Early detection of coronary artery dysfunction is of paramount cardiovascular clinical importance, but a non-invasive assessment is lacking. Indeed, the brachial artery flow-mediated dilation test only weakly correlated with acetylcholine-induced coronary artery function (r=0.36). However, brachial artery flow-mediated dilation methodologies have, over time, substantially improved. This study sought to determine if updates to this technique have improved the relationship with coronary artery function and the non-invasive indication of coronary artery dysfunction. Coronary artery and brachial artery function were assessed in 28 patients referred for cardiac catheterization (61±11 years). Coronary artery function was determined by the change in artery diameter with a 1.82 μg/min intracoronary acetylcholine infusion. Based on the change in vessel diameter, patients

Little is known about vascular mitochondrial respiratory function and the impact of age. Therefore, skeletal muscle feed arteries (SMFAs) were harvested from young (33±7yrs, n=10), middle (54±5yrs, n=10), and old (70±7yrs, n=10) subjects, and mitochondrial respiration as well as citrate synthase (CS) activity were assessed. Complex I (CI) and complex I+II (CI+II), state 3 respiration were greater in the young (CI: 10.4±0.8, CI+II: 12.4±0.8 pmol/s/mg, P<0.05) compared to both middle (CI: 7±0.6, CI+II: 8.3±0.5 pmol/s/mg) and old (CI: 7.2±0.4, CI+II: 7.6±0.5 pmol/s/mg) and, in addition to CII state 3, were inversely correlated with age (CI: r=-0.56, CI+II: r=-0.7, CII: r=0.4; P<0.05). In contrast, state 4 respiration and mitochondria-specific superoxide levels were not different across groups. The respiratory control ratio (RCR) was greater in the young (2.2±0.2, P<0.05) compared to the middle and old (1.4±0.1, 1.1±0.1) and inversely correlated with age (r=-0.71, P<0.05). As CS activity was inversely correlated with age (r=-0.54, P<0.05), when normalized for mitochondrial content, the age-related differences and relationships with state 3 were ablated. In contrast, mitochondrion-specific state 4 was now lower in the young (15±1.4 pmol/s/mg/U CS, P<0.05) than the middle and old (23.4±3.6, 27.9±3.4 pmol/s/mg/U CS), and correlated with age (r=0.46, P<0.05). Similarly, superoxide/CS levels were lower in the young (0.07±0.01) than the old (0.19±0.41), and correlated with age (r=0.44, P<0.05). Therefore, with aging vascular mitochondrial respiratory function declines, predominantly as a consequence of falling mitochondrial content. However, per mitochondrion, aging likely results in greater mitochondrial-derived oxidative stress, which may contribute to age-related vascular dysfunction.

The impact of COVID-19 has been largely described after symptom development. Although the SARS-CoV-2 virus elevates heart rate (HR) prior to symptom onset, whether this virus evokes other presymptomatic alterations is unknown. This Case Study details the presymptomatic impact of COVID-19 on vascular and skeletal muscle function in a young woman (24yrs, 173.5cm, 89kg, BMI: 29.6kg·m-2). Vascular and skeletal muscle function were assessed as part of a separate study with the first and second visits separated by 2 weeks. On the evening following the second visit, the participant developed a fever and a rapid antigen test confirmed a positive COVID-19 diagnosis. Compared to the first visit, the participant presented with a markedly elevated HR (~ 30 bpm) and lower mean blood pressure (~8 mmHg) at the second visit. Vascular function measured by brachial artery flow-mediated dilation, reactive hyperemia, and passive leg movement were all noticeably attenuated (25-65%) as was leg blood flow during knee extension exercise. Muscle strength was diminished as was ADP stimulated respiration (30%), assessed in vitro, while there was a 25% increase in the apparent Km. Lastly, an elevation in IL-10 was observed prior to symptom onset. Notably, 2.5 months after diagnosis symptoms of fatigue and cough were still present. Together, these findings provide unique insight into the physiological responses immediately prior to COVID-19 symptom onset; they suggest that SARS-CoV-2 negatively impacts vascular and skeletal muscle function prior to the onset of common symptoms and may set the stage for the widespread sequelae observed following COVID-19 diagnosis.

The PARADIGM-HF trial identified a marked reduction in the risk of death and hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril-valsartan, but the physiologic processes underpinning these improvements are unclear. We tested the hypothesis that treatment with sacubitril-valsartan improves peripheral vascular function, functional capacity, and inflammation in patients with HFrEF. We prospectively studied patients with HFrEF (n=11, 10M/1F, left ventricular ejection fraction 27±8%) on optimal, guideline-directed medical treatment who were subsequently prescribed sacubitril-valsartan (open-label, uncontrolled, and unblinded). Peripheral vascular function (brachial artery flow-mediated dilation (FMD, conduit vessel function) and reactive hyperemia (RH, microvascular function)), functional capacity (six-minute walk test (6MWT) distance), and the pro-inflammatory biomarkers, tumor necrosis factor-alpha (TNF-α) and interleukin-18 (IL-18) were obtained at baseline and again at 1, 2, and 3 months of treatment. %FMD improved after 1 month of treatment, and this favorable response persisted for months 2 and 3 (baseline: 3.25±1.75%; 1mo: 5.23±2.36%; 2mo: 5.81±1.79%; 3mo: 6.35±2.77%), while RH remained unchanged. 6MWT distance increased at months 2 and 3 (baseline: 420±92 m; 1mo: 436±98 m; 2mo: 465±115 m; 3mo: 460±110 m), and there was a sustained reduction in TNF-α (baseline: 2.38±1.35 pg/mL; 1mo: 2.06±1.52 pg/mL; 2mo: 1.95±1.34 pg/mL; 3mo: 1.92±1.37 pg/mL) and a reduction in IL-18 at months 3 (baseline: 654±150 pg/mL; 1mo: 595±140 pg/mL; 2mo: 601±176 pg/mL; 3mo: 571±127 pg/mL). This study provides new evidence for the potential of this new drug class to improve conduit vessel function, functional capacity, and inflammation in patients with HFrEF.

Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite NO synthase (NOS) inhibition. Therefore, in 9 young healthy men (25±4 yrs), this investigation aimed to determine if the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement) when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of NG-monomethyl L-arginine (L-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P450 (CYP450) by L-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF (LBFAUC) response to both PLM (control: 456±194, L-NMMA: 168±127 ml, p<0.01) and sPLM (control: 185±171, L-NMMA: 62±31 ml, p=0.03). The combined inhibition of NOS, COX, and CYP450 (i.e. L-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBFAUC: 271±97 ml, p>0.05) or sPLM (LBFAUC: 72±45 ml, p>0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent, hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests.

New Findings What is the central question of this study?What is the distribution of the hyperaemic response to passive leg movement (PLM) in the common (CFA), deep (DFA) and superficial (SFA) femoral arteries? What is the impact of lower leg cuff‐induced blood flow occlusion on this response? What is the main finding and its importance?Of the total blood that passed through the CFA, the majority was directed to the DFA and this was unaffected by cuffing. As a small fraction does pass through the SFA to the lower leg, cuffing during PLM should be considered to emphasize the thigh‐specific hyperaemia. Abstract It has yet to be quantified how passive leg movement (PLM)‐induced hyperaemia, an index of vascular function, is distributed beyond the common femoral artery (CFA), into the deep femoral (DFA) and the superficial femoral (SFA) arteries, which supply blood to the thigh and lower leg, respectively. Furthermore, the impact of cuffing the lower leg, a common practice, especially with drug infusions during PLM, on the hyperaemic response is, also, unknown. Therefore, PLM was performed with and without cuff‐induced blood flow (BF) occlusion to the lower leg in 10 healthy subjects, with BF assessed by Doppler ultrasound. In terms of BF distribution during PLM, of the 380 ± 191 ml of blood that passed through the CFA, 69 ± 8% was directed to the DFA, while only 31 ± 8% passed through the SFA. Cuff occlusion of the lower leg significantly attenuated the PLM‐induced hyperaemia through the SFA (∼30%), which was reflected by a fall in BF through the CFA (∼20%), but not through the DFA. Additionally, cuff occlusion significantly attenuated the PLM‐induced peak change in BF (BFΔpeak) in the SFA (324 ± 159 to 214 ± 114 ml min−1), which was, again, reflected in the CFA (1019 ± 438 to 833 ± 476 ml min−1), but not in the DFA. Thus, the PLM‐induced hyperaemia predominantly passes through the DFA and this was unaltered by cuffing. However, as a small fraction of the PLM‐induced hyperaemia does pass through the SFA to the lower leg, cuffing the lower leg during PLM should be considered to emphasize thigh‐specific hyperaemia in the PLM assessment of vascular function.

New Findings What is the central question of this study?The passive leg movement (PLM) assessment of vascular function utilizes the blood flow response in the common femoral artery (CFA): what is the impact of baseline CFA blood flow on the PLM response? What is the main finding and its importance?Although an attenuated PLM response is not an obligatory consequence of increased baseline CFA blood flow, increased blood flow through the deep femoral artery will diminish the response. Care should be taken to ensure that a genuine baseline leg blood flow is obtained prior to performing a PLM vascular function assessment. Abstract The passive leg movement (PLM) assessment of vascular function utilizes the blood flow response in the common femoral artery (CFA). This response is primarily driven by vasodilation of the microvasculature downstream from the deep (DFA) and, to a lesser extent, the superficial (SFA) femoral artery, which facilitate blood flow to the upper and lower leg, respectively. However, the impact of baseline CFA blood flow on the PLM response is unknown. Therefore, to manipulate baseline CFA blood flow, PLM was performed with and without upper and lower leg cutaneous heating in 10 healthy subjects, with blood flow (ultrasound Doppler) and blood pressure (finometer) assessed. Baseline blood flow was significantly increased in the CFA (∼97%), DFA (∼109%) and SFA (∼78%) by upper leg heating. This increase in baseline CFA blood flow significantly attenuated the PLM‐induced total blood flow in the DFA (∼62%), which was reflected by a significant fall in blood flow in the CFA (∼49%), but not in the SFA. Conversely, lower leg heating increased blood flow in the CFA (∼68%) and SFA (∼160%), but not in the DFA. Interestingly, this increase in baseline CFA blood flow only significantly attenuated the PLM‐induced total blood flow in the SFA (∼60%), and not in the CFA or DFA. Thus, although an attenuated PLM response is not an obligatory consequence of an increase in baseline CFA blood flow, an increase in baseline blood flow through the DFA will diminish the PLM response. Therefore, care should be taken to ensure that a genuine baseline leg blood flow is obtained prior to performance of a PLM vascular function assessment.

Cerebral blood flow (CBF) is commonly inferred from blood velocity measurements in the middle cerebral artery (MCA), using nonimaging, transcranial Doppler ultrasound (TCD). However, both blood velocity and vessel diameter are critical components required to accurately determine blood flow, and there is mounting evidence that the MCA is vasoactive. Therefore, the aim of this study was to employ imaging TCD (ITCD), utilizing color flow images and pulse wave velocity, as a novel approach to measure both MCA diameter and blood velocity to accurately quantify changes in MCA blood flow. ITCD was performed at rest in 13 healthy participants (7 men/6 women; 28 ± 5 yr) with pharmaceutically induced vasodilation [nitroglycerin (NTG), 0.8 mg] and without (CON). Measurements were taken for 2 min before and for 5 min following NTG or sham delivery (CON). There was more than a fivefold, significant, fall in MCA blood velocity in response to NTG (∆−4.95 ± 4.6 cm/s) compared to negligible fluctuation in CON (∆−0.88 ± 4.7 cm/s) ( P < 0.001). MCA diameter increased significantly in response to NTG (∆0.09 ± 0.04 cm) compared with the basal variation in CON (∆0.00 ± 0.04 cm) ( P = 0.018). Interestingly, the product of the NTG-induced fall in MCA blood velocity and increase in diameter was a significant increase in MCA blood flow following NTG (∆144 ± 159 ml/min) compared with CON (∆−5 ± 130 ml/min) ( P = 0.005). These juxtaposed findings highlight the importance of measuring both MCA blood velocity and diameter when assessing CBF and document ITCD as a novel approach to achieve this goal.