PHD2 deletion in endothelial or arterial smooth muscle cells reveals vascular cell type-specific responses in pulmonary hypertension and fibrosis

Hypoxia plays an important regulatory role in the vasculature to adjust blood flow to meet metabolic requirements. At the level of gene transcription, the responses are mediated by hypoxia-inducible factor (HIF) the stability of which is controlled by the HIF prolyl 4-hydroxylase-2 (PHD2). In the lungs hypoxia results in vasoconstriction, however, the pathophysiological relevance of PHD2 in the major arterial cell types; endothelial cells (ECs) and arterial smooth muscle cells (aSMCs) in the adult vasculature is incompletely characterized. Here, we investigated PHD2-dependent vascular homeostasis utilizing inducible deletions of PHD2 either in ECs (Phd2∆ECi) or in aSMCs (Phd2∆aSMC). Cardiovascular function and lung pathologies were studied using echocardiography, Doppler ultrasonography, intraventricular pressure measurement, histological, ultrastructural, and transcriptional methods. Cell intrinsic responses were investigated in hypoxia and in conditions mimicking hypertension-induced hemodynamic stress. Phd2∆ECi resulted in progressive pulmonary disease characterized by a thickened respiratory basement membrane (BM), alveolar fibrosis, increased pulmonary artery pressure, and adaptive hypertrophy of the right ventricle (RV). A low oxygen environment resulted in alterations in cultured ECs similar to those in Phd2∆ECi mice, involving BM components and vascular tone regulators favoring the contraction of SMCs. In contrast, Phd2∆aSMC resulted in elevated RV pressure without alterations in vascular tone regulators. Mechanistically, PHD2 inhibition in aSMCs involved actin polymerization -related tension development via activated cofilin. The results also indicated that hemodynamic stress, rather than PHD2-dependent hypoxia response alone, potentiates structural remodeling of the extracellular matrix in the pulmonary microvasculature and respiratory failure.

EVALUATION OF DEXMEDETOMIDINE ON HEMODYNAMIC STRESS RESPONSE DURING LARYNGOSCOPY AND INTUBATION

Objective: To compare the efficacy of Dexmedetomidine (Precedex) in addressing the mean haemodynamic stress response to laryngoscopy and endotracheal intubation (L&I). Study Design: Quasi-experimental study. Place and Duration of Study: Anesthesiology Department, Combined Military Hospital, Rawalpindi, from Jun 2019 Jun 2020. Methodology: The patients were divided into two groups. Group A was given Inj. Dexmedetomidine and group B (placebo). Operation theatre assistant randomly assigned the patients to either group A or group B each day. The second person administered the drug or placebo. The third person (researcher) recorded all the parameters mentioned in the proforma. Results: There were 100 patients with an age range of 18-60 years. The majority of the patients were ASA-I physical status. The main surgical procedure was laparoscopic cholecystectomy. Recording of heart rate and systolic blood pressure during laryngoscopy and intubation, after administration of drug or placebo, showed mean heart rate less than mean basal value in group-A and 22% above mean basal value in group-B, and it was statistically highly significant (p-value <0.001). Whereas mean systolic blood pressure in group-A was 122.42 ± 14.91 (less than the mean basal value) as compared to group B, 155.00 ± 18.32/min (20% above mean basal value). This change was also statistically highly significant (p-value <0.001). Conclusion: It is concluded that dexmedetomidine showed statistically significant stabilizing effects on the expected changes of the hemodynamic stress response.

Aplastic or twig-like middle cerebral artery harboring unruptured cerebral aneurysms treated by clipping and bypass surgery: illustrative case

BACKGROUND Aplastic or twig-like middle cerebral artery (Ap/T-MCA) is a congenital MCA anomaly. It may present with symptoms of both hemorrhage and ischemia, similar to moyamoya disease, and hemodynamic stress may play an essential role in the development of symptoms in both clinical entities. The optimal treatment remains controversial in symptomatic patients with Ap/T-MCA. This report discussed the treatment method for a patient with Ap/T-MCA with unruptured aneurysms who presented with intraventricular hemorrhage (IVH) treated by aneurysm clipping and bypass surgery. OBSERVATIONS In a 46-year-old woman with a sudden headache, computed tomography showed left IVH. Magnetic resonance angiography showed a left MCA aneurysm and MCA trunk stenosis. Three-dimensional angiography demonstrated a plexiform arterial network and multiple aneurysms arising from the MCA and in the plexiform network, leading to the diagnosis of Ap/T-MCA harboring unruptured aneurysms. The patient was successfully treated by craniotomy with aneurysm clipping and bypass surgery to prevent further intracranial hemorrhages and/or aneurysm rupture. LESSONS Especially in cases such as Ap/T-MCA, in which hemodynamic stress has a significant effect, the optimal treatment method should be based on vascular morphology and the impact of hemodynamic stress.

Comparison of hemodynamic stress in healthy vessels after parent artery occlusion and flow diverter stent treatment for internal carotid artery aneurysm

OBJECTIVE De novo aneurysms generally develop in healthy vessels after parent artery occlusion for large internal carotid artery (ICA) aneurysm, possibly owing to increased hemodynamic stress in the remaining vessels. In recent years, there has been a shift toward flow diverter stent treatment. However, there is a lack of direct evidence and data that prove this change in hemodynamic stress in healthy vessels after parent artery occlusion and flow diverter stent treatment. The authors compared hemodynamic stress in healthy-side vessels before and after parent artery occlusion and flow diverter treatments. METHODS The authors included patients who underwent 3D cine phase-contrast MRI before and after large ICA aneurysm treatment. Spatially and temporally averaged volume flow rates and spatially averaged systolic wall shear stress (WSS) in healthy-side ICA distal to the posterior communicating artery (C1 segment according to Fisher’s classification) were measured before and after parent artery occlusion and flow diverter treatments. RESULTS Seventeen patients were included (5 patients in the parent artery occlusion group and 12 in the flow diverter group). At 1–2 months after treatment, median volume flow rate in healthy-side ICA increased from 5.36 ml/sec to 6.28 ml/sec (total increase 117%, p = 0.04) in the parent artery occlusion group and from 4.65 ml/sec to 4.93 ml/sec (total increase 106%, p = 0.02) in the flow diverter group. In the parent artery occlusion group, median WSS in the C1 segment of the healthy-side ICA increased from 3.91 Pa to 5.61 Pa (total increase 143%, p = 0.08); however, no significant increase was observed in the flow diverter group (4.29 Pa to 4.57 Pa [total increase 107%, p = 0.21]). CONCLUSIONS Postoperatively, volume flow rate and WSS in the C1 segment of the healthy-side ICA significantly increased in the parent artery occlusion group. Therefore, the parent artery occlusion group was more prone to de novo aneurysm than the flow diverter group.

PKM1 Exerts Critical Roles in Cardiac Remodeling Under Pressure Overload in the Heart

Background: Metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. The elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, its role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully illustrated. Here, we aimed to dissect the role of cardiac PKM1 (pyruvate kinase muscle isozyme 1) in glucose metabolic regulation and cardiac response under pressure overload. Methods: Cardiac specific deletion of PKM1 was achieved by crossing the floxed PKM1 mouse model with the cardiomyocyte-specific Cre transgenic mouse. PKM1 transgenic mice were generated under the control of tetracycline response elements, and cardiac specific overexpression of PKM1 was induced by doxycycline administration in adult mice. Pressure overload was triggered by transverse aortic constriction (TAC). Primary neonatal rat ventricular myocytes were used to dissect molecular mechanisms. Moreover, metabolomics and NMR spectroscopy analyses were conducted to determine cardiac metabolic flux in response to pressure overload. Results: We found that PKM1 expression is reduced in failing human and mouse hearts. Importantly, cardiomyocyte-specific deletion of PKM1 exacerbates cardiac dysfunction and fibrosis in response to pressure overload. Inducible overexpression of PKM1 in cardiomyocytes protects the heart against TAC-induced cardiomyopathy and heart failure. At the mechanistic level, PKM1 is required for the augmentation of glycolytic flux, mitochondrial respiration, and ATP production under pressure overload. Furthermore, deficiency of PKM1 causes a defect in cardiomyocyte growth and a decrease in pyruvate dehydrogenase complex activity at both in vitro and in vivo levels. Conclusions: These findings suggest that PKM1 plays an essential role in maintaining a homeostatic response in the heart under hemodynamic stress.

Abstract 052: Hypertensive Diseases In Pregnancy And Hemodynamic Stress Later In Life

Background: Hypertensive diseases in pregnancy have been associated with cardiovascular diseases later in life. However, less is known about the relationship between hypertensive diseases in pregnancy and hemodynamic stress later in life. We evaluated the relationship between hypertensive diseases in pregnancy and plasma levels of biomarkers of hemodynamic stress later in life in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Methods and Results: We investigated 1605 women from the GENOA study (mean age 61±10 years, 57.1% African American).Women were classified as self-reported as nulliparous women (n=140), a history of normotensive pregnancies (n=1,195), a history of a hypertensive pregnancy (n= 229), or a history of preeclampsia (n= 41). We compared adjusted associations among this groups with 4 biomarkers of hemodynamic stress using generalized estimating equations to account for familial clustering. After adjusting for age, race, level of education, smoking history, hypertension, body mass index (BMI), history of coronary artery disease, and diabetes, women with a history of preeclampsia had higher levels of C-terminal proendothelin (CT-proET) compared to women with a history of normotensive pregnancies (Table, p=0.01). There were no significant differences in the levels of midregional proatrial natriuretic peptide (MR-proANP), midregional proadrenomedullin (MR-proADM), and C-Terminal proarginine vasopressin (CT-proAVP) in this groups. Conclusions: Elevated levels of CT-proET (a precursor to the potent vasoconstrictor Endothelin 1) demonstrates a strong relationship among those with a history of preeclampsia. Future studies are warranted to further explore the relationship between CT-proET in the pathogenesis of preeclampsia as well as subsequent changes in cardiovascular structure and function associated with a history of preeclampsia later in life.

Relationship between markers of inflammation and hemodynamic stress and death in patients with out-of-hospital cardiac arrest

Biomarkers that reflect hemodynamic stress, inflammation, extracellular matrix remodeling, angiogenesis, and endothelial dysfunction may improve risk stratification and add valuable pathobiological insight in patients with out-of-hospital cardiac arrest (OHCA). In total, 120 patients with OHCA who survived at least 48 h after return of spontaneous circulation were consecutively included in the present analysis. Concentrations of 30 biomarkers were measured simultaneously using a multi-panel biomarker assay. Cox regression models were adjusted for age, sex, estimated glomerular filtration rate, lactate concentration, bystander resuscitation, initial cardiac rhythm, and type of targeted temperature management. Overall, 57 patients (47.5%) had a favorable neurological outcome (Cerebral Performance Category ≤ 2) at 30 days, while palliative care was initiated in 49 patients (40.8%), and 52 patients (43.3%) died. After correction for multiple testing with Bonferroni-Holm, 8 biomarkers (including Angiopoietin-2, Procalcitonin, Resistin, IL-4Rα, MMP-8, TNFα, Renin, and IL-1α) were significantly associated with all-cause death. After multivariable adjustment, only angiopoietin-2 (Adjusted (Adj) hazard ratio (HR) per 1-unit increase in standardized biomarker concentrations 1.52 (95% CI 1.16–1.99)) and renin (Adj HR 1.32 (95% CI 1.06–1.65) remained independently associated with an increased risk of death. The discriminatory performance indicated good performance for angiopoietin-2 (area under the curve (AUC): 0.75 (95% CI 0.66–0.75) and was significantly higher (P = 0.011) as compared with renin (AUC: 0.60, 95% CI 0.50–0.60). In conclusion, angiopoietin-2 was significantly associated with all-cause mortality in patients with OHCA who survived the first 48 h and may prove to be useful for risk stratification of these patients.