Tissue desaturation is not a major determinant of aging-related impairment in skeletal muscle reactive hyperemia: A retrospective analysis.

Near-infrared spectroscopy (NIRS) combined with vascular occlusion test (NIRS-VOT) is a reactive hyperemia technique for in vivo evaluation of skeletal muscle microvascular reactivity. Previous studies using NIRS-VOT have been shown to be able to detect impairments in microvascular function in high-risk cardiovascular disease (CVD) populations such as older individuals. It has been demonstrated that older individuals have slower reactive hyperemia compared to young individuals. Importantly, older individuals also show less desaturation during ischemia compared to young. Based on these findings, it has been suggested that the slower reactive hyperemia observed in older individuals is explained by the lower desaturation during blood flow occlusion (reduced ischemic stimulus). This retrospective analysis compared reactive hyperemia in 36 young and 47 older tissue desaturation-matched individuals that underwent 5-min blood flow occlusion. Overall, we showed that older individuals have impaired reactive hyperemia compared to young when matching for the degree of desaturation and blood flow occlusion time. These findings provide evidence that lower tissue desaturation during ischemia is not a major determinant of impaired reactive hyperemia in older individuals.

Non-invasive optoacoustic imaging of dermal microcirculatory revascularization in diet-induced obese mice undergoing exercise intervention.

Microcirculatory dysfunction has been observed in the dermal white adipose tissue (dWAT) and subcutaneous white adipose tissue (scWAT) of obese humans and has been proposed as an early prediction marker for cardio-metabolic disease progression. In-vivo visualization and longitudinal monitoring of microvascular remodeling in these tissues remains challenging. We compare the performance of two optoacoustic imaging methods, i.e. multi-spectral optoacoustic tomography (MSOT) and raster-scanning optoacoustic mesoscopy (RSOM) in visualizing lipid and hemoglobin contrast in scWAT and dWAT in a mouse model of diet-induced obesity (DIO) undergoing voluntary wheel running intervention for 32 weeks. MSOT visualized lipid and hemoglobin contrast in murine fat depots in a quantitative manner even at early stages of DIO. We show for the first time to our knowledge that RSOM allows precise visualization of the dWAT microvasculature and provides quantitative readouts of skin layer thickness and vascular density in dWAT and dermis. Combination of MSOT and RSOM resolved exercise-induced morphological changes in microvasculature density, tissue oxygen saturation, lipid and blood volume content in dWAT and scWAT. The combination of MSOT and RSOM may allow precise monitoring of microcirculatory dysfunction and intervention response in dWAT and scWAT in a mouse model for DIO. Our findings have laid out the foundation for future clinical studies using optoacoustic-derived vascular readouts from adipose tissues as a biomarker for monitoring microcirculatory function in metabolic disease.

PET/CT Assessment of Flow-Mediated Epicardial Vasodilation in Obesity and Severe Obesity.

Background: It is not known whether the transition from obesity and severe obesity, as 2 different metabolic disease entities, affect flow-mediated and, thus, endothelium-dependent epicardial vasodilation. Objectives: The purpose of this study was to investigate the effect of obesity and severe obesity on flow-mediated epicardial vasomotion with positron emission tomography/computed tomography-determined longitudinal decrease in myocardial blood flow (MBF) from the base-to-apex direction of the left ventricle or gradient. Methods: 13N-ammonia positron emission tomography/computed tomography evaluated global MBF during pharmacologically induced hyperemia and at rest for assessment of coronary microvascular function. In addition, the Δ longitudinal MBF gradient (hyperemia minus rest) was determined. Patients were then grouped according to the body mass index (BMI) into normal weight (NW) (BMI 20.0-24.9 kg/m2, n = 27), overweight (OW) (BMI 25.0-29.9 kg/m2, n = 29), obesity (OB) (BMI 30.0-39.9 kg/m2, n = 53), and severe obesity (morbid obesity: BMI ≥40 kg/m2, n = 43). Results: Compared to NW, left ventricular Δ longitudinal MBF gradient progressively declined in OW and OB (0.04 ± 0.09 mL/g/min vs -0.11 ± 0.14 mL/g/min and -0.15 ± 0.11 mL/g/min; P ≤ 0.001, respectively) but not significantly in SOB (-0.01 ± 0.11 mL/g/min, P = 0.066). Regadenoson-induced global hyperemic MBF was lower in OB than in NW (1.88 ± 0.40 mL/g/min vs 2.35 ± 0.32 mL/g/min; P ≤ 0.001), while comparable between NW and SOB (2.35 ± 0.32 mL/g/min vs 2.26 ± 0.40 mL/g/min; P = 0.302). The BMI of the study population was associated with the Δ longitudinal MBF gradient in a U-turn fashion (r = 0.362, standard error of the estimate = 0.124; P < 0.001). Conclusions: Increased body weight associates with abnormalities in coronary circulatory function that advances from an impairment flow-mediated, epicardial vasodilation in overweight and obesity to coronary microvascular dysfunction in obesity, not observed in severe obesity. The U-turn of flow-mediated epicardial vasomotion outlines obesity and severe obesity to affect epicardial endothelial function differently.

Effect of Encapsulated Purple Garlic Oil on Microvascular Function and the Components of Metabolic Syndrome: A Randomized Placebo-Controlled Study-The ENDOTALLIUM Study.

Endothelial dysfunction (ED) is associated with progressive changes contributing to clinical complications related to macro- and microvascular diseases. Garlic (Allium sativum L.) and its organosulfur components have been related to beneficial cardiovascular effects and could improve endothelial function. The ENDOTALLIUM Study aimed to evaluate the effect of the regular consumption of encapsulated purple garlic oil on microvascular function, endothelial-related biomarkers, and the components of metabolic syndrome (MetS) in untreated subjects with cardiometabolic alterations. Fifty-two individuals with at least one MetS component were randomized (1:1) in a single-center, single-blind, placebo-controlled, parallel-group study. The participants received encapsulated purple garlic oil (n = 27) or placebo (n = 25) for five weeks. Skin microvascular peak flow during post-occlusive reactive hyperemia significantly increased in the purple garlic oil group compared to the placebo group (between-group difference [95%CI]: 15.4 [1.5 to 29.4] PU; p = 0.031). Likewise, hs-CRP levels decreased in the purple garlic group compared to the control group (-1.3 [-2.5 to -0.0] mg/L; p = 0.049). Furthermore, we observed a significant reduction in the mean number of MetS components in the purple garlic group after five weeks (1.7 ± 0.9 vs. 1.3 ± 1.1, p = 0.021). In summary, regular consumption of encapsulated purple garlic oil significantly improved microvascular function, subclinical inflammatory status, and the overall MetS profile in a population with cardiometabolic alterations.

The neurovascular unit and its correlation with cognitive performance in patients with cerebral small vessel disease: a canonical correlation analysis approach.

Growing evidence indicates an important role of neurovascular unit (NVU) dysfunction in the pathophysiology of cerebral small vessel disease (cSVD). Individually measurable functions of the NVU have been correlated with cognitive function, but a combined analysis is lacking. We aimed to perform a unified analysis of NVU function and its relation with cognitive performance. The relationship between NVU function in the white matter and cognitive performance (both latent variables composed of multiple measurable variables) was investigated in 73 patients with cSVD (mean age 70 ± 10 years, 41% women) using canonical correlation analysis. MRI-based NVU function measures included (1) the intravoxel incoherent motion derived perfusion volume fraction (f) and microvascular diffusivity (D*), reflecting cerebral microvascular flow; (2) the IVIM derived intermediate volume fraction (fint), indicative of the perivascular clearance system; and (3) the dynamic contrast-enhanced MRI derived blood-brain barrier (BBB) leakage rate (Ki) and leakage volume fraction (VL), reflecting BBB integrity. Cognitive performance was composed of 13 cognitive test scores. Canonical correlation analysis revealed a strong correlation between the latent variables NVU function and cognitive performance (r 0.73; p = 0.02). For the NVU, the dominating variables were D*, fint, and Ki. Cognitive performance was driven by multiple cognitive tests comprising different cognitive domains. The functionality of the NVU is correlated with cognitive performance in cSVD. Instead of focusing on individual pathophysiological mechanisms, future studies should target NVU dysfunction as a whole to acquire a coherent understanding of the complex disease mechanisms that occur in the NVU in cSVD.Trial registration: NTR3786 (Dutch Trial Register).

Bayliss Starling Prize Lecture 2023: Neuropeptide-Y being 'unsympathetic' to the broken hearted.

William Bayliss and Ernest Starling are not only famous as pioneers in cardiovascular physiology, but also responsible for the discovery of the first hormone (from the Greek 'excite or arouse'), the intestinal signalling molecule and neuropeptide secretin in 1902. Our research group focuses on neuropeptides and neuromodulators that influence cardiovascular autonomic control as potential biomarkers in disease and tractable targets for therapeutic intervention. Acute myocardial infarction (AMI) and chronic heart failure (CHF) result in high levels of cardiac sympathetic stimulation, which is a poor prognostic indicator. Although beta-blockers improve mortality in these conditions by preventing the action of the neurotransmitter noradrenaline, a substantial residual risk remains. Recently, we have identified the sympathetic co-transmitter neuropeptide-Y (NPY) as being released during AMI, leading to larger infarcts and life-threatening arrhythmia in both animal models and patients. Here, we discuss recently published data demonstrating that peripheral venous NPY levels are associated with heart failure hospitalisation and mortality after AMI, and all cause cardiovascular mortality in CHF, even when adjusting for known risk factors (including brain natriuretic peptide). We have investigated the mechanistic basis for these observations in human and rat stellate ganglia and cardiac tissue, manipulating NPY neurochemistry at the same time as using state-of-the-art imaging techniques, to establish the receptor pathways responsible for NPY signalling. We propose NPY as a new mechanistic biomarker in AMI and CHF patients and aim to determine whether specific NPY receptor blockers can prevent arrhythmia and attenuate the development of heart failure.

The remote and local effects of ischaemic preconditioning on vascular function; a case for cumulative benefit.

Brief, repeated cycles of limb ischaemia and reperfusion (ischaemic preconditioning; IPC) can protect against vascular insult. Few papers have considered the effect of IPC on resting vascular function, and no single study has simultaneously considered the local (trained arm) and remote (untrained arm) effect of a single session of IPC, and following repeated sessions. We determined macrovascular (allometrically-scaled flow mediated dilation; FMD) and microvascular (cutaneous vascular conductance; CVC) function in healthy adults before, immediately post, 20 min post and 24 h post a single session of IPC (4 x 5 min of single arm ischaemia). These outcomes also were re-measured 24 h after 6 IPC sessions, performed over 2 weeks. FMD and CVC increased in both arms 20 min post (FMD mean difference (MD) 1.1%, P < 0.001; CVC MD 0.08 AU, P = 0.004) but not 24 hour post (FMD MD -0.2%, P = 0.459; CVC MD -0.02 AU, P = 0.526) a single session of IPC, with no differences between trained and untrained arms. Whilst FMD did not increase 24 h after one IPC session, it was elevated in both arms 24 h after the sixth session (MD 1.2%, P = 0.009). CVC was not altered in either arm 24 h after the last IPC session. These data indicate that the local and remote effect of IPC on vascular health may be equivalent, and that the benefits to FMD may be greater with sustained training compared to a single IPC exposure.

Simulation of coronary fractional flow reserve and whole-cycle flow based on optical coherence tomography in individual patients with coronary artery disease.

Computer simulations of coronary fractional flow reserve (FFR) based on coronary imaging have emerged as an attractive alternative to invasive measurements. However, most methods are proprietary and employ non-physiological assumptions. Our aims were to develop and validate a physiologically realistic open-source simulation model for coronary flow, and to use this model to predict FFR based on intracoronary optical coherence tomography (OCT) data in individual patients. We included patients undergoing elective coronary angiography with angiographic borderline coronary stenosis. Invasive measurements of coronary hyperemic pressure and absolute flow and OCT imaging were performed. A computer model of coronary flow incorporating pulsatile flow and the effect of left ventricular contraction was developed and calibrated, and patient-specific flow simulation was performed. Forty-eight coronary arteries from 41 patients were included in the analysis. Average FFR was 0.79 ± 0.14, and 50% had FFR ≤ 0.80. Correlation between simulated and measured FFR was high (r = 0.83, p < 0.001). Average difference between simulated FFR and observed FFR in individual patients was - 0.009 ± 0.076. Overall diagnostic accuracy for simulated FFR ≤ 0.80 in predicting observed FFR ≤ 0.80 was 0.88 (0.75-0.95) with sensitivity 0.79 (0.58-0.93) and specificity 0.96 (0.79-1.00). The positive predictive value was 0.95 (0.75-1.00) and the negative predictive value was 0.82 (0.63-0.94). In conclusion, realistic simulations of whole-cycle coronary flow can be produced based on intracoronary OCT data with a new, computationally simple simulation model. Simulated FFR had moderate numerical agreement with observed FFR and a good diagnostic accuracy for predicting hemodynamic significance of coronary stenoses.

Enhancing Endothelial Function with Nutrient-Enriched Table Hen Eggs: A Randomized Study in Patients Recovering from Acute Coronary Syndrome.

Purpose: This study investigated the effect of consumption of table eggs enriched with n-3 polyunsaturated fatty acids (n-3 PUFA), lutein, vitamin E and selenium on microvascular function, oxidative stress and inflammatory mediators in patients after acute coronary syndrome (ACS). Patients and Methods: In a prospective, randomized, interventional, double-blind clinical trial, ACS patients were assigned to either the Nutri4 (N=15, mean age: 57.2 ± 9.2 years), or the Control group (N=13; mean age 56.8 ± 9.6 years). The Nutri4 group consumed three enriched hen eggs daily for three weeks, providing approximately 1.785 mg of vitamin E, 0.330 mg of lutein, 0.054 mg of selenium and 438 mg of n-3 PUFAs. Biochemical parameters, including serum lipids, liver enzymes, nutrient concentrations, serum antioxidant enzyme activity (catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD)), and markers of oxidative stress (thiobarbituric acid reactive substances (TBARS) and ferric reducing ability (FRAP)), were assessed before and after the dietary interventions. Additionally, arterial blood pressure, heart rate, body composition, fluid status, anthropometric measurements, and skin microvascular blood flow responses to various stimuli (postocclusive reactive hyperemia (PORH), acetylcholine- (Ach ID), and sodium nitroprusside- (SNP ID)) were measured using laser Doppler flowmetry (LDF) throughout the study. Results: The intake of Nutri4 eggs led to a significant reduction in LDL cholesterol levels, while the levels of total cholesterol remained within the established reference values. Consuming Nutri4 eggs resulted in a 12.7% increase in serum vitamin E levels, an 8.6% increase in selenium levels, and demonstrated a favorable impact on microvascular reactivity, as evidenced by markedly improved PORH and ACh ID. Nutri4 eggs exerted a significant influence on the activity of GPx and SOD, with no observed changes in TBARS or FRAP values. Conclusion: The consumption of Nutri4 eggs positively influenced microvascular function in individuals with ACS, without eliciting adverse effects on oxidative stress.

Associations of between- and within-day patterns of physical activity accumulation with arterial stiffness and indices of microvascular health-Evidence from The Maastricht study.

While physical activity (PA) is understood to promote vascular health, little is known about whether the daily and weekly patterns of PA accumulation associate with vascular health. Accelerometer-derived (activPAL3) 6- or 7-day stepping was analyzed for 6430 participants in The Maastricht Study (50.4% women; 22.4% Type 2 diabetes mellitus (T2DM)). Multivariable regression models examined associations between stepping metrics (average step count, and time spent slower and faster paced stepping) with arterial stiffness (measured as carotid-femoral pulse wave velocity (cfPWV)), and several indices of microvascular health (heat-induced skin hyperemia, retinal vessel reactivity and diameter), adjusting for confounders and moderators. PA pattern metrics were added to the regression models to identify associations with vascular health beyond that of stepping metrics. Analyses were stratified by T2DM status if an interaction effect was present. Average step count and time spent faster paced stepping was associated with better vascular health, and the association was stronger in those with compared to those without T2DM. In fully adjusted models a higher step count inter-daily stability was associated with a higher (worse) cfPWV in those without T2DM (std ß = 0.04, p = 0.007) and retinal venular diameter in the whole cohort (std ß = 0.07, p = 0.002). A higher within-day variability in faster paced stepping was associated with a lower (worse) heat-induced skin hyperemia in those with T2DM (std ß = -0.31, p = 0.008). Above and beyond PA volume, the daily and weekly patterns in which PA was accumulated were additionally associated with improved macro- and microvascular health, which may have implications for the prevention of vascular disease.

Microvascular Function and Exercise Training: Functional Implication of Nitric Oxide Signaling and Ion Channels.

Background: Exercise training elicits indubitable positive adaptation in microcirculation in health and disease populations. An inclusive overview of the current knowledge regarding the effects of exercise on microvascular function consolidates an in-depth understanding of microvasculature. Summary: The main physiological function of microvasculature is to maintain optimal blood flow regulation to supply oxygen and nutrition during elevated physical demands in the cardiovascular system. There are several cellular and molecular alterations in resistance vessels in response to exercise intervention, an increase in nitric oxide-mediated vasodilation through the regulation of oxidative stress, inflammatory response, and ion channels in endothelial cells, thus increasing myogenic tone via voltage-gated Ca2+ channels in smooth muscle cells. Key Messages: In the review, we postulate that exercise should be considered a medicine for people with diverse diseases through a comprehensive understanding of the cellular and molecular underlying mechanisms in microcirculation through exercise training.

Coronary Microvascular Function Following Severe Preeclampsia.

Background: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating pro- and anti-angiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. Methods: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography (PET) within 4 weeks of delivery. A control group of pre-menopausal, non-postpartum women was also included. Myocardial flow reserve (MFR), myocardial blood flow (MBF), and coronary vascular resistance (CVR) were compared across groups. Soluble fms-like tyrosine kinase receptor-1 (sFlt-1) and placental growth factor (PlGF) were measured at imaging. Results: The primary cohort included 19 women with severe preeclampsia (imaged at a mean 16.0 days postpartum), 5 with normotensive pregnancy (mean 14.4 days postpartum), and 13 non-postpartum female controls. Preeclampsia was associated with lower MFR (ß=-0.67 [95% CI -1.21 to -0.13]; P=0.016), lower stress MBF (ß=-0.68 [95% CI, -1.07 to -0.29] mL/min/g; P=0.001), and higher stress CVR (ß=+12.4 [95% CI 6.0 to 18.7] mmHg/mL/min/g; P=0.001) vs. non-postpartum controls. MFR and CVR after normotensive pregnancy were intermediate between preeclamptic and non-postpartum groups. Following preeclampsia, MFR was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest MBF (r=0.71; P<0.001), independent of hemodynamics. Conclusions: In this exploratory study, we observed reduced coronary microvascular function in the early postpartum period following severe preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves the coronary microcirculation. Further research is needed to establish interventions to mitigate risk of preeclampsia-associated cardiovascular disease.

Effects of ischaemic post-conditioning on eccentric exercise-induced muscle damage.

Exercise-induced muscle damage (EIMD) is a common phenomenon resulting from high-intensity exercise that impairs subsequent performance. Ischaemic post-conditioning (IPOC) is a simple intervention that has been shown to reduce muscle damage after prolonged ischaemia, a condition mechanistically similar to EIMD. The purpose of this study was to determine whether IPOC could alleviate muscle damage after eccentric exercise. Thirty-two young male participants were randomized into either a sham (n = 16) or an IPOC (n = 16) intervention group. Biceps brachii muscle damage was induced by eccentric exercise, with IPOC or sham intervention applied on the dominant arm following exercise (3 cycles of 30 s ischaemia). Visual analogue scale (VAS) pain, arm circumference, muscle thickness, echo-intensity, and microvascular function (using near-infrared spectroscopy) were measured bilaterally at baseline, 24, 48, and 72 hours after eccentric exercise. Biceps curl one repetition maximum (1RM) was also measured. 1RM was higher for the IPOC group at 48 and 72 hours (both p < 0.05). On the dominant arm, VAS pain was lower at 72 hours for the IPOC group (p = 0.039). Muscle thickness was lower at all post-exercise time points for the IPOC group (all p < 0.05). VAS pain, echo-intensity, and arm circumference were elevated on the non-dominant arm in the sham group at 72 hours (all p < 0.05). These parameters all returned to the baseline level for the IPOC group at 72 hours (all p > 0.05IPOC could attenuate the decrease in strength, and alleviate EIMD with both local and remote effects after high-intensity exercise.

Retinal microvascular function and incidence and trajectories of clinically relevant depressive symptoms: the Maastricht Study.

BACKGROUND: Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. We investigated the association of retinal microvascular function, a proxy for microvascular function in the brain, with incidence and trajectories of clinically relevant depressive symptoms. METHODS: Longitudinal data are from The Maastricht Study of 5952 participants (59.9 ± 8.5 years/49.7% women) without clinically relevant depressive symptoms at baseline (2010-2017). Central retinal arteriolar equivalent and central retinal venular equivalent (CRAE and CRVE) and a composite score of flicker light-induced retinal arteriolar and venular dilation were assessed at baseline. We assessed incidence and trajectories of clinically relevant depressive symptoms (9-item Patient Health Questionnaire score ⩾10). Trajectories included continuously low prevalence (low, n = 5225 [87.8%]); early increasing, then chronic high prevalence (early-chronic, n = 157 [2.6%]); low, then increasing prevalence (late-increasing, n = 247 [4.2%]); and remitting prevalence (remitting, n = 323 [5.4%]). RESULTS: After a median follow-up of 7.0 years (range 1.0-11.0), 806 (13.5%) individuals had incident clinically relevant depressive symptoms. After full adjustment, a larger CRAE and CRVE were each associated with a lower risk of clinically relevant depressive symptoms (hazard ratios [HRs] per standard deviation [s.d.]: 0.89 [95% confidence interval (CI) 0.83-0.96] and 0.93 [0.86-0.99], respectively), while a lower flicker light-induced retinal dilation was associated with a higher risk of clinically relevant depressive symptoms (HR per s.d.: 1.10 [1.01-1.20]). Compared to the low trajectory, a larger CRAE was associated with lower odds of belonging to the early-chronic trajectory (OR: 0.83 [0.69-0.99]) and a lower flicker light-induced retinal dilation was associated with higher odds of belonging to the remitting trajectory (OR: 1.23 [1.07-1.43]). CONCLUSIONS: These findings support the hypothesis that cerebral microvascular dysfunction contributes to the development of depressive symptoms.

An interventional sheep model of severe aortic valve stenosis hemodynamics for the evaluation of alterations in coronary physiology and microvascular function.

We aimed to develop a large animal model of subcoronary aortic stenosis (AS) to study intracoronary and microcirculatory hemodynamics. A total of three surgical techniques inducing AS were evaluated in 12 sheep. Suturing the leaflets together around a dilator (n = 2) did not result in severe AS. Suturing of a pericardial patch with a variable opening just below the aortic valve (n = 5) created an AS which was poorly tolerated if the aortic valve area (AVA) was too small (0.38-1.02 cm2), but was feasible with an AVA of 1.2 cm2. However, standardization of aortic regurgitation (AR) with this technique is difficult. Therefore, we opted for implantation of an undersized AV-bioprosthesis with narrowing sutures on the leaflets (n = 5). Overall, five sheep survived the immediate postoperative period of which three had severe AS (one patch and two bioprostheses). The surviving sheep with severe AS developed left ventricular hypertrophy and signs of increased filling-pressures. Intracoronary assessment of physiological indices in these AS sheep pointed toward the development of functional microvascular dysfunction, with a significant increase in coronary resting flow and hyperemic coronary resistance, resulting in a significantly higher index of microvascular resistance (IMR) and lower myocardial resistance reserve (MRR). Microscopic analysis showed myocardial hypertrophy and signs of fibrosis without evidence of capillary rarefaction. In a large animal model of AS, microvascular changes are characterized by increased resting coronary flow and hyperemic coronary resistance resulting in increased IMR and decreased MRR. These physiological changes can influence the interpretation of regularly used coronary indices.NEW & NOTEWORTHY In an animal model of aortic valve stenosis (AS), coronary physiological changes are characterized by increased resting coronary flow and hyperemic coronary resistance. These changes can impact coronary indices frequently used to assess concomitant coronary artery disease (CAD). At this point, the best way to assess and treat CAD in AS remains unclear. Our data suggest that fractional flow reserve may underestimate CAD, and nonhyperemic pressure ratios may overestimate CAD severity before aortic valve replacement.

Early signs of myocardial systolic dysfunction in patients with type 2 diabetes are strongly associated with myocardial microvascular dysfunction independent of myocardial fibrosis: a prospective cohort study.

BACKGROUND: Patients with diabetes demonstrate early left ventricular systolic dysfunction. Notably reduced global longitudinal strain (GLS) is related to poor outcomes, the underlying pathophysiology is however still not clearly understood. We hypothesized that pathophysiologic changes with microvascular dysfunction and interstitial fibrosis contribute to reduced strain. METHODS: 211 patients with type 2 diabetes and 25 control subjects underwent comprehensive cardiovascular phenotyping by magnetic resonance imaging. Myocardial blood flow (MBF), perfusion reserve (MPR), extracellular volume (ECV), and 3D feature tracking GLS and global circumferential (GCS) and radial strain (GRS) were quantified. RESULTS: Patients (median age 57 [IQR 50, 67] years, 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. Compared to control subjects GLS, GCS, and GRS were reduced in the total diabetes cohort, and GLS was also reduced in the sub-group of patients without diabetic complications compared to control subjects (controls - 13.9 ± 2.0%, total cohort - 11.6 ± 3.0%; subgroup - 12.3 ± 2.6%, all p < 0.05). Reduced GLS, but not GCS or GRS, was associated with classic diabetes complications of albuminuria (UACR ≥ 30 mg/g) [ß (95% CI) 1.09 (0.22-1.96)] and autonomic neuropathy [ß (95% CI) 1.43 (0.54-2.31)] but GLS was not associated with retinopathy or peripheral neuropathy. Independently of ECV, a 10% increase in MBF at stress and MPR was associated with higher GLS [multivariable regression adjusted for age, sex, hypertension, smoking, and ECV: MBF stress (ß (95% CI) - 0.2 (- 0.3 to - 0.08), MPR (ß (95% CI) - 0.5 (- 0.8 to - 0.3), p < 0.001 for both]. A 10% increase in ECV was associated with a decrease in GLS in univariable [ß (95% CI) 0.6 (0.2 to 1.1)] and multivariable regression, but this was abolished when adjusted for MPR [multivariable regression adjusted for age, sex, hypertension, smoking, and MPR (ß (95% CI) 0.1 (- 0.3 to 0.6)]. On the receiver operating characteristics curve, GLS showed a moderate ability to discriminate a significantly lowered stress MBF (AUC 0.72) and MPR (AUC 0.73). CONCLUSIONS: Myocardial microvascular dysfunction was independent of ECV, a biomarker of myocardial fibrosis, associated with GLS. Further, 3D GLS could be a potential screening tool for myocardial microvascular dysfunction. Future directions should focus on confirming these results in longitudinal and/or interventional studies.

Ranolazine for improving coronary microvascular function in patients with nonobstructive coronary artery disease: a systematic review and meta-analysis with a trial sequential analysis of randomized controlled trials.

Background: Microvascular dysfunction in patients with nonobstructive coronary artery disease is increasingly being recognized as an important health issue. This systematic review and meta-analysis evaluated the effectiveness of ranolazine, an antianginal agent, in improving coronary microvascular function. Methods: We conducted a comprehensive literature search of the Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure, the Chinese BioMedical Literature Database, and gray literature databases until September 30, 2023. The included studies were randomized controlled trials (RCTs) published in the English or Chinese languages that screened for eligibility using two independent investigators. Risk of bias was evaluated with the Cochrane Collaboration tool. Subgroup and sensitivity analyses were used to identify sources of heterogeneity. Meta-analysis was performed using RevMan version 5.4 (Cochrane) and Stata version 16.0 (StataCorp). Results: From 1,470 citations, 8 RCTs involving 379 participants were included in this analysis. Our findings showed that ranolazine increased coronary flow reserve (CFR) over an 8 to 12-week follow-up period [standardized mean difference =1.16; 95% confidence interval (CI): 0.4-1.89; P=0.002]. Ranolazine increased the global myocardial perfusion reserve index (MPRI) [weighted mean difference (WMD) =0.18; 95% CI: 0.07-0.29; P=0.002] and the midsubendocardial MPRI (WMD =0.10; 95% CI: 0.02-0.19; P=0.02). Moreover, ranolazine improved 3 of the 5 Seattle Angina Questionnaire scores, namely, physical functioning (WMD =4.89; 95% CI: 0.14 to 9.64; P=0.04), angina stability (WMD =17.31; 95% CI: 7.13-27.49; P=0.0009), and quality of life (WMD =10.11; 95% CI: 3.57-16.65; P=0.0003). Trial sequential analysis showed that the meta-analysis of angina stability and quality of life scores had a sufficient sample size and statistical power. Conclusions: Our analysis suggests that ranolazine is associated with improvements in CFR, myocardial perfusion, and the Seattle Angina Questionnaire scores in patients with nonobstructive coronary artery disease. However, further large-scale RCTs with long-term follow-up are recommended to validate these findings and provide a more comprehensive understanding of the effects of ranolazine on coronary microvascular function.

Doxorubicin alters G-protein coupled receptor-mediated vasocontraction in rat coronary arteries.

Doxorubicin (Doxo)-associated cardio-and vasotoxicity has been recognised as a serious complication of cancer chemotherapy. The purpose of this novel paper was to determine the effect of Doxo on G-protein coupled receptor (GPCR)-mediated vasocontraction located on vascular smooth muscle cells. Rat left anterior descending artery segments were incubated for 24 h with 0.5 µM Doxo. The vasocontractile responses by activation of endothelin receptor type A (ETA) and type B (ETB), serotonin receptor 1B (5-HT1B) and thromboxane A2 prostanoid receptor (TP) were investigated by a sensitive myography using specific agonists, while the specificity of the GPCR agonists was verified by applying selective antagonists (i.e. ETA and ETB agonist = 10- 14-10- 7.5 M endothelin-1 (ET-1); ETA antagonist = 10 µM BQ123; ETB agonists = 10- 14-10- 7.5 M sarafotoxin 6c (S6c) and ET-1; ETB antagonist = 0.1 µM BQ788; 5-HT1B agonist = 10- 12-10- 5.5 M 5-carboxamidotryptamine (5-CT); 5-HT1B antagonist = 1 µM GR55562; TP agonist = 10- 12-10- 6.5 M U46619; TP antagonist = 1 µM Seratrodast). Our results show that 0.5 µM Doxo incubation of LAD segments leads to an increased VSMC vasocontraction through the ETB, 5-HT1B and TP GPCRs, with a 2.2-fold increase in ETB-mediated vasocontraction at 10- 10.5 M S6c, a 2.0-fold increase in 5-HT1B-mediated vasocontraction at 10- 5.5 M 5-CT, and a 1.3-fold increase in TP-mediated vasocontraction at 10- 6.5 M U46619. Further studies unravelling the involvement of intracellular GPCR signalling pathways will broaden our understanding of the Doxo-induced vasotoxicity, and thus pave the way to mitigate the adverse effects by potential implementation of adjunct therapy options.

Cytomegalovirus infection is associated with impaired myocardial flow reserve after heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits long-term survival after heart transplantation (HT). This study evaluates the relationship between clinically significant cytomegalovirus infection (CS-CMVi) and CAV using cardiac positron emission tomography (PET). METHODS: We retrospectively evaluated HT patients from 2005 to 2019 who underwent cardiac PET for CAV evaluation. Multivariable linear and logistic regression models were used to evaluate the association between CS-CMVi and myocardial flow reserve (MFR). Kaplan-Meier and Cox regression analyses were used to assess the relationship between CS-CMV, MFR, and clinical outcomes. RESULTS: Thirty-two (31.1%) of 103 HT patients developed CS-CMVi at a median 9 months after HT. Patients with CS-CMVi had a significantly lower MFR at year 1 and 3, driven by reduction in stress myocardial blood flow. Patients with CS-CMVi had a faster rate of decline in MFR compared to those without infection (-0.10 vs -0.06 per year, p < 0.001). CS-CMVi was an independent predictor of abnormal MFR (<2.0) (odds ratio: 3.8, 95% confidence intervals (CI): 1.4-10.7, p = 0.001) and a lower MFR (ß = -0.39, 95% CI: -0.63 to -0.16, p = 0.001) at year 3. In adjusted survival analyses, both abnormal MFR (log-rank p < 0.001; hazard ratio [HR]: 5.7, 95% CI: 4.2-7.2) and CS-CMVi (log-rank p = 0.028; HR: 3.3, 95% CI: 1.8-4.8) were significant predictors of the primary outcome of all-cause mortality, retransplantation, heart failure hospitalization, and acute coronary syndrome. CONCLUSIONS: CS-CMVi is an independent predictor of reduced MFR following HT. These findings suggest that CMV infection is an important risk factor in the development and progression of CAV.

Associations of measured and genetically predicted leukocyte telomere length with vascular phenotypes: a population-based study.

Shorter leukocyte telomere length (LTL) is associated with cardiovascular dysfunction. Whether this association differs between measured and genetically predicted LTL is still unclear. Moreover, the molecular processes underlying the association remain largely unknown. We used baseline data of the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany [56.2% women, age: 55.5 ± 14.0 years (range 30 - 95 years)]. We calculated genetically predicted LTL in 4180 participants and measured LTL in a subset of 1828 participants with qPCR. Using multivariable regression, we examined the association of measured and genetically predicted LTL, and the difference between measured and genetically predicted LTL (ΔLTL), with four vascular functional domains and the overall vascular health. Moreover, we performed epigenome-wide association studies of three LTL measures. Longer measured LTL was associated with better microvascular and cardiac function. Longer predicted LTL was associated with better cardiac function. Larger ΔLTL was associated with better microvascular and cardiac function and overall vascular health, independent of genetically predicted LTL. Several CpGs were associated (p < 1e-05) with measured LTL (n = 5), genetically predicted LTL (n = 8), and ΔLTL (n = 27). Genes whose methylation status was associated with ΔLTL were enriched in vascular endothelial signaling pathways and have been linked to environmental exposures, cardiovascular diseases, and mortality. Our findings suggest that non-genetic causes of LTL contribute to microvascular and cardiac function and overall vascular health, through an effect on the vascular endothelial signaling pathway. Interventions that counteract LTL may thus improve vascular function.