Cardiac Fibrosis in heart failure: Focus on non-invasive diagnosis and emerging therapeutic strategies

Heart failure is a leading cause of mortality and hospitalization worldwide. Cardiac fibrosis, resulting from the excessive deposition of collagen fibers, is a common feature across the spectrum of conditions converging in heart failure. Eventually, either reparative or reactive in nature, in the long-term cardiac fibrosis contributes to heart failure development and progression and is associated with poor clinical outcomes. Despite this, specific cardiac antifibrotic therapies are lacking, making cardiac fibrosis an urgent unmet medical need. In this context, a better patient phenotyping is needed to characterize the heterogenous features of cardiac fibrosis to advance toward its personalized management. In this review, we will describe the different phenotypes associated with cardiac fibrosis in heart failure and we will focus on the potential usefulness of imaging techniques and circulating biomarkers for the non-invasive characterization and phenotyping of this condition and for tracking its clinical impact. We will also recapitulate the cardiac antifibrotic effects of existing heart failure and non-heart failure drugs and we will discuss potential strategies under preclinical development targeting the activation of cardiac fibroblasts at different levels, as well as targeting additional extracardiac processes

Interpretable Mechanistic and Machine Learning Models for Pre-dicting Cardiac Remodeling from Biochemical and Biomechanical Features

Biochemical and biomechanical signals drive cardiac remodeling, resulting in altered heart physiology and the precursor for several cardiac diseases, the leading cause of death for most racial groups in the USA. Reversing cardiac remodeling requires medication and device-assisted treatment such as Cardiac Resynchronization Therapy (CRT), but current interventions produce highly variable responses from patient to patient. Mechanistic modeling and Machine learning (ML) approaches have the functionality to aid diagnosis and therapy selection using various input features. Moreover, \u27Interpretable\u27 machine learning methods have helped make machine learning models fairer and more suited for clinical application. The overarching objective of this doctoral work is to develop computational models that combine an extensive array of clinically measured biochemical and biomechanical variables to enable more accurate identification of heart failure patients prone to respond positively to therapeutic interventions. In the first aim, we built an ensemble ML classification algorithm using previously acquired data from the SMART-AV CRT clinical trial. Our classification algorithm incorporated 26 patient demographic and medical history variables, 12 biomarker variables, and 18 LV functional variables, yielding correct CRT response prediction in 71% of patients. In the second aim, we employed a machine learning-based method to infer the fibrosis-related gene regulatory network from RNA-seq data from the MAGNet cohort of heart failure patients. This network identified significant interactions between transcription factors and cell synthesis outputs related to cardiac fibrosis - a critical driver of heart failure. Novel filtering methods helped us prioritize the most critical regulatory interactions of mechanistic forward simulations. In the third aim, we developed a logic-based model for the mechanistic network of cardiac fibrosis, integrating the gene regulatory network derived from aim two into a previously constructed cardiac fibrosis signaling network model. This integrated model implemented biochemical and biomechanical reactions as ordinary differential equations based on normalized Hill functions. The model elucidated the semi-quantitative behavior of cardiac fibrosis signaling complexity by capturing multi-pathway crosstalk and feedback loops. Perturbation analysis predicted the most critical nodes in the mechanistic model. Patient-specific simulations helped identify which biochemical species highly correlate with clinical measures of patient cardiac function

A randomized trial of neprilysin inhibition with sacubitril/valsartan vs irbesartan in chronic kidney disease

BACKGROUND: The effects of neprilysin inhibition in people with advanced chronic kidney disease (CKD) are unclear. UK Heart and Renal Protection (HARP)-III aimed to examine the effects of sacubitril/valsartan compared with irbesartan, on kidney function, other renal and cardiovascular outcomes and safety in CKD. METHODS: UK HARP-III was a randomized trial, including 414 people with CKD with an estimated glomerular filtration rate (GFR) of 20 to 60 mL/min/1.73m2 . Participants were allocated to sacubitril/valsartan or irbesartan. The primary outcome was measured GFR at 12 months. All analyses were intention to treat. RESULTS: 207 participants were allocated sacubitril/valsartan and 207 irbesartan. At 12 months, there was no difference in measured GFR among those allocated sacubitril/valsartan compared with irbesartan (mean difference -0.1 [SE 0.7] mL/min/1.73m2 ). The effect of sacubitril/valsartan did not differ in a range of prespecified subgroups. There was no significant difference in urinary albumin:creatinine ratio (study average difference -9%; 95% CI -18 to 1) or estimated GFR (mean difference 0.1 mL/min/1.73m2 ; 95% CI -0.5 to 0.7; P=0.66) over 12 months between treatments. Sacubitril/valsartan, compared with irbesartan, significantly reduced study average systolic and diastolic blood pressure by 5.4 (95% CI 3.4-7.4) and 2.1 (95% CI 1.0-3.3) mmHg respectively. Concentrations of cardiac biomarkers N-terminal of prohormone brain natriuretic peptide and troponin I were by reduced by 18% (95% CI 11-25) and 16% (95% CI 8- 23) respectively. Incidence of serious adverse events (29.5% versus 28.5%; RR 1.07; 95% CI 0.75-1.53), non-serious adverse reactions (36.7% versus 28.0%; rate ratio 1.35; 95% CI 0.96-1.90) and renal adverse events were not significantly different between randomized treatments. CONCLUSIONS: Over 12 months allocation to sacubitril/valsartan, compared with irbesartan, had no significant effects on kidney function or albuminuria, but did significantly reduce blood pressure and cardiac biomarkers. It was not associated with any major adverse effects in people with advanced CKD

Smoking and Second Hand Smoking in Adolescents with Chronic Kidney Disease: A Report from the Chronic Kidney Disease in Children (CKiD) Cohort Study

The goal of this study was to determine the prevalence of smoking and second hand smoking [SHS] in adolescents with CKD and their relationship to baseline parameters at enrollment in the CKiD, observational cohort study of 600 children (aged 1-16 yrs) with Schwartz estimated GFR of 30-90 ml/min/1.73m2. 239 adolescents had self-report survey data on smoking and SHS exposure: 21 [9%] subjects had “ever” smoked a cigarette. Among them, 4 were current and 17 were former smokers. Hypertension was more prevalent in those that had “ever” smoked a cigarette (42%) compared to non-smokers (9%), p\u3c0.01. Among 218 non-smokers, 130 (59%) were male, 142 (65%) were Caucasian; 60 (28%) reported SHS exposure compared to 158 (72%) with no exposure. Non-smoker adolescents with SHS exposure were compared to those without SHS exposure. There was no racial, age, or gender differences between both groups. Baseline creatinine, diastolic hypertension, C reactive protein, lipid profile, GFR and hemoglobin were not statistically different. Significantly higher protein to creatinine ratio (0.90 vs. 0.53, p\u3c0.01) was observed in those exposed to SHS compared to those not exposed. Exposed adolescents were heavier than non-exposed adolescents (85th percentile vs. 55th percentile for BMI, p\u3c 0.01). Uncontrolled casual systolic hypertension was twice as prevalent among those exposed to SHS (16%) compared to those not exposed to SHS (7%), though the difference was not statistically significant (p= 0.07). Adjusted multivariate regression analysis [OR (95% CI)] showed that increased protein to creatinine ratio [1.34 (1.03, 1.75)] and higher BMI [1.14 (1.02, 1.29)] were independently associated with exposure to SHS among non-smoker adolescents. These results reveal that among adolescents with CKD, cigarette use is low and SHS is highly prevalent. The association of smoking with hypertension and SHS with increased proteinuria suggests a possible role of these factors in CKD progression and cardiovascular outcomes

The Impact of Vitamin D Status upon Markers of Athlete Health

Introduction At present there is a pandemic of low serum vitamin D (25[OH]D) concentration, partly due to a lack of sun exposure (the primary route for synthesis) and modern lifestyle choices. The bioactive form of vitamin D, 1,25-dihydroxyvitamin D (1,25[OH]2D3) exerts its biological activity by binding to the vitamin D receptor (VDR). These receptors play a central role in the biological actions of vitamin D and are expressed in nearly every tissue and cell type in the body (M. Holick, 2007). Vitamin D deficiency is widespread within many general and athletic populations and associated with a number of detrimental health conditions, including a long-term impact on cardiovascular health (M. Holick, 2007; Larson-Meyer & Willis, 2010; Pittas, Lau, Hu, & Dawson-Hughes, 2007), and the aetiology of osteomalacia and osteoporosis (M. F. Holick, 2009). Given the prevalence and potential negative morbidity associated with deficiency (Larson-Meyer & Willis, 2010), regular vitamin D testing has been recommended as part of routine athlete screening. Current literature shows inconsistent associations between vitamin D status and bone mineral density and cardiac health; (Bischoff-Ferrari, Kiel, et al., 2009; Marwaha et al., 2011) particularly in racial minorities and athletic populations. Whilst it is considered that athletes should have ‘sufficient’ vitamin D concentrations, the exact value to ‘optimise’ health is equivocal. Finally, there appears to be a ‘paradoxical relationship’ between ethnicity and vitamin D concentration, that has largely been ignored, i.e. blacks generally present with the lowest vitamin D concentrations but the greatest bone mineral density (BMD) and reduced risk of fracture (Cauley et al., 2005). Vitamin D–binding protein (DBP) may account for observed racial differences in manifestations of vitamin D (Powe et al., 2013). To date, research on vitamin D status in athletes has overlooked DBP. Whilst there are data that support the associations between vitamin D and markers of bone and cardiac health in the general population, definitive relationships in the athletic population are yet to be established. Therefore, the aim of this thesis was to examine the relationship between vitamin D and measures of bone mass and cardiac structure and function within a large, ethnically diverse cohort of healthy athletes, with a focus to the role of DBP in determining racial differences in bioavailable levels. Studies 1. Oral vs. Intramuscular Vitamin D Supplementation for Treating Insufficient Athletes 2. No Association between Vitamin D Deficiency and Markers of Bone Mass in Athletes 3. No Association between Vitamin D Status and Markers of Bone Mass in Non-Weight Bearing Athletes 4. Why don’t serum Vitamin D concentrations associate with BMD by DXA? A case of being ‘bound’ to the wrong assay? Implications for Vitamin D screening 5. Severely Vitamin D-Deficient Athletes Present Smaller Hearts than Sufficient Athletes Methodical overview Male athletes registered with the Qatar Olympic Committee (QOC) presented for pre-competition medical assessment at Aspetar Sports Medicine Hospital, Qatar. All athletes completed a vitamin D questionnaire that included questions specifically related to country of origin, sporting discipline, skin type, self-reported exposure to daily sunlight, use of sunscreen, dietary supplements and/or medication, and an assessment of skin colour. All individuals undertook bone densitometry and body composition analysis by dual-energy x-ray absorptiometry (DXA; Osteocore III, Perols, France, version 5.22b). Venous blood samples were collected from athletes following an overnight fast and was analysed for PTH, calcium, albumin and serum 25[OH]D. Athletes were split into four 25[OH]D categories; severely deficient (30 ng/mL). Serum vitamin D binding protein (DBP) concentrations (μg/mL) were determined using a commercially available kit (R&D Systems, UK). Free, bioavailable, and DBP-bound 25[OH]D were calculated using equations from supplementary material of (Powe et al., 2013). Lastly, all individuals assessed for family history of cardiovascular disease and personal symptoms, with a physical examination, 12-lead electrocardiogram and an echocardiogram. Results The key findings from the thesis are 1) serum 25[OH]D concentrations are not associated with markers of bone mass 2) bioavailable vitamin D is a better preceptor of BMD that serum 25[OH]D concentration and 3) severely 25[OH]D deficient athletes present with smaller cardiac structure that sufficient athletes. Conclusion In a healthy, ethnically diverse athletic population, there is no relationship between serum 25[OH]D concentration and makers of bone mass, regardless of sporting type and that bioavailable vitamin D is a better predictor of bone mineral density. Suggesting that our chosen method of assessment may not be appropriate to identify true deficiencies. Systematic screening to determine 25[OH]D concentrations is expensive, and demonstrates a poor relationship to bone mass in an ethnically diverse athletic population. It can be argued that vitamin D testing should be reserved for the symptomatic athlete (i.e. musculoskeletal injury, REDs). In turn, prophylactic vitamin D supplementation (2000IU/d D3) to ‘correct’ insufficient athletes with normal bone health can be questioned, since supplementation recommendations are based on a measure that is not associated with bone health. Severely 25[OH]D deficient athletes present with smaller (30 ng/ml) athletes. The precise mechanism(s) causing this cardiac hypertrophy (or in our case, lack of hypertrophy) in the 25[OH]D-deficient state remains unclear. Clinically low vitamin D concentrations are detrimental to aspects of health that influence athletic performance. Therefore, the widespread prevalence of low serum 25[OH]D concentrations should not be ignored. However, vitamin D metabolism is a rapidly evolving field, with the prospect of a more complete picture of this complex endocrine system becoming ever so closer. The challenge for future research is to determine ethnically specific concentration ranges and evidenced based guidelines for the diagnosis and treatment of ‘true’ vitamin D deficiency and its impact on athlete health and performance