1 in Female mRen2.Lewis Rats

The G protein-coupled estrogen receptor (GPER) is expressed in various tissues including the heart. Since the mRen2.Lewis strain exhibits salt-dependent hypertension and early diastolic dysfunction, we assessed the effects of the GPER agonist (G-1, 40 nmol/kg/hr for 14 days) or vehicle (VEH, DMSO/EtOH) on cardiac function and structure.Intact female mRen2.Lewis rats were fed a normal salt (0.5% sodium; NS) diet or a high salt (4% sodium; HS) diet for 10 weeks beginning at 5 weeks of age.Prolonged intake of HS in mRen2.Lewis females resulted in significantly increased blood pressure, mildly reduced systolic function, and left ventricular (LV) diastolic compliance (as signified by a reduced E deceleration time and E deceleration slope), increased relative wall thickness, myocyte size, and mid-myocardial interstitial and perivascular fibrosis. G-1 administration attenuated wall thickness and myocyte hypertrophy, with nominal effects on blood pressure, LV systolic function, LV compliance and cardiac fibrosis in the HS group. G-1 treatment significantly increased LV lusitropy [early mitral annular descent (e')] independent of prevailing salt, and improved the e'/a' ratio in HS versus NS rats (P<0.05) as determined by tissue Doppler.Activation of GPER improved myocardial relaxation in the hypertensive female mRen2.Lewis rat and reduced cardiac myocyte hypertrophy and wall thickness in those rats fed a high salt diet. Moreover, these advantageous effects of the GPER agonist on ventricular lusitropy and remodeling do not appear to be associated with overt changes in blood pressure

Methods development for the in vitro assessment of cutaneous drug metabolism

The major objective of this work was development of procedures for the quantification of cutaneous microsomal cytochrome P-450 mediated metabolism using model substrates. The Fischer-344 rat was the species of choice for this developmental work. The versatility of this method was demonstrated through its application to a variety of species including man. An extension of the rat microsomal work entailed the use of inducing agents, specifically, the Aroclor series of polychlorinated biphenyls. The effects of these inducing agents were demonstrated and characterized in skin and liver with respect to microsomal marker enzymes and substrate metabolism. In addition to the microsomal studies, the use of rat skin explants in culture, provided a simple system for the characterization of phase I and phase II coupled metabolism of the model substrates

Heart Transplantation: 21st century

Video/audio presentation of Aurora St. Luke\u27s Transplant Grand Rounds on April 23, 2014, presented by Vinay Thohan, MD, FACC. 60 minutes