Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford Progeria Syndrome

Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved ZokinvyTM (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe end-stage cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, dual treatment with lonafarnib and rapamycin did not improve outcomes over that achieved with lonafarnib monotherapy.

Intensity of arterial structure acquired by Silent MRA estimates cerebral blood flow

Background Cerebral blood flow (CBF) and the morphology of the cerebral arteries are important for characterizing cerebrovascular disease. Silent magnetic resonance angiography (Silent MRA) is a MRA technique focusing on arterial structural delineation. This study was conducted to investigate the correlation between Silent MRA and CBF quantification, which has not yet been reported. Methods Both the Silent MRA and time-of-flight magnetic resonance angiography scans were applied in seventeen healthy participants to acquire the arterial structure and to find arterial intensities. Phase-contrast MRA (PC-MRA) was then used to perform the quantitative CBF measurement of 13 cerebral arteries. Due to different dataset baseline signal level of Silent MRA, the signal intensities of the selected 13 cerebral arteries were normalized to the selected ROIs of bilateral internal carotid arteries. The normalized signal intensities were used to determine the relationship between Silent MRA and CBF. Results The image intensity distribution of arterial regions generated by Silent MRA showed similar laminar shape as the phase distribution by PC-MRA (correlation coefficient > 0.62). Moreover, in both the results of individual and group-leveled analysis, the intensity value of arterial regions by Silent MRA showed positively correlation with the CBF by PC-MRA. The coefficient of determination (R2) of individual trends ranged from 0.242 to 0.956, and the R2 of group-leveled result was 0.550. Conclusions This study demonstrates that Silent MRA provides valuable CBF information despite arterial structure, rendering it a potential tool for screening for cerebrovascular disease.

RNO3 QTL Regulates Vascular Structure and Arterial Stiffness in the Spontaneously Hypertensive Rat

Increased arterial stiffness is an independent risk factor for hypertension, stroke, and cardiovascular morbidity. Thus, understanding the factors contributing to vascular stiffness is of critical importance. Here, we utilized a rat model containing a known quantitative trait loci (QTL) on chromosome 3 (RNO3) for vasoreactivity to assess potential genetic elements contributing to blood pressure, arterial stiffness and their downstream effects on cardiac structure and function. While no differences were found in blood pressure at any time point between parental Spontaneously Hypertensive Rats (SHR) and congenic SHR.BN3 rats, the SHR showed a significant increase in arterial stiffness measured by pulse wave velocity. The degree of arterial stiffness increased with age in the SHR and was associated with compensatory cardiac changes at 16 weeks of age, and decompensatory changes at 32 weeks, with no change in cardiac structure or function in the SHR.BN3 hearts at these time points. To evaluate the arterial wall structure, we utilized multiphoton microscopy to quantify cells and collagen content within the adventitia and media of SHR and SHR.BN3 arteries. No difference in cell numbers or proliferation rates were found, although phenotypic diversity was characterized in vascular smooth muscle cells. Herein, significant anatomical and physiological differences related to arterial structure and cardiovascular tone including, collagen, PWV, LV geometry and function, and VSMC contractile apparatus proteins were associated with the RNO3 QTL, thus providing a novel platform for studying arterial stiffness. Future studies delimiting the RNO3 QTL could aid in identifying genetic elements responsible for arterial structure and function.

“The Accessory Ethmoidal Canal Does Not Necessarily Contain an Arterial Structure”

Introduction: The aim of our study is to describe the prevalence of the accessory ethmoidal artery in endonasal endoscopic cadaver dissections and to identify its intraorbital origin. Material and Methods: From 2018 to 2020, thirty-four nasal dissections were performed in seventeen adult cadaveric heads. We performed a complete ethmoidectomy to identify the ethmoidal canals. Then, we removed the bony canal and the lamina papiracea to verify the injected vessel and to confirm the vascular structure inside the canal. Results: We found the anterior ethmoidal canal (AEC) and the posterior ethmoidal canal (PEC) in 100% of nasal cavities (34/34). We identified 4 accessory ethmoidal canals (AcEC) in the 34 nasal fossae dissected (12%). All AEC contained an arterial vessel. The AcEC contained an arterial vascular structure in 2 cases, a neural structure in other specimen, and in the fourth case no structure could be verified. In 32 of 34 nasal cavities, the PEC contained an artery and only in 2 cases the PEC did not contain any vascular structure. In these specimens, we observed that the AcEC with an arterial vessel inside (6%) was closer to the posterior canal than the anterior canal. Conclusion: According to our findings, we can suggest that the presence of a canal does not necessarily imply the presence of an arterial vessel, and that presence of the accessory ethmoidal artery could be associated with the absence of posterior ethmoidal artery.

Hypertriglyceridemia impact on arterial parameters in patients with metabolic syndrome

Background The development of metabolic syndrome (MS) augments risk for atherosclerotic cardiovascular disease (CVD), but pathophysiological mechanisms of this relation are still under discussion. Overlapping CVD risk factors make it difficult to assess the importance of individual elements. This study aimed to analyze subclinical atherosclerosis based on arterial structure and function parameters in patients with MS and different triglycerides levels. Methods Patients (aged 40–65 years) were divided into two groups: patients with MS and with or without hypertriglyceridemia (hTG). Noninvasive assessment of vascular parameters—aortic augmentation index adjusted for heart rate 75 bpm (AIxHR75), pulse wave velocity (PWV), and common carotid artery intima-media thickness (cIMT) were performed. Results Carotid-femoral PWV (cfPWV) and carotid-radial PWV (crPWV) were significantly higher in patients with hTG. After adjusting for age, gender, waist circumference, fasting glucose, smoking status, cardiovascular family history and mean arterial pressure, crPWV (OR 1.150; CI 95% 1.04–1.28), cfPWV (OR 1.283; CI 95% 1.14–1.42) and cIMT (OR 1.13; CI 95% 1.02–1.25) were significantly associated with hTG (p < 0.05), while AIxHR75 did not show significant association. Conclusion Increased triglycerides are independently associated with a cfPWV, crPWV, and cIMT and may modify CVD risk in patients with MS.

Intimal thickening and disruption of the media occur in the arterial walls of coronary arteries not associated with coronary arterial aneurysms in patients with Kawasaki disease

Background Coronary artery aneurysm (CAA) is an important complication of Kawasaki disease (KD) that is associated with arterial structure damage. However, few studies have examined structural changes in coronary arteries that are not associated with CAA. Methods We examined coronary arteries in KD patients with CAAs who underwent follow-up coronary angiography (CAG) and optical coherence tomography (OCT). Coronary arterial branches with no abnormal findings during the most recent CAG were classified into two groups. Arteries with an acute-phase CAA that later regressed were classified as group R; arteries with no abnormal findings on either acute or convalescent phase CAG were classified as group N. Coronary arterial wall structural changes were compared between groups using OCT. Results Fifty-seven coronary arterial branches in 23 patients were evaluated by OCT. Thirty-six branches showed no abnormality during the most recent CAG. Both groups R and N comprised 18 branches. Maximum intimal thicknesses in groups R and N were 475 and 355 µm, respectively (p = 0.007). The incidences of media disruption were 100% and 67%, respectively (p = 0.02). Calcification, macrophage accumulation, and thrombus were not found in either group. Conclusions Intimal thickening and disruption of the media occur in coronary arteries with acute phase CAAs that later regress in the convalescent phase, as well as in arteries with normal CAG findings in the acute and convalescent phases.

Changes in Body Size during Early Growth Are Independently Associated with Arterial Properties in Early Childhood

Nutritional status in early life stages has been associated with arterial parameters in childhood. However, it is still controversial whether changes in standardized body weight (z-BW), height (z-BH), BW for height (z-BWH) and/or body mass index (z-BMI) in the first three years of life are independently associated with variations in arterial structure, stiffness and hemodynamics in early childhood. In addition, it is unknown if the strength of the associations vary depending on the growth period, nutritional characteristics and/or arterial parameters analyzed. Aims: First, to compare the strength of association between body size changes (Δz-BW, Δz-BH, Δz-BWH, Δz-BMI) in different time intervals (growth periods: 0–6, 0–12, 0–24, 0–36, 12–24, 12–36, 24–36 months (m)) and variations in arterial structure, stiffness and hemodynamics at age 6 years. Second, to determine whether the associations depend on exposure to cardiovascular risk factors, body size at birth and/or on body size at the time of the evaluation (cofactors). Anthropometric (at birth, 6, 12, 24, 36 m and at age 6 years), hemodynamic (peripheral and central (aortic)) and arterial (elastic (carotid) and muscular (femoral) arteries; both hemi-bodies) parameters were assessed in a child cohort (6 years; n =632). The association between arterial parameters and body size changes (Δz-BW, Δz-BH, Δz-BWH, Δz-BMI) in the different growth periods was compared, before and after adjustment by cofactors. Results: Δz-BW 0–24 m and Δz-BWH 0–24 m allowed us to explain inter-individual variations in structural arterial properties at age 6 years, with independence of cofactors. When the third year of life was included in the analysis (0–36, 12–36, 24–36 m), Δz-BW explained hemodynamic (peripheral and central) variations at age 6 years. Δz-BH and Δz-BMI showed limited associations with arterial properties. Conclusion: Δz-BW and Δz-BWH are the anthropometric variables with the greatest association with arterial structure and hemodynamics in early childhood, with independence of cofactors.

Intimal Thickening and Disruption of The Media Occur in The Arterial Walls of Coronary Arteries Not Associated With Coronary Arterial Aneurysms in Patients With Kawasaki Disease

Background Coronary artery aneurysm (CAA) is an important complication of Kawasaki disease (KD) that is associated with arterial structure damage. However, few studies have examined structural changes in coronary arteries not associated with CAA.Methods We examined coronary arteries in KD patients with CAAs who underwent follow-up coronary angiography (CAG) and optical coherence tomography (OCT). Coronary arterial branches with no abnormal findings on most recent CAG were classified into two groups. Arteries with an acute-phase CAA that later regressed were classified as group R and arteries with no abnormal findings on either acute or convalescent phase CAG were classified as group N. Coronary arterial wall structural changes were compared between groups using OCT.ResultsFifty-seven coronary arterial branches in 23 patients were evaluated by OCT. Thirty-six branches showed no abnormality on most recent CAG. Both groups R and N comprised 18 branches. Maximum intimal thickness in groups R and N was 475 and 355 µm, respectively (p = 0.007). The incidence of disruption of the media was 100% and 67%, respectively (p = 0.02). Calcification, macrophage accumulation, and thrombus were not found in either group.ConclusionsIntimal thickening and disruption of the media occur not only in coronary arteries with acute phase CAAs that later regress in the convalescent phase, but also in arteries with normal CAG findings in the acute and convalescent phases.

The Effect of Hypertriglyceridemia on Arterial Structure and Function Parameters in Patients with Metabolic Syndrome

The authors have requested that this preprint be withdrawn due to erroneous posting.