Novel pathways of heart failure with preserved ejection fraction

INTRODUCTION: Diastolic heart failure (HF) i.e., HF with preserved ejection fraction (HFpEF) accounts for ~50% of all clinical HF presentations; but unlike systolic HF i.e., HF with reduced ejection fraction (HFrEF), there are no evidenced based therapies. Obesity is commonly associated with HFpEF. However, there exist a sub-group of obese patients that exhibit a higher survival rate to HFpEF as compared to average patients. Hypertension is the most important risk factor for HFpEF, with a prevalence of 60-89% reported by large controlled trials, epidemiological studies and HF registries. HFpEF morbidity and mortality rates are staggering: 50-60% 5 year mortality rate, 50% 6 month rehospitalization rate and severe clinical disability. However, there remains an incomplete mechanistic understanding about HFpEF. OBJECTIVES: We wanted to explore new pathways related to HFpEF in order to better understand the mechamisms behind its pathophysiology. To do so, we first wanted to explore the potential crosstalk between the heart and adipose tissue during HFpEF by analyzing the adipose tissue in our HFpEF model. Secondly, we sought to test the hypothesis that chronic ETA/ETB inhibition with macitentan (mac) modulates pathologic cardiac remodeling in hypertension-induced HFpEF. METHODS: Mice (20-25 g) were anesthetized, underwent uninephrectomy and received either a continuous infusion of saline (sham) or d-aldosterone (0.3 ug/hour for 4-weeks via osmotic minipumps). All mice were maintained on standard rodent chow and 1.0% sodium chloride drinking water for 4 weeks and then harvested. Second group of mice underwent the same surgical procedure and infusion. They were maintained on standard chow for 2 weeks and then each group was randomized to chow containing macitentan (30 mg/kg/day, HFpEFmac) or standard rodent chow. After 2 additional weeks, the 4 groups of mice (n=4-8/group) were harvested. Blood pressure (BP) was obtained weekly. Prior to sacrifice, body weight and echocardiography parameters (total wall thickness (TWT) and relative wall thickness (RWT)) were determined. We also obtained diastolic dysfunction parameters including deceleration time (DT), isovolumetric relaxation time (IVRT), and E/A ratio. Furthermore, we measured organ weight after harvesting the mice and obtained histological images for the adipose tissues collected. Glucose tolerance test and acute cold tolerance test were performed on HFpEF mice to determine their metabolic state. RESULTS: HFpEF mice developed hypertension, LV hypertrophy, and diastolic dysfunction. Epididymal and inguinal adipose tissue showed significantly reduced weight and adipocyte size. HFpEF mice displayed regular glucose metabolism but were not able to endure a cold tolerance test as their body temperature dropped too low. After 4 weeks, there was no difference in body weight between sham, HFpEF, shammac and HFpEFmac. As expected HFpEF increased systolic BP (117±14 vs 133±16mmHg; P=NS); macitentan did not lower systolic BP after 2 weeks in either shammac or HFpEFmac. Similarly there was no difference in systolic BP between HFpEF and HFpEFmac. Both kidney and spleen weights were increased in HFpEF but not altered by macitentan therapy. There was no change in lung congestion as measured by wet-dry lung ratio. HFpEF increased TWT (0.998±0.04 vs. 0.79±0.11 mm; P<0.01 vs. sham) and RWT (0.686± 0.10 vs. 0.476±0.05 mm; P<0.001 vs. sham) but were modulated by macitentan (HFpEF vs. HFpEFmac; P<0.05 and P<0.001, respectively). There was no difference in chamber size between HFpEF and HFpEFmac. Similarly, IVRT, DT, left ventricular ejection fraction were no different between HFpEF and and HFpEFmac. Furthermore E/A ratio was increased in HFpEF but was not affected by macitentan CONCLUSIONS: Adipose tissue collected from our HFpEF mice displayed a very different phenotype. This demonstrates that inter-tissue communication is definitely occurring between the adipose tissue and the heart. Further research is required to explore what that communication encompasses and how they can be used to improve HFpEF. Macitentan did not lower systolic BP in sham or mice with HFpEF after the development of hypertension. Diastolic dysfunction, as measured by an increased E/A ratio, was not affected by macitentan. Macitentan significantly modulated TWT and RWT after 2 weeks of therapy. It is thus plausible that macitentan may improve HFpEF by improving adverse cardiac remodeling

Novel pathways of heart failure with preserved ejection fraction

INTRODUCTION: Diastolic heart failure (HF) i.e., HF with preserved ejection fraction (HFpEF) accounts for ~50% of all clinical HF presentations; but unlike systolic HF i.e., HF with reduced ejection fraction (HFrEF), there are no evidenced based therapies. Obesity is commonly associated with HFpEF. However, there exist a sub-group of obese patients that exhibit a higher survival rate to HFpEF as compared to average patients. Hypertension is the most important risk factor for HFpEF, with a prevalence of 60-89% reported by large controlled trials, epidemiological studies and HF registries. HFpEF morbidity and mortality rates are staggering: 50-60% 5 year mortality rate, 50% 6 month rehospitalization rate and severe clinical disability. However, there remains an incomplete mechanistic understanding about HFpEF. OBJECTIVES: We wanted to explore new pathways related to HFpEF in order to better understand the mechamisms behind its pathophysiology. To do so, we first wanted to explore the potential crosstalk between the heart and adipose tissue during HFpEF by analyzing the adipose tissue in our HFpEF model. Secondly, we sought to test the hypothesis that chronic ETA/ETB inhibition with macitentan (mac) modulates pathologic cardiac remodeling in hypertension-induced HFpEF. METHODS: Mice (20-25 g) were anesthetized, underwent uninephrectomy and received either a continuous infusion of saline (sham) or d-aldosterone (0.3 ug/hour for 4-weeks via osmotic minipumps). All mice were maintained on standard rodent chow and 1.0% sodium chloride drinking water for 4 weeks and then harvested. Second group of mice underwent the same surgical procedure and infusion. They were maintained on standard chow for 2 weeks and then each group was randomized to chow containing macitentan (30 mg/kg/day, HFpEFmac) or standard rodent chow. After 2 additional weeks, the 4 groups of mice (n=4-8/group) were harvested. Blood pressure (BP) was obtained weekly. Prior to sacrifice, body weight and echocardiography parameters (total wall thickness (TWT) and relative wall thickness (RWT)) were determined. We also obtained diastolic dysfunction parameters including deceleration time (DT), isovolumetric relaxation time (IVRT), and E/A ratio. Furthermore, we measured organ weight after harvesting the mice and obtained histological images for the adipose tissues collected. Glucose tolerance test and acute cold tolerance test were performed on HFpEF mice to determine their metabolic state. RESULTS: HFpEF mice developed hypertension, LV hypertrophy, and diastolic dysfunction. Epididymal and inguinal adipose tissue showed significantly reduced weight and adipocyte size. HFpEF mice displayed regular glucose metabolism but were not able to endure a cold tolerance test as their body temperature dropped too low. After 4 weeks, there was no difference in body weight between sham, HFpEF, shammac and HFpEFmac. As expected HFpEF increased systolic BP (117±14 vs 133±16mmHg; P=NS); macitentan did not lower systolic BP after 2 weeks in either shammac or HFpEFmac. Similarly there was no difference in systolic BP between HFpEF and HFpEFmac. Both kidney and spleen weights were increased in HFpEF but not altered by macitentan therapy. There was no change in lung congestion as measured by wet-dry lung ratio. HFpEF increased TWT (0.998±0.04 vs. 0.79±0.11 mm; P<0.01 vs. sham) and RWT (0.686± 0.10 vs. 0.476±0.05 mm; P<0.001 vs. sham) but were modulated by macitentan (HFpEF vs. HFpEFmac; P<0.05 and P<0.001, respectively). There was no difference in chamber size between HFpEF and HFpEFmac. Similarly, IVRT, DT, left ventricular ejection fraction were no different between HFpEF and and HFpEFmac. Furthermore E/A ratio was increased in HFpEF but was not affected by macitentan CONCLUSIONS: Adipose tissue collected from our HFpEF mice displayed a very different phenotype. This demonstrates that inter-tissue communication is definitely occurring between the adipose tissue and the heart. Further research is required to explore what that communication encompasses and how they can be used to improve HFpEF. Macitentan did not lower systolic BP in sham or mice with HFpEF after the development of hypertension. Diastolic dysfunction, as measured by an increased E/A ratio, was not affected by macitentan. Macitentan significantly modulated TWT and RWT after 2 weeks of therapy. It is thus plausible that macitentan may improve HFpEF by improving adverse cardiac remodeling

Polyelectrolyte interlayers with a broad processing window for high efficiency inverted organic solar cells towards mass production

Neutral polyelectrolyte interfacial layers in organic solar cells are well-known for their ability to tailor the work function of electrodes, improve charge carrier extraction and maximize open circuit voltage. However, they also suffer from low charge carrier conductivity, and therefore the interlayer must be kept thin, which in turn requires very precise deposition. This prerequisite significantly reduces the robustness of the fabrication process and makes such structures difficult to up-scale for roll-to-roll mass production. Herein, we find that by washing the polyelectrolyte layer with N,N-dimethylformamide (DMF) after deposition, solar cell efficiency jumps to near optimum levels, no matter what the original thickness of the polyelectrolyte layer. Subsequent characterization of the DMF-washed ZnO/PEI interlayer reveals a changed surface structure, passivated surface trap states, and thus improved transport properties and lower recombination losses. We demonstrate the general applicability of the method to other state-of-the-art material systems, namely P3HT:ICBA, PTB7:PC71BM and PTB7-Th:PC71BM. We find that the more efficient the material system, the larger the improvement in efficiency after DMF washing. Thus, this method represents a general way to relax the fabrication criteria for high efficiency organic solar cells. We anticipate that this method could be of use in other classes of devices such as OTFTs and OLEDs

Combining plasmonic trap filling and optical backscattering for highly efficient third generation solar cells

© The Royal Society of Chemistry. Metal oxide contact layers such as ZnO and TiOx are commonly used in third generation solar cells as they can be solution processed and have a relatively high conductivity. It is well known that by ultraviolet (UV) light-soaking such devices, their overall device efficiency can be boosted. This improvement in efficiency is due to high energy UV light exciting hot carriers which then fill the trap states in the metal oxide film. Unfortunately, UV causes degradation of the active layer and thus must be filtered out if long lifetimes are to be achieved. In this work, we use plasmonically excited metal nano-structures embedded in a ZnO metal oxide layer to generate hot charge carriers from visible light alone, thus removing the need for UV light soaking. Using this approach, the solar cells also exhibit better charge transport/recombination properties as well as enhanced light trapping behavior. We demonstrate that the power conversion efficiency of a low-bandgap thieno[3,4-b]thiophene/benzodithiophene (PTB7) based solar cell can be increased from 7.91% to 9.36%

Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R$^2$= 0.4078, P 25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P 80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR > 25% (which translates to a median OS of approximately 15 months) and a sample size of ≥ 40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study

Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P &lt; .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P &lt; .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P &lt; .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR&gt;25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P &lt; .01) and adequate power (&gt;80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR &gt;25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.</p

New Approaches to Joint Modeling of Longitudinal and Time-to-Event Outcomes: with Applications to Dynamic Prediction of Health Outcomes Using Massive Biobank Data

It is often of interest to study the temporal patterns of longitudinal biomarker(s) that are potentially correlated and predictive of time-to-event outcomes in biomedical studies. In this dissertation, I develop new approaches for joint modeling of longitudinal and time-to-event data. My dissertation consists of three projects. In Chapter 2, I develop customized linear scan algorithms to speed up the computation of semi-parametric joint models by linearizing the computational burden of the estimation procedure from $O(n^2)$ or $O(n^3)$ to $O(n)$. Compared to the existing software and packages on semi-parametric joint models, our implementations can provide more than thousands of speed-ups when the sample size goes large. In Chapter 3, motivated by the Multi-Ethnic Study of Atherosclerosis (MESA), I propose a novel joint model to account for the heterogeneity of within-subject variability of a longitudinal outcome and demonstrate that it improves the dynamic prediction accuracy of predicting the future event probabilities of both heart failure and death across MESA individuals. In Chapter 4, I extend the joint model described in Chapter 3 to handle interval-censored covariates as missing data due to the unknown initial event time. Using age at diagnosis of diabetes as an interval-censored covariate, we revisit the UK-Biobank data to illustrate that our proposed joint model can yield clinically meaningful parameter estimates, compared to the existing methods such as midpoint imputation, which can lead to problematic conclusion on the effect of covariates on the outcomes