Impact of sex on Transcatheter aortic valve replacement outcomes: Results of a single-center study.

BACKGROUND: Early studies on transcatheter aortic valve replacement (TAVR) outcomes showed that female sex was associated with better survival. With increased use of new-generation valves, the impact of sex on contemporary TAVR outcomes is less well known. METHODS: Retrospective analysis using institutional National Cardiovascular Data Registry STS/ACC TVT data was performed on all patients undergoing TAVR at Yale New Haven Hospital from July 2012 to August 2019. New-generation valves were Evolut PRO, Evolut R, and SAPIEN 3. Old-generation valves were CoreValve, SAPIEN, and SAPIEN XT. Log-rank test and Kaplan-Meier curves were used to compare sex differences in survival up to 1 year after TAVR. Cox modeling was used to adjust for baseline and procedural characteristic differences. RESULTS: 927 consecutive patients (41.4% women) underwent TAVR. Women were older (82.8 vs 80.6 years old; p < 0.001) with higher STS mortality scores compared with men (7.6% vs 6.4%; p < 0.001) despite lower prevalence of cardiovascular comorbidities including coronary artery disease, peripheral artery disease, and smoking. Most cases used transfemoral access (90.5%) and new-generation devices (72.3%). Women received smaller valves compared with men (20-26 mm: 78.0% vs 32.9%; 29-34 mm: 22.1% vs 67.1%; overall p < 0.0001). There were no statistically significant differences between sexes in both unadjusted and adjusted 1-year mortality. CONCLUSION: Our data show no significant difference in 1-year survival between sexes using primarily new generation valves. Further studies should reassess the impact of sex on TAVR outcomes and whether newer technologies like new valve design and sizes, and CT imaging may have eliminated sex-based disparities.

Percutaneous Transluminal Angioplasty for Infrapopliteal Chronic Limb-Threatening Ischemia: A Systematic Review and Meta-analysis of Primary Patency and Binary Restenosis Rates.

PURPOSE: Percutaneous transluminal angioplasty (PTA) remains the mainstay of endovascular therapy for infrapopliteal chronic limb-threatening ischemia (CLTI), but outcomes have not been well characterized using high-quality data. The aim of this meta-analysis was to provide an updated benchmark for rates of primary patency and binary restenosis after PTA using prospectively collected, predominantly core-lab adjudicated randomized controlled trial (RCT) data. MATERIALS AND METHODS: MEDLINE, EMBASE, Cochrane Central, and ClinicalTrials.gov were queried for RCTs published through November 2022 using PTA as a control arm and including patients with infrapopliteal CLTI. Studies were excluded if >25% of patients had intermittent claudication, other vessels were included, or primary patency or binary restenosis were not outcomes. Outcomes were analyzed using random effects models. This analysis was publicly registered (PROSPERO ID#394543). No funding was utilized. RESULTS: Seventeen RCTs were included (1048 patients, 1279 lesions). Pooled primary patency rates using data from 6 RCTs were 68% at 6 months (95% confidence interval [CI]=45%-84%) and 66% at 12 months (95% CI=51%-79%). Pooled binary restenosis rates using data from 11 RCTs were 54% at 6 months (95% CI=33%-73%) and 60% at 9 to 12 months (95% CI=39%-78%). Significant heterogeneity was present in all outcomes (I2>50%, p<0.0001). Publication bias was not observed (Egger's p>0.1). CONCLUSIONS: This meta-analysis provides estimates for binary restenosis and primary patency following PTA utilizing prospectively collected, predominantly core-lab adjudicated data. Results demonstrate 1-year primary patency rates that are 10% to 20% higher than what has been historically used in power calculations. These new estimates will help facilitate more accurate power analysis for future RCTs. CLINICAL IMPACT: Rates of primary patency and binary restenosis after percutaneous transluminal angioplasty (PTA) have not been well-described using high-quality data, and investigators have been utilizing estimates of 40% to 50% and 45% to 65%, respectively, when performing power calculations for trials. This meta-analysis demonstrates using high-quality, prospectively collected, and predominantly core-lab adjudicated randomized controlled trial data that actual rates of primary patency are closer to 60% up to 1 year following PTA and provides the first meta-analysis estimate of binary restenosis rates up to 1 year after PTA. These estimates will help facilitate more accurate power calculations for future RCTs in this space.

Chocolate Touch Versus Lutonix Drug-Coated Balloon for Femoropopliteal Lesions in Diabetes: The Chocolate Touch Study.

BACKGROUND: The randomized Chocolate Touch Study demonstrated that in patients undergoing treatment of femoropopliteal artery lesions, the Chocolate Touch drug-coated balloon (DCB) was safe and had superior efficacy at 12 months compared with the Lutonix DCB. We report the prespecified diabetes subanalysis comparing outcomes among patients with and without diabetes mellitus (DM). METHODS: Patients with claudication or ischemic rest pain (Rutherford class 2-4) were randomized to Chocolate Touch or Lutonix DCB. The primary efficacy endpoint was DCB success defined as primary patency at 12 months (peak systolic velocity ratio <2.4 by duplex ultrasound without clinically driven target lesion revascularization in the absence of bailout stenting). The primary safety endpoint was freedom from major adverse events at 12 months, a composite of target limb-related death, major amputation, or reintervention. RESULTS: A total of 313 patients (38% DM [n=119]) were randomized to either Chocolate Touch (n=66/152) or Lutonix DCB (n=53/161). Among patients with DM, DCB success was 77.2% and 60.5% (p=0.08), and in non-DM patients, DCB success was 80% and 71.3% (p=0.2114) for the Chocolate Touch and Lutonix DCB, respectively. The primary safety endpoint was similar for both cohorts regardless of DM status (interaction test, p=0.96). CONCLUSIONS: This randomized trial demonstrated similar safety and efficacy for the treatment of femoropopliteal disease with the Chocolate Touch DCB compared with using the Lutonix DCB regardless of DM status at 12 months. CLINICAL IMPACT: This substudy of the Chocolate Touch Study demonstrated similar safety and efficacy for treatment of femoropopliteal disease of the Chocolate Touch DCB compared with the Lutonix DCB regardless of diabetes (DM) status at 12 months. Endovascular therapy has become the therapy of choice for the treatment of most symptomatic femoropopliteal lesions regardless of DM status. These results give clinicians another option when treating femoropopliteal disease in this high-risk patient population.

Impact of New-Onset Conduction Disturbances following Transcatheter Aortic Valve Replacement on Outcomes: A Single-Center Study.

Background: Transcatheter aortic valve replacement (TAVR) is known to increase the incidence of conduction disturbances compared to surgical aortic valve replacement; however, there are limited data on the impact and duration of these conduction disturbances on longer term outcomes. Objective: To determine the differential impact of persistent versus nonpersistent new-onset conduction disturbances on TAVR-related complications and outcomes. Methods: This is a single-center retrospective analysis of 927 consecutive patients with aortic stenosis who underwent TAVR at Yale New Haven Hospital from July 2012 to August 2019. Patients with new-onset conduction disturbances within 7 days following TAVR were selected for this study. Persistent and nonpersistent disturbances were, respectively, defined as persisting or not persisting on all patient ECGs for up to 1.5 years after TAVR or until death. Results: Within 7 days after TAVR, conduction disturbances occurred in 42.3% (392/927) of the patients. Conduction disturbances persisted in 150 (38%) patients and did not persist in 187 (48%) patients, and 55 (14%) patients were excluded for having mixed (both persistent and nonpersistent) disturbances. Compared with nonpersistent disturbances, patients with persistent disturbances were more likely to receive a PPM within 7 days after the TAVR procedure (46.0% versus 4.3%, p < 0.001) and had a greater unadjusted 1-year cardiac-related and all-cause mortality risk (HR 2.54, p=0.044 and HR 1.90, p=0.046, respectively). Conclusion: Persistent conduction disturbances were associated with a greater cardiac and all-cause mortality rate at one year following TAVR. Future research should investigate periprocedural factors to reduce persistent conduction disturbances and outcomes beyond one year follow-up.

Impella Versus Intra-Aortic Balloon Pump for High-Risk PCI: A Propensity-Adjusted Large-Scale Claims Dataset Analysis.

Impella was approved by the Food and Drug Administration in 2015 for use during high-risk percutaneous coronary interventions (PCIs); however, its safety and efficacy compared with intra-aortic balloon pump (IABP) has not been evaluated in contemporary practice and remains debated. We aimed to compare postapproval outcomes and costs of Impella versus IABP support for high-risk PCI in real-world practice across hospitals in the United States. We identified patients from the Premier Healthcare Database undergoing nonemergent Impella- or IABP-supported high-risk PCI. We used propensity adjustment to control baseline, procedure, and post-PCI medical treatment differences between treatment groups. We included patients undergoing nonemergent single-PCI procedures with either Impella or IABP support and excluded patients presenting with acute ST-elevation myocardial infarction or cardiogenic shock or requiring >1 mechanical support devices during index hospitalization. Outcomes included in-hospital survival, myocardial infarction (MI), cardiogenic shock, stroke, bleeding requiring transfusion, acute kidney injury, index hospitalization length of stay, and costs. From April 2016 to June 2019, a total of 48,179 patients were treated with Impella or IABP mechanical circulatory support at 304 hospitals in the United States. Among these, we identified 2,156 patients undergoing nonemergent high-risk PCI treated with Impella (n = 1,447) or IABP (n = 709). After propensity adjustment, Impella use was associated with improved survival (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.02 to 2.36) and less MI (OR 0.29, 95% CI 0.18 to 0.46) and cardiogenic shock (OR 0.54, 95% CI 0.39 to 0.74). Stroke, bleeding requiring transfusion, and acute kidney injury were similar between groups. In conclusion, this Premier Healthcare Database propensity-adjusted analysis, Impella use during nonemergent high-risk PCI was associated with improved survival and reduced in-hospital MI and cardiogenic shock compared with IABP.

Randomized Trial of Chocolate Touch Compared With Lutonix Drug-Coated Balloon in Femoropopliteal Lesions (Chocolate Touch Study).

BACKGROUND: First-generation drug-coated balloons (DCBs) have significantly reduced the rate of restenosis compared with balloon angioplasty alone; however, high rates of bailout stenting and dissections persist. The Chocolate Touch DCB is a nitinol constrained balloon designed to reduce acute vessel trauma and inhibit neointima formation and restenosis. METHODS: Patients with claudication or ischemic rest pain (Rutherford class 2-4) and superficial femoral or popliteal disease (≥70% stenosis) were randomized 1:1 to Chocolate Touch or Lutonix DCB at 34 sites in the United States, Europe, and New Zealand. The primary efficacy end point was DCB success, defined as primary patency at 12 months (peak systolic velocity ratio <2.4 by duplex ultrasound without clinically driven target lesion revascularization in the absence of clinically driven bailout stenting). The primary safety end point was freedom from major adverse events at 12 months, a composite of target limb-related death, major amputation, or reintervention. Both primary end points were tested for noninferiority, and if met, sequential superiority testing for efficacy followed by safety was prespecified. An independent clinical events committee, and angiographic and duplex ultrasound core laboratories blinded to treatment allocation reviewed all end points. RESULTS: A total of 313 patients were randomized to Chocolate Touch (n=152) versus Lutonix DCB (n=161). Follow-up at 1 year was available in 94% of patients. The mean age was 69.4±9.5 years, the average lesion length was 78.1±46.9 mm, and 46.2% had moderate-to-severe calcification. The primary efficacy rates of DCB success at 12 months was 78.8% (108/137) with Chocolate Touch and 67.7% (88/130) with Lutonix DCB (difference, 11.1% [95% CI, 0.6-21.7]), meeting noninferiority (Pnoninferiority<0.0001) and sequential superiority (Psuperiority=0.04). The primary safety event rate was 88.9% (128/144) with Chocolate Touch and 84.6% (126/149) with Lutonix DCB (Pnoninferiority<0.001; Psuperiority=0.27). CONCLUSIONS: In this prospective, multicenter, randomized trial, the second-generation Chocolate Touch DCB met both noninferiority end points for efficacy and safety and was more effective than Lutonix DCB at 12 months for the treatment of femoropopliteal disease. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02924857.

Long term outcomes of ultrathin versus standard thickness second-generation drug eluting stents: Meta-analysis of randomized trials.

OBJECTIVE: Identify the effect of ultrathin drug eluting stents on long term outcomes in coronary artery disease. BACKGROUND: Although second-generation drug eluting stents (DES) are superior to first-generation DES, persistence of adverse outcomes has led to continued refinement in design. Ultrathin second-generation DES have been shown to improve outcomes at 1-year follow-up. Beyond 1-year their effect remains unknown. METHODS: PubMed, Embase and Cochrane Database were searched for randomized controlled trials that compared ultrathin (defined as <70 um) to standard thickness second-generation DES. Studies were chosen according to the PROSPERO protocol (CRD42020185374). Data from randomized controlled trials were pooled using random-effects model (Mantel-Haenszel). The primary outcome was target lesion failure (TLF) at 2 years, a composite of cardiac death, target vessel myocardial infarction, and ischemia-driven target vessel revascularization. Secondary outcomes included TLF at 3 and 5 years, the components of TLF and definite or probable stent thrombosis. Differences in outcomes between groups were presented in Forest plots as risk ratios (RR) with corresponding 95% confidence intervals (CIs) for each trial. RESULTS: We identified 18 publications from 10 trials with14,649 patients. At 2-years there was a significant 12% reduction in TLF (RR, 0.88; 95% CI 0.78-0.99; p < 0.05) associated with the use of ultrathin DES. At 3-years, there was a significant 19% reduction in TLF with ultrathin DES (RR, 0.79; 95% CI 0.64-0.98; p < 0.05). CONCLUSION: In patients undergoing percutaneous coronary intervention, ultrathin DES improve long term clinical outcomes.

Meta-Analysis of Gender Disparities in In-hospital Care and Outcomes in Patients with ST-Segment Elevation Myocardial Infarction.

Gender disparities in ST-segment elevation myocardial infarction (STEMI) outcomes continue to be reported worldwide; however, the magnitude of this gap remains unknown. To evaluate gender-based discrepancies in clinical outcomes and identify the primary driving factors a global meta-analysis was performed. Studies were selected if they included all comers with STEMI, reported gender specific patient characteristics, treatments, and outcomes, according to the registered PROSPERO protocol: CRD42020161469. A total of 56 studies (705,098 patients, 31% females) were included. Females were older, had more comorbidities and received less antiplatelet therapy and primary percutaneous coronary intervention (PCI). Females experienced significantly longer delays to first medical contact (mean difference 42.5 min) and door-to-balloon time (mean difference 4.9 min). In-hospital, females had increased rates of mortality (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.84 to 1.99, p <0.00001), repeat myocardial infarction (MI) (OR 1.25, 95% CI 1.00 to 1.56, p=0.05), stroke (OR 1.67, 95% CI 1.27 to 2.20, p <0.001), and major bleeding (OR 1.82, 95% CI 1.56 to 2.12, p <0.00001) compared with males. Older age at presentation was the primary driver of excess mortality in females, although other factors including lower rates of primary PCI and aspirin usage, and longer door-to-balloon times contributed. In contrast, excess rates of repeat MI and stroke in females appeared to be driven, at least in part, by lower use of primary PCI and P2Y12 inhibitors, respectively. In conclusion, despite improvements in STEMI care, women continue to have in-hospital rates of mortality, repeat MI, stroke, and major bleeding up to 2-fold higher than men. Gender disparities in in-hospital outcomes can largely be explained by age differences at presentation but comorbidities, delays to care and suboptimal treatment experienced by women may contribute to the gender gap.

Sex-Specific Outcomes in Cardiovascular Device Evaluations.

Background: Females have historically been underrepresented in cardiovascular device trials. As a result, differences in outcomes for males and females are not possible to be determined in subanalyses. Materials and Methods: Against a backdrop of troubling trends in cardiovascular outcomes for females, we provide a narrative review on the differences in outcomes observed in females undergoing device evaluations in multiple fields of cardiovascular medicine, including coronary revascularization, structural heart disease, and heart failure. We also review predictors of cardiovascular trial nonparticipation as it may provide avenues by which female enrollment in cardiovascular device trials can be improved. Results: Advances have been made in structural heart therapy, where female representation in transcatheter aortic valve replacement studies was nearly 50%. For other indications, coronary revascularization and heart failure, there was clearly a disparity in female recruitment. On average, female representation was 25% in major clinical trials evaluating drug eluting stents, implantable cardioverter defibrillators, cardiac resynchronization defibrillators, and ventricular assist devices. As a result, the best treatment recommendations for females in these fields are currently guided by outcomes evaluated primarily in males. Conclusions: Female enrollment in device clinical trials for coronary revascularization and heart failure has lagged, leaving uncertainty in making benefit/risk assessments of device therapy. The predictors of female nonparticipation in clinical trials can inform a comprehensive strategy to facilitate and enrich the enrollment of females in cardiovascular device trials. This is critical to ensure that sex differences can be considered in treatment selection, so that patients can receive the best available care.

Angiotensin Receptor Neprilysin Inhibitor Attenuates Myocardial Remodeling and Improves Infarct Perfusion in Experimental Heart Failure.

Angiotensin receptor blocker-neprilysin inhibitor (ARNi) therapy improves the prognosis of heart failure patients. However, the mechanisms remain unclear. This study investigated the biological effects of ARNi with neprilysin inhibitor sacubitril and angiotensin receptor blocker valsartan on myocardial remodeling and cardiac perfusion in experimental heart failure (HF) after myocardial infarction (MI). Male Lewis rats (10-weeks old) with confirmed HF were randomized one-week post-MI to treatment with vehicle (water), sacubitril/valsartan or valsartan, as comparator group, for either 1 or 5 weeks. Sacubitril/valsartan for 1-week limited LV contractile dysfunction vs. vehicle and both sacubitril/valsartan and valsartan attenuated progressive LV dilation after 1 and 5 weeks treatment. After 5 weeks, both sacubitril/valsartan and valsartan reduced CTGF expression in the remote myocardium, although only sacubitril/valsartan prevented interstitial fibrosis. In the border zone, sacubitril/valsartan and valsartan reduced hypertrophic markers, but only sacubitril/valsartan reduced cardiomyocyte size and increased VEGFA expression. In the infarct, sacubitril/valsartan induced an early uptake of 99mTc-NC100692 (a radiotracer of angiogenesis) and improved perfusion, as determined by 201Tl microSPECT/CT imaging. In conclusion, ARNi improved global LV function, limited remodeling in the remote and border zones, and increased perfusion to the infarct. Sacubitril/valsartan had more consistent effects than valsartan on LV remodeling in experimental HF.

Tissue-specific miRNA Expression Profiling in Mouse Heart Sections Using In Situ Hybridization.

micro-RNAs (miRNAs) are single-stranded RNA transcripts that bind to messenger RNAs (mRNAs) and inhibit their translation or promote their degradation. To date, miRNAs have been implicated in a large number of biological and disease processes, which has signified the need for the reliable detection methods of miRNA transcripts. Here, we describe a detailed protocol for digoxigenin-labeled (DIG) Locked Nucleic Acid (LNA) probe-based miRNA detection, combined with protein immunostaining on mouse heart sections. First, we performed an in situ hybridization technique using the probe to identify miRNA-182 expression in heart sections from control and cardiac hypertrophy mice. Next, we performed immunostaining for cardiac Troponin T (cTnT) protein, on the same sections, to co-localize miRNA-182 with the cardiomyocyte cells. Using this protocol, we were able to detect miRNA-182 through an alkaline phosphatase based colorimetric assay, and cTnT through fluorescent staining. This protocol can be used to detect the expression of any miRNA of interest through DIG-labeled LNA probes, and relevant protein expression on mouse heart tissue sections.

miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart.

Myocardial hypertrophy is an adaptive response to hemodynamic demands. Although angiogenesis is critical to support the increase in heart mass with matching blood supply, it may also promote a hypertrophic response. Previously, we showed that cardiac angiogenesis induced by placental growth factor (PlGF), promotes myocardial hypertrophy through the paracrine action of endothelium-derived NO, which triggers the degradation of regulator of G protein signaling 4 (RGS4) to activate the Akt/mTORC1 pathways in cardiomyocytes. Here, we investigated whether miRNAs contribute to the development of hypertrophic response associated with myocardial angiogenesis. We show that miR-182 is upregulated concurrently with the development of hypertrophy in PlGF mice, but not when hypertrophy was blocked by concomitant expression of PlGF and RGS4, or by PlGF expression in eNOS(-/-) mice. Anti-miR-182 treatment inhibits the hypertrophic response and prevents the Akt/mTORC1 activation in PlGF mice and NO-treated cardiomyocytes. miR-182 reduces the expression of Bcat2, Foxo3 and Adcy6 to regulate the hypertrophic response in PlGF mice. Particularly, depletion of Bcat2, identified as a new miR-182 target, promotes Akt(Ser473)/p70-S6K(Thr389) phosphorylation and cardiomyocyte hypertrophy. LV pressure overload did not upregulate miR-182. Thus, miR-182 is a novel target of endothelial-cardiomyocyte crosstalk and plays an important role in the angiogenesis induced-hypertrophic response.

Live cell imaging of primary rat neonatal cardiomyocytes following adenoviral and lentiviral transduction using confocal spinning disk microscopy.

Primary rat neonatal cardiomyocytes are useful in basic in vitro cardiovascular research because they can be easily isolated in large numbers in a single procedure. Due to advances in microscope technology it is relatively easy to capture live cell images for the purpose of investigating cellular events in real time with minimal concern regarding phototoxicity to the cells. This protocol describes how to take live cell timelapse images of primary rat neonatal cardiomyocytes using a confocal spinning disk microscope following lentiviral and adenoviral transduction to modulate properties of the cell. The application of two different types of viruses makes it easier to achieve an appropriate transduction rate and expression levels for two different genes. Well focused live cell images can be obtained using the microscope's autofocus system, which maintains stable focus for long time periods. Applying this method, the functions of exogenously engineered proteins expressed in cultured primary cells can be analyzed. Additionally, this system can be used to examine the functions of genes through the use of siRNAs as well as of chemical modulators.

Multimodality imaging approach for serial assessment of regional changes in lower extremity arteriogenesis and tissue perfusion in a porcine model of peripheral arterial disease.

BACKGROUND: A standard quantitative imaging approach to evaluate peripheral arterial disease does not exist. Quantitative tools for evaluating arteriogenesis in vivo are not readily available, and the feasibility of monitoring serial regional changes in lower extremity perfusion has not been examined. METHODS AND RESULTS: Serial changes in lower extremity arteriogenesis and muscle perfusion were evaluated after femoral artery occlusion in a porcine model using single photon emission tomography (SPECT)/CT imaging with postmortem validation of in vivo findings using gamma counting, postmortem imaging, and histological analysis. Hybrid 201Tl SPECT/CT imaging was performed in pigs (n=8) at baseline, immediately postocclusion, and at 1 and 4 weeks postocclusion. CT imaging was used to identify muscle regions of interest in the ischemic and nonischemic hindlimbs for quantification of regional changes in CT-defined arteriogenesis and quantification of 201Tl perfusion. Four weeks postocclusion, postmortem tissue 201Tl activity was measured by gamma counting, and immunohistochemistry was performed to assess capillary density. Relative 201Tl retention (ischemic/nonischemic) was reduced immediately postocclusion in distal and proximal muscles and remained lower in calf and gluteus muscles 4 weeks later. Analysis of CT angiography revealed collateralization at 4 weeks within proximal muscles (P<0.05). SPECT perfusion correlated with tissue gamma counting at 4 weeks (P=0.01). Increased capillary density was seen within the ischemic calf at 4 weeks (P=0.004). CONCLUSIONS: 201Tl SPECT/CT imaging permits serial, regional quantification of arteriogenesis and resting tissue perfusion after limb ischemia. This approach may be effective for detection of disease and monitoring therapy in peripheral arterial disease.

NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth.

Myocardial hypertrophy is an adaptation to increased hemodynamic demands. An increase in heart tissue must be matched by a corresponding expansion of the coronary vasculature to maintain and adequate supply of oxygen and nutrients for the heart. The physiological mechanisms that underlie the coordination of angiogenesis and cardiomyocyte growth are unknown. We report that induction of myocardial angiogenesis promotes cardiomyocyte growth and cardiac hypertrophy through a novel NO-dependent mechanism. We used transgenic, conditional overexpression of placental growth factor (PlGF) in murine cardiac tissues to stimulate myocardial angiogenesis and increase endothelial-derived NO release. NO production, in turn, induced myocardial hypertrophy by promoting proteasomal degradation of regulator of G protein signaling type 4 (RGS4), thus relieving the repression of the Gßγ/PI3Kγ/AKT/mTORC1 pathway that stimulates cardiomyocyte growth. This hypertrophic response was prevented by concomitant transgenic expression of RGS4 in cardiomyocytes. NOS inhibitor L-NAME also significantly attenuated RGS4 degradation, and reduced activation of AKT/mTORC1 signaling and induction of myocardial hypertrophy in PlGF transgenic mice, while conditional cardiac-specific PlGF expression in eNOS knockout mice did not induce myocardial hypertrophy. These findings describe a novel NO/RGS4/Gßγ/PI3Kγ/AKT mechanism that couples cardiac vessel growth with myocyte growth and heart size.

Endothelial nuclear factor-κB-dependent regulation of arteriogenesis and branching.

BACKGROUND: Arteriogenesis and collateral formation are complex processes requiring integration of multiple inputs to coordinate vessel branching, growth, maturation, and network size. Factors regulating these processes have not been determined. METHODS AND RESULTS: We used an inhibitor of NFκB activation (IκBαSR) under control of an endothelial-specific inducible promoter to selectively suppress endothelial nuclear factor-κB activation during development, in the adult vasculature, or in vitro. Inhibition of nuclear factor-κB activation resulted in formation of an excessively branched arterial network that was composed of immature vessels and provided poor distal tissue perfusion. Molecular analysis demonstrated reduced adhesion molecule expression leading to decreased monocyte influx, reduced hypoxia-inducible factor-1α levels, and a marked decrease in δ-like ligand 4 expression with a consequent decrease in Notch signaling. The latter was the principal cause of increased vascular branching as treatment with Jagged-1 peptide reduced the size of the arterial network to baseline levels. CONCLUSIONS: These findings identify nuclear factor-κB as a key regulator of adult and developmental arteriogenesis and collateral formation. Nuclear factor-κB achieves this by regulating hypoxia-inducible factor-1α-dependent expression of vascular endothelial growth factor-A and platelet-derived growth factor-BB, which are necessary for the development and maturation of the arterial collateral network, and by regulating δ-like ligand 4 expression, which in turn determines the size and complexity of the network.

[A new risk factor in glaucoma?]. / Un nou factor de risc in glaucom?

We observed that intraocular pressure was higher at the same glaucoma patient when he/she was fatigued or under a great stress. Several questions appeared: is this fact a rule? If yes, is there a critical level of fatigue to decompensate intraocular pressure? Does it appear in normal individuals? What is the pathogenesis?