A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8.

Adult (3 month) mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an increased cAMP-induced cardiac workload (~30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here, we show classical cardiac hypertrophy markers were absent in TGAC8, and that total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes, and a network of small interstitial proliferative non-cardiac myocytes compared to wild type (WT) littermates; Protein synthesis, proteosome activity, and autophagy were enhanced in TGAC8 vs WT, and Nrf-2, Hsp90α, and ACC2 protein levels were increased. Despite increased energy demands in vivo LV ATP and phosphocreatine levels in TGAC8 did not differ from WT. Unbiased omics analyses identified more than 2,000 transcripts and proteins, comprising a broad array of biological processes across multiple cellular compartments, which differed by genotype; compared to WT, in TGAC8 there was a shift from fatty acid oxidation to aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, marked overexpression of AC8 engages complex, coordinate adaptation "circuity" that has evolved in mammalian cells to defend against stress that threatens health or life (elements of which have already been shown to be central to cardiac ischemic pre-conditioning and exercise endurance cardiac conditioning) that may be of biological significance to allow for proper healing in disease states such as infarction or failure of the heart.

Volume Load Rather Than Resting Interval Influences Muscle Hypertrophy During High-Intensity Resistance Training.

ABSTRACT: Longo, AR, Silva-Batista, C, Pedroso, K, de Salles Painelli, V, Lasevicius, T, Schoenfeld, BJ, Aihara, AY, de Almeida Peres, B, Tricoli, V, and Teixeira, EL. Volume load rather than resting interval influences muscle hypertrophy during high-intensity resistance training. J Strength Cond Res 36(6): 1554-1559, 2022-Interset rest interval has been proposed as an important variable for inducing muscle mass and strength increases during resistance training. However, its influence remains unclear, especially when protocols with differing intervals have equalized volume. We aimed to compare the effects of long (LI) vs. short rest interval (SI) on muscle strength (one repetition maximum [1RM]) and quadriceps cross-sectional area (QCSA), with or without equalized volume load (VL). Twenty-eight subjects trained twice a week for 10 weeks. Each subject's leg was allocated to 1 of 4 unilateral knee extension protocols: LI, SI, SI with VL -matched by LI (VLI-SI), and LI with VL-matched by SI (VSI-LI). A 3-minute rest interval was afforded in LI and VSI-LI protocols, while SI and VLI-SI employed a 1-minute interval. All subjects trained with a load corresponding to 80% 1RM. One repetition maximum and QCSA were measured before and after training. All protocols significantly increased 1RM values in post-training (p < 0.0001; LI: 27.6%, effect size [ES] = 0.90; VLI-SI: 31.1%, ES = 1.00; SI: 26.5%, ES = 1.11; and VSI-LI: 31.2%, ES = 1.28), with no significant differences between protocols. Quadriceps cross-sectional area increased significantly for all protocols in post-training (p < 0.0001). However, absolute changes in QCSA were significantly greater in LI and VLI-SI (13.1%, ES: 0.66 and 12.9%, ES: 0.63) than SI and VSI-LI (6.8%, ES: 0.38 and 6.6%, ES: 0.37) (both comparisons, p < 0.05). These data suggest that maintenance of high loads is more important for strength increases, while a greater VL plays a primary role for hypertrophy, regardless of interset rest interval.

Protocol for accelerated skeletal muscle regeneration and hypertrophic muscle formation in mice.

The skeletal muscle system is the major organ associated with movement of the body. Myogenesis and regeneration induced post-injury contribute to muscle formation and maintenance. Here, we provide detailed protocol for the accelerated repair of injured skeletal muscles and generation of hypertrophic muscle fibers. This protocol includes cardiotoxin induced muscle injury and also describes isolation of satellite cells from skeletal muscle tissues of mice. This protocol can be used to study the mechanisms associated with accelerated muscle repair and hypertrophy. For complete details on the use and execution of this protocol, please refer to Ray et al. (2021).

From skeletal muscle damage and regeneration to the hypertrophy induced by exercise: what is the role of different macrophage subsets?

Macrophages are one of the top players when considering immune cells involved with tissue homeostasis. Recently, increasing evidence has demonstrated that macrophages could also present two major subsets during tissue healing: proliferative macrophages (M1-like), which are responsible for increasing myogenic cell proliferation, and restorative macrophages (M2-like), which are involved in the end of the mature muscle myogenesis. The participation and characterization of these macrophage subsets are critical during myogenesis to understand the inflammatory role of macrophages during muscle recovery and to create supportive strategies that can improve mass muscle maintenance. Indeed, most of our knowledge about macrophage subsets comes from skeletal muscle damage protocols, and we still do not know how these subsets can contribute to skeletal muscle adaptation. Thus, this narrative review aims to collect and discuss studies demonstrating the involvement of different macrophage subsets during the skeletal muscle damage/regeneration process, showcasing an essential role of these macrophage subsets during muscle adaptation induced by acute and chronic exercise programs.

A dataset of dual calcium and voltage optical mapping in healthy and hypertrophied murine hearts.

Pathological hypertrophy underlies sudden cardiac death due to its high incidence of occurrence of ventricular arrhythmias. The alteration of transmural electrophysiological properties in hypertrophic cardiac murine tissue has never been explored previously. In this dataset, we have for the first time conducted high-throughput simultaneous optical imaging of transmembrane potential and calcium transients (CaT) throughout the entire hypertrophic murine hearts at high temporal and spatial resolution. Using ElectroMap, we have conducted multiple parameters analysis including action potential duration/calcium transient duration, conduction velocity, alternans and diastolic interval. Voltage-calcium latency was measured as time difference between action potential and CaT peak. The dataset therefore provides the first high spatial resolution transmural electrophysiological profiling of the murine heart, allowing interrogation of mechanisms driving ventricular arrhythmias associated with pathological hypertrophy. The dataset allows for further reuse and detailed analyses of geometrical, topological and functional analyses and reconstruction of 2-dimensional and 3-dimentional models.

Incremental value of left atrial strain to predict atrial fibrillation recurrence after cryoballoon ablation.

OBJECTIVE: Atrial fibrillation (AF) recurrence occurs in approximately 25% of the patients undergoing cryoballoon ablation (CBA), leading to repeated ablations and complications. Left atrial (LA) dilation has been proposed as a predictor of AF recurrence. However, LA strain is a surrogate marker of LA mechanical dysfunction, which might appear before the enlargement of the LA. The purpose of this study was to evaluate the additional predictive value of LA function assessed using strain echocardiography for AF recurrence after CBA. METHODS: 172 consecutive patients (62.2 ± 12.2 years, 61% male) were prospectively analyzed. Echocardiography was performed before CBA. Blanking period was defined as the first three months post-ablation. The primary endpoint was AF recurrence after the blanking period. RESULTS: 50 (29%) patients had AF recurrence. In the overall study population, peak atrial longitudinal strain (PALS) ≤ 17% had the highest incremental predictive value for AF recurrence (HR = 9.45, 95%CI: 3.17-28.13, p < 0.001). In patients with non-dilated LA, PALS≤17% remained an independent predictor of AF recurrence (HR = 5.39, 95%CI: 1.66-17.52, p = 0.005). CONCLUSIONS: This study showed that LA function assessed by PALS provided an additional predictive value for AF recurrence after CBA, over LA enlargement. In patients with non-dilated LA, PALS also predicted AF recurrence. These findings emphasize the added value of LA strain, suggesting that it should be implemented in the systematic evaluation of AF patients before CBA.

Raptor is critical for increasing the mitochondrial proteome and skeletal muscle force during hypertrophy.

Loss of skeletal muscle mass and force is of critical importance in numerous pathologies, like age-related sarcopenia or cancer. It has been shown that the Akt-mTORC1 pathway is critical for stimulating adult muscle mass and function, however, it is unknown if mTORC1 is the only mediator downstream of Akt and which intracellular processes are required for functional muscle growth. Here, we show that loss of Raptor reduces muscle hypertrophy after Akt activation and completely prevents increases in muscle force. Interestingly, the residual hypertrophy after Raptor deletion can be completely prevented by administration of the mTORC1 inhibitor rapamycin. Using a quantitative proteomics approach we find that loss of Raptor affects the increases in mitochondrial proteins, while rapamycin mainly affects ribosomal proteins. Taken together, these results suggest that mTORC1 is the key mediator of Akt-dependent muscle growth and its regulation of the mitochondrial proteome is critical for increasing muscle force.

The effects of resistance training with blood flow restriction on muscle strength, muscle hypertrophy and functionality in patients with osteoarthritis and rheumatoid arthritis: A systematic review with meta-analysis.

INTRODUCTION: Rheumatoid arthritis(RA) and osteoarthritis(OA) patients showed systemic manifestations that may lead to a reduction in muscle strength, muscle mass and, consequently, to a reduction in functionality. On the other hand, moderate intensity resistance training(MIRT) and high intensity resistance training(HIRT) are able to improve muscle strength and muscle mass in RA and OA without affecting the disease course. However, due to the articular manifestations caused by these diseases, these patients may present intolerance to MIRT or HIRT. Thus, the low intensity resistance training combined with blood flow restriction(LIRTBFR) may be a new training strategy for these populations. OBJECTIVE: To perform a systematic review with meta-analysis to verify the effects of LIRTBFR on muscle strength, muscle mass and functionality in RA and OA patients. MATERIALS AND METHODS: A systematic review with meta-analysis of randomized clinical trials(RCTs), published in English, between 1957-2021, was conducted using MEDLINE(PubMed), Embase and Cochrane Library. The methodological quality was assessed using Physiotherapy Evidence Database scale. The risk of bias was assessed using RoB2.0. Mean difference(MD) or standardized mean difference(SMD) and 95% confidence intervals(CI) were pooled using a random-effects model. A P<0.05 was considered statistically significant. RESULTS: Five RCTs were included. We found no significant differences in the effects between LIRTBFR, MIRT and HIRT on muscle strength, which was assessed by tests of quadriceps strength(SMD = -0.01[-0.57, 0.54], P = 0.96; I² = 58%) and functionality measured by tests with patterns similar to walking(SMD = -0.04[-0.39, 0.31], P = 0.82; I² = 0%). Compared to HIRT, muscle mass gain after LIRTBFR was reported to be similar. When comparing LIRTBFR with low intensity resistance training without blood flow restriction(LIRT), the effect LIRTBFR was reported to be higher on muscle strength, which was evaluated by the knee extension test. CONCLUSION: LIRTBFR appears to be a promising strategy for gains in muscle strength, muscle mass and functionality in a predominant sample of RA and OA women.

Tissue sodium content correlates with hypertrophic vascular remodeling in type 2 diabetes.

BACKGROUND: Prospective studies describe a linkage between increased sodium intake and higher incidence of cardiovascular organ damage and end points. We analyzed whether tissue sodium content in the skin and muscles correlate with vascular hypertrophic remodeling, a risk factor for cardiovascular disease. METHODS: In patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles. The structural parameters of retinal arterioles assessed by Scanning Laser Doppler Flowmetry were vessel (VD) and lumen diameter (LD), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was measured with a 3.0 T clinical 23Sodium-Magnetic Resonance Imaging (23Na-MRI) system. RESULTS: In patients with type 2 diabetes (N = 52) we observed a significant correlation between muscle sodium content and VD (p = 0.005), WT (p = 0.003), WCSA (p = 0.002) and WLR (p = 0.013). With respect to skin sodium content a significant correlation has been found with VD (p = 0.042), WT (p = 0.023) and WCSA (p = 0.019). Further analysis demonstrated that tissue sodium content of skin and muscle is a significant determinant of hypertrophic vascular remodeling independent of age, gender, diuretic use and 24-hour ambulatory BP. CONCLUSION: With the 23Na-MRI technology we could demonstrate that high tissue sodium content is independently linked to hypertrophic vascular remodeling in type 2 diabetes. TRIAL REGISTRATION: Trial registration number: NCT02383238 Date of registration: March 9, 2015.

Postsynaptic cleft density changes with combined exercise protocols in an experimental model of muscular hypertrophy.

The vertical ladder-based protocols contribute to the NMJ junction's adaptations, and when combined with and without load, can be potentiated. The present study aimed to investigate postsynaptic regions of the biceps brachii muscle in adult male Wistar rats submitted to different vertical ladder-based protocols (Sedentary - S; Climbing - C; Climbing with Load - LC and Combined Climbing - CC). The protocols (C, LC, CC) were performed in 24 sessions, 3 x/week, for 8 weeks. The myofibrillar ATPase analysis showed an increase in cross-sectional area (CSA) of the muscle fibers Type I in all trained Groups; Type II in C and LC and reduction in CC; Type IIx higher in all trained Groups. In the postsynaptic cleft, the stained area presents smaller in Groups C, LC, and CC; the total area showed smaller than LC and higher in C and CC. The stained and total perimeter, and dispersion showed a reduction in C, LC, and CC, higher maximum diameter in Groups C and CC, and decreased in LC. Regarding the postsynaptic cleft distribution, the stained area presented a decrease in all trained Groups. The integrated density presented higher principally in CC. The NMJ count showed an increase in all trained Groups. We concluded that the vertical ladder-based protocols combined contributed to the postsynaptic region adaptations.

Isolated- and Beckwith-Wiedemann syndrome related- lateralised overgrowth (hemihypertrophy): Clinical and molecular correlations in 94 individuals.

The congenital imprinting disorder, Beckwith-Wiedemann syndrome (BWS) is associated with variable clinical features including hemihypertrophy/lateralised overgrowth (LO) and embryonal tumour predisposition. BWS-associated (epi)genetic alterations occur in a subset of patients with isolated LO (ILO), leading to the concept of BWS spectrum disorder (BWSp). We investigated the relationship between clinical features and molecular diagnostic results in a cohort with LO using the BWSp international consensus group (BWSICG) clinical scoring system. Clinical/molecular findings in 94 previously-unreported patients with LO referred for BWSp molecular studies were reviewed retrospectively. The BWSICG score was assigned and diagnostic rate calculated. BWSp-associated (epi)genetic alteration was identified in 15/94 (16%). The molecular diagnostic rate by MS-MLPA (blood DNA) for BWS-related molecular findings in patients with LO was positively correlated with the BWSICG score. 3/48 with ILO had a molecular alteration. No individuals with ILO had developed an embryonal tumour at last follow up. Among a cohort of individuals with LO referred for BWSp molecular testing, the BWSICG score correlated with diagnostic yield. The embryonal tumour risk in children with ILO and negative molecular testing appeared very low, however longer- and more complete follow up is required to better define tumour risks in this group.

Developmental and lifelong dioxin exposure induces measurable changes in cardiac structure and function in adulthood.

Congenital heart disease (CHD) is the most common congenital abnormality. A precise etiology for CHD remains elusive, but likely results from interactions between genetic and environmental factors during development, when the heart adapts to physiological and pathophysiological conditions. Further, it has become clearer that early exposure to toxins that do not result in overt CHD may be associated with adverse cardiac outcomes that are not manifested until later life. Previously, interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, was shown to cause structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. Here, we show that continuous exposure to TCDD from fertilization throughout adulthood caused male mice to underperform at exercise tolerance tests compared to their control and female counterparts, confirming previous observations of a sexually dimorphic phenotype. Renin-angiotensin stimulation by angiotensin II (Ang II) caused measurable increases in blood pressure and left ventricle mass, along with decreased end diastolic volume and preserved ejection fraction. Interestingly, TCDD exposure caused measurable reductions in the myocardial hypertrophic effects of Ang II, suggesting that endogenous AHR signaling present in adulthood may play a role in the pathogenesis of hypertrophy. Overall, the findings reported in this pilot study highlight the complex systems underlying TCDD exposure in the development of cardiac dysfunction in later life.

Application and side effects of blood flow restriction technique: A cross-sectional questionnaire survey of professionals.

ABSTRACT: The physiological benefits of applying blood flow restriction (BFR) in isolation or in the presence of physical exercise have been widely documented in the scientific literature. Most investigations carried out under controlled laboratory conditions have found the technique to be safe. However, few studies have analyzed the use of the technique in clinical settings.To analyze how the BFR technique has been applied by professionals working in the clinical area and the prevalence of side effects (SEs) resulting from the use of this technique.This is a cross-sectional study. A total of 136 Brazilian professionals who perform some function related to physical rehabilitation, sports science, or physical conditioning participated in this study. Participants answered a self-administered online questionnaire consisting of 21 questions related to the professional profile and methodological aspects and SEs of the BFR technique.Professionals reported applying the BFR technique on individuals from different age groups from youth (≤18 years; 3.5%) to older adults (60-80 years; 30.7%), but mainly on people within the age group of 20 to 29 years (74.6%). A total of 99.1% of the professionals coupled the BFR technique with resistance exercise. Their main goals were muscle hypertrophy and physical rehabilitation. The majority (60.9%) of interviewees reported using BFR in durations of less than 5 minutes and the pressure used was mainly determined through the values of brachial blood pressure and arterial occlusion. Moreover, 92% of professionals declared observing at least 1 SE resulting from the BFR technique. Most professionals observed tingling (71.2%) and delayed onset of muscle soreness (55.8%). Rhabdomyolysis, fainting, and subcutaneous hemorrhaging were reported less frequently (1.9%, 3.8%, and 4.8%, respectively).Our findings indicate that the prescription of blood flow restriction technique results in minimal serious side effects when it is done in a proper clinical environment and follows the proposed recommendations found in relevant scientific literature.

Do larger reductions yield larger returns? patient-reported outcomes as a function of specimen weight in bilateral reduction mammoplasty.

BACKGROUND: Patients undergoing breast reduction mammoplasty for symptomatic macromastia have a significantly improved quality of life postoperatively. However, there are no data that examine the effect of reduction mammoplasty on quality of life as a function of the weight of tissue removed. Because the process by which insurance providers consider patients' candidacy for this breast reduction mammoplasty is most often based on the proposed weight of tissue to be removed, this gap in our understanding is particularly glaring. We therefore designed a prospective trial with the intent of investigating the correlation between breast reduction specimen weight and postoperative pain and quality of life. METHODS: After obtaining institutional review board (IRB) approval, patients presenting for breast reduction mammoplasty at a single academic medical center between January 2016 and September 2019 were prospectively enrolled in the study. Study participants completed the Numerical Pain Rating Scale (NPRS), the short-form McGill Pain Questionnaire (SF-MPQ), and the BREAST-Q at set time points (preoperatively, 1 week/1 month/3 months/6 months postoperatively). Patients were divided into three cohorts based on breast reduction specimen weights: small (<500 g reduction), intermediate (500-1000 g reduction), and large (>1000 g reduction). The surveys were then analyzed while controlling for demographic factors and complications. RESULTS: A total of 85 women were enrolled in the study and completed pre- and postoperative surveys (small reduction n = 21 (25%), intermediate n = 45 (53%), and large n = 19 (22%)). Regardless of reduction specimen weight, patients reported decreased overall pain and increased satisfaction with their breasts, as well as improved psychosocial, sexual, and physical well-being at each postoperative visit. Preoperative SF-MPQ pain scores were significantly lower in the small specimen weight group compared with either the intermediate or the large group (p = 0.001). Postoperatively, both the intermediate and large groups reported significant improvement in pain at each time point. The small specimen weight group did not report significant pain improvement until 3 months postoperatively. CONCLUSIONS: Patients undergoing breast reduction mammoplasty experience decreased pain and improved quality of life regardless of reduction specimen weight. Improvement in these parameters manifests as early as 1 week postoperatively and maintained at 3 months postoperatively. These data suggest that many patients who are denied coverage for reduction mammoplasty on the basis of low projected reduction specimen weight would derive significant benefit from the procedure.

Left ventricular fibrosis and hypertrophy are associated with mortality in heart failure with preserved ejection fraction.

Cardiac magnetic resonance (CMR) is emerging as an important tool in the assessment of heart failure with preserved ejection fraction (HFpEF). This study sought to investigate the prognostic value of multiparametric CMR, including left and right heart volumetric assessment, native T1-mapping and LGE in HFpEF. In this retrospective study, we identified patients with HFpEF who have undergone CMR. CMR protocol included: cines, native T1-mapping and late gadolinium enhancement (LGE). The mean follow-up period was 3.2 ± 2.4 years. We identified 86 patients with HFpEF who had CMR. Of the 86 patients (85% hypertensive; 61% males; 14% cardiac amyloidosis), 27 (31%) patients died during the follow up period. From all the CMR metrics, LV mass (area under curve [AUC] 0.66, SE 0.07, 95% CI 0.54-0.76, p = 0.02), LGE fibrosis (AUC 0.59, SE 0.15, 95% CI 0.41-0.75, p = 0.03) and native T1-values (AUC 0.76, SE 0.09, 95% CI 0.58-0.88, p < 0.01) were the strongest predictors of all-cause mortality. The optimum thresholds for these were: LV mass > 133.24 g (hazard ratio [HR] 1.58, 95% CI 1.1-2.2, p < 0.01); LGE-fibrosis > 34.86% (HR 1.77, 95% CI 1.1-2.8, p = 0.01) and native T1 > 1056.42 ms (HR 2.36, 95% CI 0.9-6.4, p = 0.07). In multivariate cox regression, CMR score model comprising these three variables independently predicted mortality in HFpEF when compared to NTproBNP (HR 4 vs HR 1.65). In non-amyloid HFpEF cases, only native T1 > 1056.42 ms demonstrated higher mortality (AUC 0.833, p < 0.01). In patients with HFpEF, multiparametric CMR aids prognostication. Our results show that left ventricular fibrosis and hypertrophy quantified by CMR are associated with all-cause mortality in patients with HFpEF.

Diabetic condition induces hypertrophy and vacuolization in glomerular parietal epithelial cells.

Diabetic nephropathy (DN) is accompanied by characteristic changes in the glomerulus, but little is known about the effect of diabetes on parietal epithelial cells (PECs). In this study, a descriptive analysis of PECs was undertaken in diabetic db/db mice and in diabetic patients. PEC hypertrophy was significantly more prominent in diabetic mice than in nondiabetic mice, and this was evident even at the early stage. Additionally, the number of vacuoles in PECs was markedly increased in diabetic mice, suggesting the presence of cellular injury in PECs in DN. Although rare, binuclear cells were observed in mice with early diabetes. In cultured PECs, a high glucose condition, compared with normal glucose condition, induced cellular hypertrophy and apoptosis. Flow cytometry showed that some PECs in the G0 phase reentered the cell cycle but got arrested in the S phase. Finally, in human diabetic subjects, hypertrophy and vacuolization were observed in the PECs. Our data showed that PECs undergo substantial changes in DN and may participate in rearrangement for differentiation into podocytes.

Non-invasive evaluation of retinal vascular remodeling and hypertrophy in humans: intricate effect of ageing, blood pressure and glycaemia.

BACKGROUND: Ageing, hypertension and diabetes have an intricate effect on microvascular structure. In the retina, the respective contribution of remodeling and hypertrophy in such process is still unclear. We aimed at disentangling age, blood pressure and glycaemia effects on retinal microcirculation using the non-invasive adaptive optics ophthalmoscopy (AOO). METHODS: We included 429 subjects, distributed into 4 groups according to normal (nBP) or high blood pressure (hBP) and/or normal (nGly) or high fasting glycaemia (hGly). The nBP/nGly group was stratified in age tertiles to isolate the effect of ageing. AOO was used to measure arteriolar wall thickness (WT, µm), arteriolar (aID, µm) and venular internal diameter (vID, µm) and calculate arteriolar wall-to-lumen ratio (WLR), wall cross-sectional area (WCSA, µm2). One-way ANOVA for parametric variables and Kruskal-Wallis test for non-parametric variables were used for comparison among groups. A multivariate regression analysis including age, gender, BP, hGly and antihypertensive treatment was performed to calculate independent predictors of retinal remodeling. RESULTS: WT was increased with ageing (tertile1: 22.5 ± 3.2, tertile2: 24.2 ± 3.5, tertile 3: 25.2 ± 3.8, p = 0.001) and BP (hBP: 25.2 ± 4.1 vs nBP: 23.9 ± 3.7, p = 0.003). aID decreased with BP (hBP: 90.2 ± 13.4 vs nBP: 93.6 ± 11.6, p = 0.013) and increased with glycaemia (hGly: 97.7 ± 12.5 vs nGly: 93.6 ± 11.6, p = 0.002). A multivariate analysis showed independent association of hBP with WLR; hGly with WCSA; ageing with WLR and WCSA. CONCLUSIONS: AOO non-invasively identifies retinal structural changes in human confirming that microvascular remodeling is exclusively related to hypertension, whereas vascular growth is related to ageing and hyperglycaemia.