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Harry A Silber,1 Nisha A Gilotra,1 Thomas L Miller2,3 1Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Enalare Therapeutics, Inc, Princeton, NJ, USA; 3Department of Pediatrics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USACorrespondence: Harry A Silber, Johns Hopkins Bayview Medical Center, Cardiology Suite 2400, 301 Building, 4940 Eastern Avenue, Baltimore, MD, 21224, USA, Tel +1 410 550 5717, Fax +1 410 550 0012, Email hsilber@jhmi.eduPurpose: The change in the amplitude of a peripheral pulse in response to a Valsalva maneuver has diagnostic utility for assessing volume status at the bedside. We have developed a device to automatically quantify the Valsalva pulse response (VPR) to a standardized Valsalva maneuver that the device guides a user to perform. In this study, we sought to determine whether VPR by the device, Indicor, is sensitive enough to detect the acute increase in central pressure and volume load that occurs with a passive leg raise (PLR) in healthy volunteers.Methods: Healthy volunteers were tested semirecumbently at 45 degrees, then again after being leaned back on a pivoted wedge with legs raised at 45 degrees and torso and head flat, and then again in the semirecumbent position. The device recorded a finger photoplethysmography (PPG) signal during a 10-second expiratory effort of 20 mmHg as guided by the device. VPR was automatically calculated as the ratio of the end-Valsalva pulse amplitude to the baseline pulse amplitude.Results: In the 30 participants who completed testing, VPR increased from baseline to PLR in every participant, from 0.34 ± 0.13 to 0.60 ± 0.14 (p < 0.0001). Back upright, VPR decreased back to 0.33 ± 0.10 (p < 0.0001 versus PLR; NS versus baseline position).Conclusion: In this proof-of-concept study of healthy participants, the Indicor device, a noninvasive, convenient device that automatically calculates VPR from a finger photoplethysmography signal during a standardized Valsalva maneuver, was sensitive enough to detect the increase in VPR that occurred with an acute central volume load from a PLR. Future studies should examine whether VPR responds differently to a PLR in heart failure patients with abnormal cardiac performance and/or congestion.Plain Language Summary: It is often important clinically to determine whether there has been a change in the volume of fluid in the heart and chest (known as central volume). We have developed a noninvasive technique for assessing changes in central volume. The technique involves measuring the change in blood volume in a fingertip while a person blows into a closed tube for 10 seconds. An index is calculated from the change in fingertip blood volume. In this study, we measured this index before and after a central volume change in healthy participants. We produced an increase in central volume in the participants by changing their position from legs flat and head elevated, to legs elevated and head flat. Thirty participants successfully completed testing. In all participants, the index increased when they changed position to legs up and head down. Thus, this technique can detect an acute increase in central volume. Future studies should examine whether the index can detect longer-term changes in central volume in patients with abnormal heart conditions such as heart failure.Keywords: Valsalva maneuver, photoplethysmography, filling pressure, fluid volume, passive leg raise, fluid load, pulse amplitude

Background: Endothelial dysfunction is associated with increased risk of cardiovascular disease (CVD). Currently available noninvasive methods of measuring endothelial function have limitations. We tested a novel device that provides an automated measurement of the difference between baseline and post-ischemic, hyperemia-induced, brachial arterial compliance, a phenomenon known to be endothelium-dependent. The association between the calculated index, Flow-mediated Compliance Response (FCR), and established CVD risk indices was determined., Methods: Adults with CVD risk factors or known coronary artery disease (CAD) were enrolled. Framingham Risk Score (FRS) was calculated and presence of metabolic syndrome (MetSyn) was assessed. Carotid artery plaques were identified by ultrasound. Cardiorespiratory fitness was assessed by 6-minute walk test (6MWT). FCR was measured using the device., Results: Among 135 participants, mean age 49.3 +/- 17.9 years, characteristics included: 48% female, 7% smokers, 7% CAD, 10% type 2 diabetes, 34% MetSyn, and 38% with carotid plaque. Those with MetSyn had 24% lower FCR than those without (p < 0.001). Lower FCR was associated with higher FRS percentile (r = -0.29, p < 0.001), more MetSyn factors (r = -0.30, p < 0.001), more carotid plaques (r = -0.22, p = 0.01), and lower 6MWT (r = 0.34, p < 0.0001)., Conclusion: FCR, an index of arterial reactivity obtained automatically using a novel, operator-independent device, was inversely associated with established CVD risk indices, increased number of carotid plaques, and lower cardiorespiratory fitness. Whether measuring FCR could play a role in screening for CVD risk and assessing whether endothelial function changes in response to treatments aimed at CVD risk reduction, warrants further study., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: A noninvasive system for determining left ventricular (LV) filling pressure may help to improve personalized fluid removal goals in hemodialysis patients. We previously showed that the change in photoplethysmography (PPG) pulse amplitude measured by finger PPG during a Valsalva maneuver correlates with invasively measured left ventricular end-diastolic pressure (LVEDP). This key PPG change, the ratio of finger PPG pulse amplitude at end-Valsalva to baseline, is known as the Pulse Amplitude Ratio, PAR. The objective of this study was to determine how PAR changes after fluid removal in hemodialysis., Methods: We tested subjects with end-stage renal disease, before and after hemodialysis. Each subject performed a Valsalva maneuver with an effort of 20 mmHg for 10 s, guided by the device display. Finger PPG was recorded continuously before and during the maneuver. PAR was calculated automatically., Results: Twenty-seven subjects (21 Males) ages 25-75 years were tested. Access sites were AV-fistulas of the arm predominantly. Weight decreased from 99.7 ± 36.9 kg to 97.0 ± 6.0 kg (p < 0.0003) with an average fluid removal of 3.07 ± 1.08 l. Correspondingly, PAR decreased from 0.74 ± 0.24 to 0.62 ± 0.23 (p = 0.003). The change in PAR was correlated with baseline PAR (r = 0.48, p = 0.01)., Conclusion: An index of left heart filling pressure obtained noninvasively using finger photoplethysmography during the Valsalva maneuver is sensitive enough to detect reductions in filling pressure after fluid removal with hemodialysis. Further studies are warranted to determine if this method can be used to guide fluid removal during hemodialysis.

When food is heated to high temperatures, the characteristic "browning" generates advanced glycation end products (AGEs). AGEs are associated with an increased risk of cardiovascular disease, diabetes, and other adverse outcomes. Whether dietary AGEs are absorbed and are harmful to human health remains highly controversial. The objective of this study was to compare the effects of a diet high or low in AGEs on endothelial function, circulating AGEs, inflammatory mediators, and circulating receptors for AGEs in healthy adults. A randomized, parallel-arm, controlled dietary intervention was conducted for 6 wk with 24 healthy adults, aged 50-69 y, that compared isocaloric, food-equivalent diets that were prepared at either high or mild temperatures. Peripheral arterial tonometry, serum and urine carboxymethyl-lysine (CML), inflammatory mediators (interleukin-6, C-reactive protein, vascular adhesion molecule-1, and tumor necrosis factor-α receptors I and II), soluble receptor for AGEs, and endogenous secretory receptor for AGEs were measured at baseline and after 6 wk of dietary intervention. In the low-AGE diet group, the following changed from baseline to 6 wk (mean ± SE): serum CML from 763 ± 24 to 679 ± 29 ng/mL (P = 0.03) and urine CML from 1.37 ± 1.47 to 0.77 ± 2.01 μg/mL creatinine (P = 0.02). There were no significant changes in serum and urinary CML concentrations from baseline to follow-up in the high-AGE diet group. A high- or low-AGE diet had no significant impact on peripheral arterial tonometry or any inflammatory mediators after 6 wk of dietary intervention. In healthy middle-aged to older adults, consumption of a diet high or low in AGEs for 6 wk had no impact on endothelial function and inflammatory mediators, 2 precursors of cardiovascular disease., (© 2014 American Society for Nutrition.)

Objective: To examine the effect of exercise on abdominal adipose tissue in adults with and without type 2 diabetes mellitus (T2DM)., Design: Post hoc analysis of two randomised controlled trials., Setting: Outpatient secondary prevention programme in Baltimore, Maryland, USA., Participants: 97 men and women with prehypertension, stage 1 or medically controlled hypertension. 49% of the sample was also diagnosed with T2DM., Intervention: All participants completed a 26-week (6.5 months) supervised aerobic and resistance exercise programme following American College of Sports Medicine guidelines., Primary and Secondary Outcome Measures: The main outcomes in this post hoc analysis were total abdominal adipose tissue (TAT), subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) measured by MRI. Secondary outcomes were to determine whether the magnitude of abdominal fat change differed by diabetes status in men and women and to identify the predictors of change in abdominal fat distribution with exercise., Results: Overall, participants (mean age 61±6 years; 45% women) significantly improved peak oxygen uptake by 15% (p<0.01) and reduced weight by 2% (p<0.01). No change in SAT was observed after training. The reduction in VAT following exercise was attenuated in participants with T2DM (-3%) compared with participants who were non-T2DM (-18%, p<0.001 for the difference in change). The magnitude of VAT loss was associated with a decrease in body weight (r=0.50, p<0.001). After adjustment for weight change using regression analysis, diabetes status remained an independent predictor of the change in VAT., Conclusions: Although participants with and without T2DM attained an exercise training effect as evidenced by increased fitness, VAT was unchanged in T2DM compared to those without T2DM, suggesting that these individuals may be resistant to this important benefit of exercise. The strategies for reducing cardiovascular disease risk in T2DM may be most effective when they include a weight loss component., Clinical Trials Registration: Clinicaltrials.gov Registry NCT00212303.

Background: Increased blood pressure (BP) in type 2 diabetes (T2DM) markedly increases cardiovascular disease morbidity and mortality risk compared to having increased BP alone., Objective: To investigate whether exercise reduces suboptimal levels of untreated suboptimal BP or treated hypertension., Design: Prospective, randomized controlled trial for 6 months., Setting: Single center in Baltimore, MD, USA., Patients: 140 participants with T2DM not requiring insulin and untreated SBP of 120-159 or DBP of 85-99 mmHg, or, if being treated for hypertension, any SBP <159 mmHg or DBP<99 mmHg; 114 completed the study., Intervention: Supervised exercise, 3 times per week for 6 months compared with general advice about physical activity., Measurements: Resting SBP and DBP (primary outcome); diabetes status, arterial stiffness assessed as carotid-femoral pulse-wave velocity (PWV), body composition and fitness (secondary outcomes)., Results: Overall baseline BP was 126.8 ± 13.5 / 71.7 ± 9.0 mmHg, with no group differences. At 6 months, BP was unchanged from baseline in either group, BP 125.8 ± 13.2 / 70.7 ± 8.8 mmHg in controls; and 126.0 ± 14.2 / 70.3 ± 9.0 mmHg in exercisers, despite attaining a training effects as evidenced by increased aerobic and strength fitness and lean mass and reduced fat mass (all p<0.05), Overall baseline PWV was 959.9 ± 333.1 cm/s, with no group difference. At 6-months, PWV did not change and was not different between group; exercisers, 923.7 ± 319.8 cm/s, 905.5 ± 344.7, controls., Limitations: A completion rate of 81 %., Conclusions: Though exercisers improve fitness and body composition, there were no reductions in BP. The lack of change in arterial stiffness suggests a resistance to exercise-induced BP reduction in persons with T2DM.

It is often challenging to assess cardiac filling pressure clinically. An improved system for detecting or ruling out elevated cardiac filling pressure may help reduce hospitalizations for heart failure. The blood pressure response to the Valsalva maneuver reflects left heart filling pressure, but its underuse clinically may be due in part to lack of continuous blood pressure recording along with lack of standardization of expiratory effort. In this study, we tested whether Valsalva-induced changes in the pulse amplitude of finger photoplethysmography (PPG), a technology already widely available in medical settings, correlate with invasively measured left ventricular end-diastolic pressure (LVEDP). We tested 33 subjects before clinically scheduled cardiac catheterizations. A finger photoplethysmography waveform was recorded during a Valsalva effort of 20 mmHg expiratory pressure sustained for 10 s, an effort most patients can achieve. Pulse amplitude ratio (PAR) was calculated as the PPG waveform amplitude just before release of expiratory effort divided by the waveform amplitude at baseline. PAR was well correlated with LVEDP (r = 0.68; P < 0.0001). For identifying LVEDP > 15 mmHG, PAR > 0.4 was 85% sensitive [95% confidence interval (95CI): 54-97%] and 80% specific (95CI: 56-93%). In conclusion, finger PPG, a technology already ubiquitous in medical centers, may be useful for assessing clinically meaningful categories of left heart filling pressure, using simple analysis of the waveform after a Valsalva maneuver effort that most patients can achieve.

Objectives: Our goal was to investigate whether the association between established cardiovascular risk factors and arterial reactivity differs between the lower and upper extremities., Background: Resistance artery reactivity in the arm is associated with cardiovascular risk factors, coronary disease, and events. However, the relationship of lower versus upper extremity vasoreactivity to increasing cardiovascular risk factors has not been determined., Methods: We studied 82 subjects in 3 groups: 33 young healthy (YH) (21 to 41 years), 30 older healthy (OH) (>50 years), and 19 older type 2 diabetic subjects (OD). We directly measured systolic shear rate, flow, and radius in brachial and femoral arteries at rest and during post-occlusion hyperemia using magnetic resonance imaging., Results: Brachial and femoral systolic shear rate, flow, and radius were similar among the groups at rest. Brachial hyperemic shear rate and hyperemic flow normalized as a function of baseline radius were not statistically different when YH were compared with OH and OH with OD. In contrast, femoral hyperemic shear rate and hyperemic flow normalized to baseline radius were lower in OH than YH (680 +/- 236 s(-1) vs. 843 +/- 157 s(-1), p = 0.001, and 0.84 +/- 0.25 mm(1.27)/s vs. 1.01 +/- 0.16 mm(1.27)/s, p = 0.001) and lower in OD than OH (549 +/- 183 s(-1), p = 0.02, and 0.74 +/- 0.19 mm(1.27)/s, p = 0.046)., Conclusions: Persons with increasing cardiovascular risk factor burden had progressively reduced arterial reactivity in lower but not upper extremities. This may help to explain why atherosclerosis usually develops more severely in legs than in arms, and suggests that legs may be more sensitive than arms for assessing early global atherosclerotic risk.

Flow-mediated dilation (FMD) is strongly dependent on arterial size, but the reasons for this phenomenon are poorly understood. We have previously shown that FMD is greater in small brachial arteries because the shear stress stimulus is greater in small brachial arteries. However, it is unclear why the shear stimulus is greater in small arteries. Furthermore, this relationship has not been investigated in other, differently sized arterial beds. Postischemic systolic shear stress and resulting FMD were evaluated in the brachial and femoral arteries of 24 young, healthy adults using phase-contrast magnetic resonance imaging. Arterial shear and radius were calculated from the velocity profile via a best-fit parabola before and after occlusion. Summing the velocity pixels provided hyperemic systolic flow. FMD was proportional to hyperemic shear in the brachial and femoral arteries (P < 0.0001, r = 0.60). Hyperemic systolic flow was proportional to radius2 (P < 0.0001, r = 0.93). Applying this relationship to the Poiseuille equation (shear is proportional to flow/radius3) shows that hyperemic shear is proportional to radius2/radius3 and, therefore, explains why hyperemic shear is proportional to 1/radius. We conclude that FMD is proportional to hyperemic systolic shear stress in both the brachial and the femoral arteries. The hyperemic shear stimulus for FMD is greater in small arteries due to the dependence of postischemic systolic flow on radius squared. Therefore, greater FMD in small arteries does not necessarily reflect better conduit artery endothelial function. Evaluating the shear stimulus using phase-contrast magnetic resonance imaging enhances the understanding of mechanisms underlying FMD.

We investigated whether endothelial-dependent arterial constriction during reduced shear can be measured using phase contrast magnetic resonance imaging (PCMRI). A cross-section of the femoral artery was acquired during a 5-minute distal occlusion in 33 subjects. Systolic shear rate and radius were measured from the velocity profile via a best-fit parabola. Systolic shear rate decreased immediately after cuff inflation (404 +/- 78 to 233 +/- 75 sec(-1) p < .0001). Radius decreased at 2 min into inflation (3.52 +/- .41 to 3.43 +/- .42 mm, p < .0001). In conclusion, arterial constriction during reduced flow can be measured using PCMRI. This new method may add important information toward a comprehensive evaluation of endothelial function.

An exaggerated SBP response to exercise has been associated with increased left ventricular (LV) mass in some but not all studies. A total of 43 women and 34 men, aged 55-75 years, without evidence of cardiovascular disease, with a mean resting BP of 142+/-9/77+/-8 mmHg had their BP measured at rest and during maximal treadmill exercise. LV mass was measured using magnetic resonance imaging. LV mass was adjusted for lean body mass, which was assessed by dual energy X-ray absorptiometry. LV mass was within the normal range for the majority of the subjects. Among the resting and exercise BP indices, maximal SBP was the strongest correlate of LV mass (r=0.41, P<0.05). In multivariate analysis, maximal SBP was independently associated with LV mass after adjustment for lean body mass and gender, explaining 3% of the variance (P<0.05). Maximal exercise SBP is a modest but still independent predictor of LV mass in older persons with normal LV mass. These results raise the possibility that the SBP response to maximal exercise is an early marker of LV hypertrophy.

Objectives: We sought: 1) to investigate the relationship between vascular wall shear stress and flow-mediated dilation (FMD) in humans, and 2) to investigate whether this relationship could explain why FMD is greater in small arteries., Background: Arterial wall shear stress (WSS) is considered to be the primary stimulus for the endothelial-dependent FMD response. However, the relationship between WSS and FMD has not been investigated in humans. Furthermore, FMD is greater in small arteries, though the reasons for this phenomenon are unclear., Methods: Using phase-contrast magnetic resonance angiography (PMRCA), we measured hyperemic WSS and FMD in 18 healthy volunteers. Peak systolic WSS was calculated assuming a blunted parabolic velocity profile. Diameter by PCMRA and by ultrasound was compared in nine subjects., Results: Flow-mediated dilation was linearly proportional to hyperemic peak systolic WSS (r = 0.79, p = 0.0001). Flow-mediated dilation was inversely related to baseline diameter (r = 0.62, p = 0.006), but the hyperemic peak WSS stimulus was also inversely related to baseline diameter (r = 0.47, p = 0.049). Phase-contrast magnetic resonance angiography and ultrasound diameters were compared in nine subjects and correlated well (r = 0.84, p < 0.0001), but diameter by PCMRA was greater (4.1 +/- 0.7 mm vs. 3.7 +/- 0.5 mm, p = 0.009)., Conclusion: Arterial FMD is linearly proportional to peak hyperemic WSS in normal subjects. Thus, the endothelial response is linearly proportional to the stimulus. Furthermore, the greater FMD response in small arteries is accounted for, at least partially, by a greater hyperemic WSS stimulus in small arteries. By allowing the calculation of vascular WSS, which is the stimulus for FMD, and by imaging a fixed arterial cross-section, thus reducing operator dependence, PCMRA enhances the assessment of vascular endothelial function.