Reducing Hypermuscularization of the Transitional Segment between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage

International audienceBackground: Spontaneous deep intracerebral hemorrhage (ICH) is a devastating subtype of stroke without specific treatments. It has been thought that smooth muscle cell (SMC) degeneration at the site of arteriolar wall rupture may be sufficient to cause hemorrhage. However, deep ICHs are rare in some aggressive small vessel diseases that are characterized by significant arteriolar SMC degeneration. Here we hypothesized that a second cellular defect may be required for the occurrence of ICH. Methods: We studied a genetic model of spontaneous deep ICH using Col4a1+/G498V and Col4a1+/G1064D mouse lines that are mutated for the alpha1 chain of Collagen type IV. We analyzed cerebroretinal microvessels, performed genetic rescue experiments, vascular reactivity analysis and computational modeling. We examined post-mortem brain tissues from patients with sporadic deep ICH. Results: We identified in the normal cerebroretinal vasculature a novel segment between arterioles and capillaries, herein called the transitional segment (TS), that is covered by mural cells distinct from SMCs and pericytes. In Col4a1 mutant mice, this TS was hypermuscularized, with a hyperplasia of mural cells expressing more contractile proteins, whereas the upstream arteriole exhibited a loss of SMCs. Mechanistically, TS showed a transient increase in proliferation of mural cells during post-natal maturation. Mutant brain microvessels, unlike mutant arteries, displayed a significant upregulation of SM genes and Notch3 target genes, and genetic reduction of Notch3 in Col4a1+/G498V mice protected against ICH. Retina analysis showed that hypermuscularization of the TS was attenuated but arteriolar SMC loss unchanged in Col4a1+/G498V, Notch3+/- mice. Moreover, hypermuscularization of the retinal TS increased its contractility and tone and raised the intravascular pressure in the upstream feeding arteriole. We similarly found hypermuscularization of the TS and focal arteriolar SMC loss in brain tissues from patients with sporadic deep ICH. Conclusions: Our results suggest that hypermuscularization of the TS, via increased Notch3 activity, is involved in the occurrence of ICH in Col4a1 mutant mice, by raising the intravascular pressure in the upstream feeding arteriole and promoting its rupture at the site of SMC loss. Our human data indicate that these 2 mutually reinforcing vascular defects may represent a general mechanism of deep ICH

Renalism with Renin Angiotensin Aldosterone System Inhibitor use in Patients Enrolled in Trials for Heart Failure with Reduced Ejection Fraction and Advanced Chronic Kidney Disease: A Systematic Review

INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), and mineralocorticoid receptor antagonists (MRA) reduce mortality and hospitalizations in heart failure with reduced ejection fraction (HFrEF) but their use is limited in advanced chronic kidney disease (CKD). METHODS: We carried out a systematic review of studies on HFrEF and CKD patients. The mean overall percentage of reported ACEI, ARB, MRA, and ARNI use, and the proportion of trials that included patients with advanced CKD grades 4-5 (estimated glomerular filtration rate (eGFR) \u3c15-30 ml/min/1.73m2) were recorded per year. The proportion of trials with advanced CKD was log-transformed, and then fitted into a time regression model. The interactions between the proportion of trials that included CKD grades 4-5 and the proportion of reported use of ACEI, ARB, and MRAs per year were explored using Pearson\u27s correlation and univariate linear regression. RESULTS: A total of 706 articles were included; 76% reported background ACEI/ARB use, while 51% reported MRA use. ACEI/ARB use averaged 83% and MRA 50%. Of the trials, 57% included CKD grades 4-5. Over 10 years, the proportion of trials with CKD grades 4-5 increased while ACEI/ARB use decreased. MRA use rates remained about the same. There was an inverse association found between the proportion of trials with CKD grades 4-5 and ACEI/ARB use per year. CONCLUSION: In the past 10 years, CKD grades 4-5 patients have been increasingly included in HFrEF clinical trials. Concurrently, ACEI/ARB use has reportedly decreased

Representation of Chronic Kidney Disease in Randomized Controlled Trials Among Patients With Heart failure With Reduced Ejection Fraction: A Systematic Review

Patients with advanced chronic kidney disease (CKD) have largely been excluded from randomized control trials (RCTs) in heart failure (HF). This creates a paucity of high quality evidence for guideline directed medical therapy (GDMT), particularly in patients with heart failure with reduced ejection fraction (HFrEF) and CKD. This is a systematic review looking at the patterns and rates of inclusion of CKD in RCTs among patients with HFrEF. The search included RCTs from January 2010 to December 2020. A heat map was constructed to reflect the stages of CKD stages. The percentage of studies that included advanced CKD (stages IV-V) was recorded and log transformed, and then fitted into a time regression model. A P value of \u3c0.05 was considered statistically significant. Out of the 3052 screened, 706 studies were included in the analysis. Only 61% of the RCTs reported at least some information on kidney function. There was a trend of increase in percentage of studies that included CKD stages IV-V from years 2010 to 2020. This was confirmed with a statistically significant linear trend P = 0.02 while the percentage of studies that included dialysis and kidney transplant recipients remained consistently low. There is a paucity of high-quality evidence for GDMT in the HFrEF population with CKD, particularly in those with advanced non-dialytic CKD, those on maintenance dialysis and kidney transplant recipients. There is a pressing need for wider inclusion of patients with advanced CKD in RCTs of GDMT in HFrEF

Representation of Chronic Kidney Disease in Randomized Controlled Trials Among Patients With Heart failure With Reduced Ejection Fraction: A Systematic Review.

Patients with advanced chronic kidney disease (CKD) have largely been excluded from randomized control trials (RCTs) in heart failure (HF). This creates a paucity of high quality evidence for guideline directed medical therapy (GDMT), particularly in patients with heart failure with reduced ejection fraction (HFrEF) and CKD. This is a systematic review looking at the patterns and rates of inclusion of CKD in RCTs among patients with HFrEF. The search included RCTs from January 2010 to December 2020. A heat map was constructed to reflect the stages of CKD stages. The percentage of studies that included advanced CKD (stages IV-V) was recorded and log transformed, and then fitted into a time regression model. A P value o

Differences in ejection fraction as inclusion criterion in randomized controlled trials among patients with heart failure with reduced ejection fraction: a systematic review.

INTRODUCTION: Heart failure (HF) with reduced ejection fraction (HFrEF) has been defined by varying ejection fraction (EF) criteria in clinical trials, leading to differences in quantifying treatment effects. AREAS COVERED: The definitions of HFrEF in randomized controlled trials from 2010 until 2020 were collected. The EF ranges were clustered into very low

Differences in ejection fraction as inclusion criterion in randomized controlled trials among patients with heart failure with reduced ejection fraction: a systematic review

INTRODUCTION: Heart failure (HF) with reduced ejection fraction (HFrEF) has been defined by varying ejection fraction (EF) criteria in clinical trials, leading to differences in quantifying treatment effects. AREAS COVERED: The definitions of HFrEF in randomized controlled trials from 2010 until 2020 were collected. The EF ranges were clustered into very low (\u3c30%), low (30-39%) and mildly reduced (40-49%) stratified by intervention. Time series regression analysis was performed.A total of 3052 articles were screened and 706 were included. Interventions included were pharmacologic (37%), device therapy (10%) and 53% a combination of programs, procedural, and laboratory testing. By EF cutoffs, 41% of the studies utilized \u3c40% while 26% used \u3c35%. About 31% did not have a clearly defined EF. Between 2010-2020, studies with HFrEF ranges 30-39% have significantly decreased (p value\u3c0.001 for trend) but those which included very low EF (\u3c30%) and mildly reduced EF (40-49%) have remained the same. EF definitions across clinical trials in HFrEF varied widely. Defining the specific target HF population phenotype when designing trials or in patient treatment is important as various beneficial effects of different heart failure treatment modalities can be modified or even attenuated across the spectrum of EF