Peripheral Microvascular Dysfunction Research Articles

Statin therapy improves locomotor muscle microvascular reactivity in patients with heart failure with preserved ejection fraction.

Peripheral microvascular dysfunction has been documented in patients with heart failure with preserved ejection fraction (HFpEF), which may be related to elevated levels of inflammation and oxidative stress. Unfortunately, few strategies have been identified to effectively ameliorate this disease-related derangement. Thus, using a parallel, double-blind, placebo-controlled design, this study evaluated the efficacy of 30-day atorvastatin administration (10 mg daily) on lower limb microvascular reactivity, functional capacity, and biomarkers of inflammation and oxidative stress in patients with HFpEF (statin, n = 8, 76 ± 6 yr; placebo, n = 8, 68 ± 9 yr). The passive limb movement (PLM)-induced hyperemic response and 6-min walk test (6MWT) distance were evaluated to assess ambulatory muscle microvascular function and functional capacity, respectively. Circulating biomarkers were also measured to assess the contribution of changes in inflammation and redox balance to these outcomes. The total hyperemic response to PLM, assessed as leg blood flow area under the curve (LBFAUC), increased following the statin intervention (pre, 60 ± 68 mL; post, 164 ± 90 mL; P < 0.01), whereas these variables were unchanged in the placebo group (P = 0.99). There were no significant differences in 6MWT distance following statin or placebo intervention. Malondialdehyde (MDA), a marker of lipid peroxidation, was significantly reduced following the statin intervention (pre, 0.68 ± 0.10; post, 0.51 ± 0.11; P < 0.01) while other circulating biomarkers were unchanged. Together, these data provide new evidence for the efficacy of low-dose statin administration to improve locomotor muscle microvascular reactivity in patients with HFpEF, which may be due, in part, to a diminution in oxidative stress.NEW & NOTEWORTHY This was the first study to investigate the impact of statin administration on locomotor muscle microvascular function in patients with HFpEF. In support of our hypothesis, the total hyperemic response to PLM, assessed as leg blood flow area under the curve, increased, and malondialdehyde, a marker of oxidative damage, was reduced following the statin intervention. Together, these data provide new evidence for the efficacy of statin administration to improve locomotor muscle microvascular reactivity in patients with HFpEF, which may be due, in part, to reduced oxidative stress.

Post-Acute COVID-19 Syndrome: Prevalence of Peripheral Microvascular Endothelial Dysfunction and Associations with NT-ProBNP Dynamics

BackgroundPost-acute COVID-19 syndrome (PACS) has been linked to microvascular endothelial dysfunction as a potential underlying pathomechanism and can manifest even following a mild course of the initial infection. Prevalence of microvascular endothelial dysfunction and circulating natriuretic peptides in such PACS patients remains unknown. MethodsThis prospective, cross-sectional cohort study enrolled 92 patients (82% females, median age 48 years) with PACS. Reactive hyperemia index (RHI) was evaluated with peripheral arterial tonometry, where <1.67 was defined as microvascular endothelial dysfunction, 1.67-2.0 as impaired function, and >2 normal endothelial function, on average 31 months after the acute infection. N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were collected at 2 different time points within over a 1-year span. ResultsIn total, 41% of PACS subjects had microvascular endothelial dysfunction and 20% had impaired RHI. No major differences in clinical characteristics, routine chemistry laboratory testing, or symptom burden were observed across the groups. Only subjects with microvascular endothelial dysfunction and impaired endothelial function had a significant increase in NT-proBNP levels over time, and those with larger increase in NT-proBNP had significantly lower RHI. There was a significant correlation between relative or absolute increase in NT-proBNP and RHI, which remained significant in a multivariable adjusted linear regression. ConclusionsPeripheral microvascular endothelial dysfunction was prevalent in a symptomatic PACS population long after recovery from a mild acute infection. Increases in NT-proBNP levels were associated with microvascular endothelial dysfunction, suggesting a link between, and providing a foundation for, future studies on post viral microvascular endothelial dysfunction in PACS.

Peripheral Microvascular Dysfunction in Children and Adults with Congenital Heart Disease: A Literature Review.

Although there is a continually growing number of patients with congenital heart disease (CHD) due to medical and surgical advances, these patients still have a poorer prognosis compared to healthy individuals of similar age. In patients with heart failure, microvascular dysfunction (MVD) has recently emerged as a crucial modulator of disease initiation and progression. Because of the substantial pathophysiological overlap between CHD and heart failure induced by other etiologies, MVD could be important in the pathophysiology of CHD as well. MVD is believed to be a systemic disease and may be manifested in several vascular beds. This review will focus on what is currently known about MVD in the peripheral vasculature in CHD. Therefore, a search on the direct assessment of the vasodilatory capacity of the peripheral microcirculation in patients with CHD was conducted in the PubMed database. Since there is little data available and the reported studies are also very heterogeneous, peripheral MVD in CHD is not sufficiently understood to date. Its exact extent and pathophysiological relevance remain to be elucidated in further research.

Ischemic Conditioning Improves the Microvascular Hyperemic Response to Passive Limb Movement in Young Adults

Background: Passive limb movement (PLM) of the lower extremity is a simple and clinically relevant approach to measure peripheral microvascular health. PLM causes an acute increase in hyperemic leg blood flow (LBF) without an increase in skeletal muscle metabolism, and the hyperemic response is ~80% nitric oxide-mediated. A known therapeutic stimulus to increase large conduit artery vascular health is ischemic conditioning (IC). Whether a single session of IC can improve the hyperemic response to PLM remains unknown. Objective: To quantify the microvascular response to PLM after a single session of IC in young adults. Hypothesis: The hyperemic response to PLM, measured as a change in peak femoral artery blood flow, will be greater following IC vs. sham-IC. Methods: This was a prospective, cross-over, blinded clinical trial (NCT05935670). Young adults aged 18-30 years who were free of cardiovascular disease were recruited, and study participants completed two study visits. Participants were seated in a Biodex dynamometer and superficial femoral artery resting blood flow and diameter were measured in the dominant leg using ultrasonography. The dynamometer then passively moved the knee 90 degrees at a frequency of 1 Hz for a single PLM while blood flow was continuously measured. The ΔLBF was calculated as the absolute (ml/min) and relative (% change) difference in LBF from rest to peak. Participants were then randomized to receive either IC or sham-IC, and the vascular assessor was blinded to the condition. For IC, the cuff was placed around the proximal dominant thigh and repetitively inflated to 225 mmHg for 5 min then deflated for 5 min, for a total of 5 cycles. For sham-IC, the thigh cuff was inflated to only 25 mmHg. Fifteen minutes after IC or sham-IC the hyperemic response to PLM was re-assessed. The pre-/post- change in the PLM hyperemic response was calculated as the difference from pre- vs. post-IC or sham-IC. Statistical analysis included one-sided paired t-tests. Results: Seven individuals (3 female, age 26 ± 4 years old) completed the study. Compared to pre-IC, the relative peak hyperemic response to PLM was augmented post-IC (%ΔLBF = 89 ± 42% pre- vs. 136 ± 49% post-IC, p=0.001). Conversely, there was no change in the relative peak hyperemic response in the sham-IC condition (%ΔLBF = 108 ± 61% pre- vs. 108 ± 77% post-sham-IC, p=0.50). The pre-/post- change score of absolute peak hyperemic response to PLM was also higher after IC vs. sham-IC (change in ΔLBF = 50 ± 78 IC ml/min vs. -44 ± 127 ml/min sham-IC, p = 0.03). Conclusion: These results show an improvement in the peripheral microvascular response to PLM following IC. Future studies should examine the mechanistic pathways responsible for an improved PLM response as well as the potential benefits of IC on microvascular health in clinical populations with underlying peripheral microvascular dysfunction. AAW was supported by the National Heart, Lung and Blood Institute (T32HL13464) and Cardiovascular Center’s A.O. Smith Fellowship Scholars Program. Research was supported by the Eunice Kennedy Shriver National Institute of Child Health &amp; Human Development R01-HD099340 (ASH and MJD) and R01-HD112258 (MJD and ASH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Contribution of Peripheral Microvascular Dysfunction to Mild Cognitive Impairment

Contribution of Peripheral Microvascular Dysfunction to Mild Cognitive Impairment

Peripheral microvascular function is linked to cardiac involvement on cardiovascular magnetic resonance in systemic sclerosis-related pulmonary arterial hypertension.

Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH). Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05). SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

Abstract 13947: Racial Differences in Peripheral Microvasculature's Association With Mild Cognitive Impairment

Introduction: Cardiovascular disease (CVD) and Alzheimer’s Dementia (AD) share numerous risk factors, with vascular dysfunction a common underlying mechanism. Individuals with mild cognitive impairment (MCI) have a high likelihood of developing AD in their lifetime. The link between microvascular dysfunction (MVD) and AD has yet to be fully established. Hypothesis: We examined the contribution of MVD to MCI with the hypothesis that Black Americans, who have a higher prevalence of MVD, will have higher rates of MCI. Methods: Participants &gt;50 years with MCI or with normal cognition (NC) were enrolled for neuropsychological and microvascular function testing using peripheral arterial tonometry. Microvascular function was measured as the reactive hyperemia index (RHI) and calculated as the ratio of the post- to pre-occlusion pulse volume in the fingertip (EndoPAT). Multivariate analyses, adjusting for demographic and CVD risk factors associated with MCI, evaluated the relationship between RHI and MCI in Black and White participants. Causal mediation analysis, using the Monte Carlo approach, was performed to investigate whether the effect of RHI on MCI was mediated through plausible mediators, including risk factors. Results: Of 152 participants (NC=104, MCI=48), 41.4% were Black and 33.6% male. Participants with MCI were more likely to be Black (58.3% vs 33.7%%, p=0.007) and have lower RHI (1.93 vs 2.27, p=0.004) compared to NC. RHI was an independent predictor of MCI with a 96% adjusted greater odds of MCI per unit reduction in RHI. Black race remained an independent predictor of MCI (OR 2.90, 95% CI [1.16, 7.56]). RHI was lower in Black compared to White participants (1.86 vs 2.37, p&lt;0.001). There was no heterogeneity in the impact of RHI on MCI. In a casual mediation analysis, MCI was mediated via RHI more in Black than in White participants (proportion mediated 24.2% vs 18.4%, p=0.034) after multivariate adjustment. Conclusions: Peripheral MVD, measured as RHI, was independently associated with MCI. Furthermore, Black participants exhibited lower RHI levels, a higher prevalence of MCI, and potentially mediated MCI through RHI to a greater extent compared to their White counterparts.

Prognostic value of peripheral endothelial function on major adverse cardiovascular events above traditional risk factors.

This study aims to identify whether adding peripheral microvascular dysfunction (PMED), a marker of atherosclerosis to established risk scores has an incremental prognostic value for major adverse cardiovascular events (MACE). This is a retrospective study of patients who underwent measuring peripheral arterial tonometry from 2006 to 2020. The optimal cut-off value of the reactive hyperaemia index (RHI) that had maximal prognostic value associated with MACE was calculated. Peripheral microvascular endothelial dysfunction was defined as the RHI lower than the cut-off. Traditional cardiovascular risk factors such as age, sex, congestive heart failure, hypertension, diabetes, stroke, and vascular disease were determined to calculate the CHA2DS2-Vasc score. The outcome was MACE defined as myocardial infarction, heart failure hospitalization, cerebrovascular events, and all-cause mortality. A total of 1460 patients were enrolled (average age 51.4 ± 13.6, 64.1% female). The optimal cut-off value of the RHI was 1.83 in the overall population and in females and males was 1.61 and 1.8, respectively. The risk of MACE during 7 [interquartile range (IQR): 5,11] years of follow-up was 11.2%. Kaplan-Meier analysis showed that lower RHI is associated with worse MACE-free survival (P < 0.001). Multivariate Cox proportional hazard analysis, controlling for classic cardiovascular risk factors or risk scores such as CHA2DS2-Vasc and Framingham risk score revealed that PMED is an independent predictor of MACE. Peripheral microvascular dysfunction predicts cardiovascular events. Non-invasive assessment of peripheral endothelial function may be useful in early detection and improving the stratification of high-risk patients for cardiovascular events.

Nailfold capillaroscopy reveals early peripheral microcirculation abnormalities in children affected by heterozygous familial hypercholesterolemia.

nailfold capillaroscopy (NCF) is a non-invasive imaging technique to seek peripheral microcirculation abnormalities in children and adults. Familial hypercholesterolemia is a genetic disorder caused by mutations capable of increasing blood levels of low-density lipoproteins cholesterol (LDL-C), thus triggering early atherosclerosis. The study aims at evaluating peripheral microcirculation in children with heterozygous familial hypercholesterolemia (HeFH) by means of NFC in comparison with healthy peers and at searching for possible correlations between these abnormalities and patients' lipid panel. thirty-six HeFH patients were enrolled (13 males and 23 females. Mean age 8±3years; age range 3-13years). They had increased levels of total cholesterol (237.9±34.2mg/dl) and LDL-C (154.2±37.6mg/dl). Both values were ≥95th gender and age specific centile. All the subjects in the study underwent NFC. In 69.4% of HeFH children nailfold capillaries were tortuous (p<0.00001 compared to healthy controls). In 41.6% the number of capillaries was markedly reduced (<7 capillaries/mm). The mean number of capillaries was 8.4±2.6/mm in HeFH and 12.2±1.4/mm in healthy controls (p<0.00001). In 100% of the sample size capillary blood flow was slowed down (p<0.00001). In 50% of the sample size a blood "sludge" phenomenon was seen (p<0.00001). No gender differences were detected. Sludge phenomenon was seen only in those with LDL-C over 99th centile (p<0.00001). NCF allows the identification of an early peripheral microvascular dysfunction in HeFH children which is similar to that already seen in atherosclerotic disease. Prompt identification of these capillary abnormalities may be crucial in implementing early prevention measures.

Sex Differences in Vascular Response to Mental Stress and Adverse Cardiovascular Events Among Patients With Ischemic Heart Disease.

Microvascular measures of vascular dysfunction during acute mental stress may be important determinants of major adverse cardiovascular events (MACE), especially among younger and middle-aged women survivors of an acute myocardial infarction. In the MIMS2 study (Myocardial Infarction and Mental Stress 2), individuals who had been hospitalized for a myocardial infarction in the past 8 months were prospectively followed for 5 years. MACE was defined as a composite index of cardiovascular death and first/recurring events for nonfatal myocardial infarction and hospitalizations for heart failure. Reactive hyperemia index and flow-mediated dilation were used to measure microvascular and endothelial function, respectively, before and 30 minutes after a public-speaking mental stress task. Survival models for recurrent events were used to examine the association between vascular response to stress (difference between poststress and resting values) and MACE. Reactive hyperemia index and flow-mediated dilation were standardized in analyses. Of 263 patients (the mean age was 51 years; range, 25-61), 48% were women, and 65% were Black. During a median follow-up of 4.3 years, 64 patients had 141 adverse cardiovascular events (first and repeated). Worse microvascular response to stress (for each SD decrease in the reactive hyperemia index) was associated with 50% greater risk of MACE (hazard ratio, 1.50 [95% CI, 1.05-2.13]; P=0.03) among women only (sex interaction: P=0.03). Worse transient endothelial dysfunction in response to stress (for each SD decrease in flow-mediated dilation) was associated with a 35% greater risk of MACE (hazard ratio, 1.35 [95% CI, 1.07-1.71]; P=0.01), and the association was similar in women and men. Peripheral microvascular dysfunction with mental stress was associated with adverse events among women but not men. In contrast, endothelial dysfunction was similarly related to MACE among both men and women. These results suggest a female-specific mechanism linking psychological stress to adverse outcomes.

Abstract P407: Sex Differences in Microvascular Response to Mental Stress and Adverse Cardiovascular Events Among Patients With Ischemic Heart Disease

Introduction: Microvascular dysfunction during acute mental stress may be an important determinant of major adverse cardiovascular outcomes (MACE) especially among middle-aged women survivors of an acute myocardial infarction (MI). Hypothesis: There are sex differences in the association between microvascular dysfunction and MACE. Methods: The Myocardial Infarction and Mental Stress Study 2 enrolled individuals who had been hospitalized for an MI in the past 8 months at the age of 60 years or younger, with an oversampling of women. Reactive hyperemia index (RHI) was used to measure digital microvascular function before and 30 minutes after a public-speaking mental stress task. This assessment was contrasted with macrovascular endothelial function at the brachial artery through flow-mediated dilation (FMD). Participants were followed for 5-years, and MACE was defined as a composite of cardiovascular death, first/recurring events for nonfatal MI, and hospitalizations for heart failure. Cox proportional hazards models were used to examine vascular response to stress (difference between post-stress and resting values) and MACE adjusting for demographics, clinical risk factors, medications, psychological factors, and mental stress ischemia. Lower RHI and FMD values are indicative of greater microvascular and endothelial dysfunction, respectively. Results: Of 263 participants, the mean age was 51 years and 48% were women. There were 64 patients with 141 adverse cardiovascular events (first and repeated). In the overall sample, there was no significant association between microvascular response to stress and MACE, but there was a significant interaction with sex (p = 0.03). Each standard deviation decrease in RHI response to stress was associated with 50% greater risk of MACE (HR: 1.50, 95% CI: 1.05, 2.13) among women only, while no association was observed in men (HR 0.93, 95% CI: 0.69, 1.26). Transient endothelial dysfunction in response to stress (for each standard deviation decrease in FMD) was associated with 35% greater risk of MACE (HR: 1.35; 95% CI: 1.07, 1.71), and was similar in women and men. Conclusions: Peripheral microvascular dysfunction with mental stress is associated with MACE among women but not among men. In contrast, brachial artery endothelial dysfunction is similarly related to MACE among both men and women. These results suggest that microvascular dysfunction is a female-specific mechanism linking psychological stress to adverse outcomes.

Decreased Peripheral Endothelial Function is Associated with Mild Cognitive Impairment and Lower Performance on Memory and Language

AbstractBackgroundThe association between cardiovascular risk factors and cognitive decline is known, but the underlying mechanisms remain unclear. We investigated whether peripheral microvascular and endothelial function, measured by pulsatile arterial tonometry (EndoPAT), is associated with cognitive performance and mild cognitive impairment (MCI).MethodThis study is based on data from 340 participants (150 with MCI, 190 with normal cognition (NC); mean age 64.9 (SD: 7.7) years, 61% female, 48% African American) enrolled in the VAScular ContribUtors to prodromaL AlzheimeR’s disease (VASCULAR) study. Peripheral microvascular function was assessed using EndoPAT (Itamar Inc.), and a reactive hyperemic index (RHI) was derived after a 5‐minute arterial occlusion period and includes a continuous or discrete (dichotomous or tertile) variable. Cognitive assessment and diagnostic categorization performed at the baseline visit included Montreal Cognitive Assessment (MoCA), Boston Naming Test, Hopkins Verbal Learning Test‐Revised (HVLT‐R), and Trail Making Test. Groups were compared with a t‐test and multivariable logistic and linear regression analyses were performed to adjust for demographic and risk factor covariates.ResultParticipants with MCI had lower RHI, indicative of greater peripheral microvascular and endothelial dysfunction, compared to NC (mean 1.9 (SD: 1.4) vs 2.2 (0.7) AU, p=0.014), which remained significant after adjustment for age, education, sex, race, systolic blood pressure, history of diabetes, hyperlipidemia, and smoking (OR: 3.91 for each 1‐unit change in RHI (95% CI: 1.00, 7.08), p=0.03). When analyzed in tertiles, a lower RHI (&lt;1.75 AU) was also associated with poorer expressive language (Boston Naming Test, p=0.03), and verbal memory performance (HVLT‐R delayed recall, p=0.01; HVLT‐R retention, p=0.02). Executive function (Trail Making Test) and overall cognitive status (MoCA) were not significantly associated with RHI.ConclusionPeripheral microvascular endothelial dysfunction, measured as RHI, was associated with MCI and with lower performances on measures of language and memory. These data highlight the importance of systemic microvascular health in cognitive health. Strategies targeting microvascular endothelial function may need further investigation in cognitive therapeutics.

Abstract 13368: Effect of Peripheral Endothelial Function Assessment in Improving the Risk Stratification of Major Cardiovascular Events Beyond CHA2DS2-Vasc

Introduction: Peripheral microvascular endothelial dysfunction (PMED) is a marker and precursor of atherosclerosis and is associated with an increased risk of cardiovascular events. The present study aims to identify the best cut-off value of PMED, assessed by the reactive hyperemia index, in predicting major adverse cardiovascular events (MACE). Additionally, we investigate whether integrating PMED to CHA2DS2-Vasc score improves the predicting accuracy of cardiovascular disease. Methods: this is a retrospective study of patients who underwent reactive hyperemia peripheral arterial tonometry (PAT). The optimal cut-off value of reactive hyperemia index associated with MACE was calculated using the area under the receiver-operating curve and the maximum Youden index. Traditional cardiovascular risk factors such as age, sex, congestive heart failure, hypertension, diabetes, stroke, vascular disease were determined to calculate the CHA2DS2-VASc score. MACE was defined as myocardial infarction, heart failure hospitalization, and cerebrovascular events. Results: 1,690 patients were enrolled (average age 51.1±13.9, 64.1% female). The optimal cut-off value of the reactive hyperemia index was 2.0 in the overall population and females and 2.17 in males. The risk of MACE during 10 (Interquartile range: 4,16) years of follow-up was 15.3%. Multivariable logistic regression revealed that PMED as an independent predictor of MACE (PMED: OR, 3.6, 95% CI, 2.6-4.9, p&lt;0.001) (Table1). Furthermore, integrating PMED to CHA2DS2-VASc significantly improved the predictive accuracy (area under the curve, 0.747 vs. 0.708, p&lt;0.001). Conclusion: PMED is a strong predictor of cardiovascular events. Non-invasive assessment of peripheral endothelial function may be useful in early detection and improving the stratification of high-risk patients for cardiovascular events.

The development of peripheral microvasculopathy with chronic metabolic disease in obese Zucker rats: a retrograde emergence?

The study of peripheral vasculopathy with chronic metabolic disease is challenged by divergent contributions from spatial (the level of resolution or specific tissue being studied) and temporal origins (evolution of the developing impairments in time). Over many years of studying the development of skeletal muscle vasculopathy and its functional implications, we may be at the point of presenting an integrated conceptual model that addresses these challenges within the obese Zucker rat (OZR) model. At the early stages of metabolic disease, where systemic markers of elevated cardiovascular disease risk are present, the only evidence of vascular dysfunction is at postcapillary and collecting venules, where leukocyte adhesion/rolling is elevated with impaired venular endothelial function. As metabolic disease severity and duration increases, reduced microvessel density becomes evident as well as increased variability in microvascular hematocrit. Subsequently, hemodynamic impairments to distal arteriolar networks emerge, manifesting as increasing perfusion heterogeneity and impaired arteriolar reactivity. This retrograde "wave of dysfunction" continues, creating a condition wherein deficiencies to the distal arteriolar, capillary, and venular microcirculation stabilize and impairments to proximal arteriolar reactivity, wall mechanics, and perfusion distribution evolve. This proximal arteriolar dysfunction parallels increasing failure in fatigue resistance, hyperemic responses, and O2 uptake within self-perfused skeletal muscle. Taken together, these results present a conceptual model for the retrograde development of peripheral vasculopathy with chronic metabolic disease and provide insight into the timing and targeting of interventional strategies to improve health outcomes.NEW & NOTEWORTHY Working from an established database spanning multiple scales and times, we studied progression of peripheral microvascular dysfunction in chronic metabolic disease. The data implicate the postcapillary venular endothelium as the initiating site for vasculopathy. Indicators of dysfunction, spanning network structures, hemodynamics, vascular reactivity, and perfusion progress in an insidious retrograde manner to present as functional impairments to muscle blood flow and performance much later. The silent vasculopathy progression may provide insight into clinical treatment challenges.

Peripheral Microangiopathy Changes in Pulmonary Arterial Hypertension Related to Systemic Sclerosis: Data From a Multicenter Observational Study

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune-system alterations, fibrosis involving the skin and internal organs and diffuse microangiopathy. Pulmonary arterial hypertension (PAH) is a severe complication of SSc affecting about 10–15% of the patients and it is a leading cause of mortality. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. Nail fold videocapillaroscopy (NVC) studies have shown a more severe peripheral microvascular dysfunction in SSc patients with PAH suggesting that abnormalities in peripheral microcirculation may correlate with pulmonary microangiopathy. This is a cross-sectional study involving four tertiary University Rheumatology Units in the Center-North of Italy. Seventy patients, 35 adults with SSc and PAH confirmed by RHC (F/M 34/1; median age 65.2 ± 8.9 SD yrs), and 35 SSc patients without PAH were enrolled (F/M 3471; median age 63.3 ± 10.3 SD yrs). Clinical, laboratoristic and instrumental data were collected and NVC was performed in all patient. Specific NVC parameters were evaluated and a semi-quantitative rating scale was adopted to score these changes. Finally, patients were distributed into the suitable NVC pattern belonging to the scleroderma pattern. Our aim was to compare the peripheral microangiopathy changes in SSc patients with and without PAH, and to investigate the relationship between NVC findings and the main hemodynamic parameters of pulmonary vasculopathy. Patients with SSc-PAH+ showed a significant higher frequency of interstitial lung disease (ILD). No significant differences regarding clinical and laboratoristic parameters were observed. NVC abnormalities, avascular areas were more frequent in SSc patients with PAH, respect to those without (p = 0.03), and capillary density was significantly lower when considering grade 3 (p = 0.02). A higher NVC semiquantitative mean was found in SSc-PAH+ patients and a greater rate of the “late” pattern was detected in SSc-PAH+ subjects in respect to PAH- (57.1% vs. 25.7%) (p = 0.03). A significant correlations between pulmonary pressure values (sPAP by TTE and mPAP by RHC) and the capillary density (Spearman's rho 0.35, p = 0.04 for both). Our findings provide additional evidence to the literature data, confirming that a higher degree of peripheral nailfold microangiopathy is more common in SSc-PAH patients, and further strengthening the concept that NVC changes may run parallel with similar abnormalities inside pulmonary microcirculation.

The Role of Systemic Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing incidence, leading to a health care problem of epidemic proportions for which no curative treatments exist. Consequently, an urge exists to better understand the pathophysiology of HFpEF. Accumulating evidence suggests a key pathophysiological role for coronary microvascular dysfunction (MVD), with an underlying mechanism of low-grade pro-inflammatory state caused by systemic comorbidities. The systemic entity of comorbidities and inflammation in HFpEF imply that patients develop HFpEF due to systemic mechanisms causing coronary MVD, or systemic MVD. The absence or presence of peripheral MVD in HFpEF would reflect HFpEF being predominantly a cardiac or a systemic disease. Here, we will review the current state of the art of cardiac and systemic microvascular dysfunction in HFpEF (Graphical ), resulting in future perspectives on new diagnostic modalities and therapeutic strategies.

High Frequency of Microvascular Dysfunction in US Outpatient Clinics: A Sign of High Residual Risk? Data from 7,105 Patients.

Previous studies have linked peripheral microvascular dysfunction measured by arterial tonometry to high residual risk in on-statin patients. Digital thermal monitoring (DTM) of microvascular function is a new and simplified technique based on fingertip temperature measurements that has been correlated with the burden of atherosclerosis and its risk factors. Here, we report analyses of DTM data from two large US registries: Registry-I (6,084 cases) and Registry-II (1,021 cases) across 49 US outpatient clinics. DTM tests were performed using a VENDYS device during a 5-minute arm-cuff reactive hyperemia. Fingertip temperature falls during cuff inflation and rebounds after deflation. Adjusted maximum temperature rebound was reported as vascular reactivity index (VRI). VRI distributions were similar in both registries, with mean ± SD of 1.58 ± 0.53 in Registry-I and 1.52 ± 0.43 in Registry-II. In the combined dataset, only 18% had optimal VRI (≥2.0) and 82% were either poor (<1.0) or intermediate (1.0-2.0). Women had slightly higher VRI than men (1.62 ± 0.56 vs. 1.54 ± 0.47, p < 0.001). VRI was inversely but mildly correlated with age (r = −0.19, p < 0.001). Suboptimal VRI was found in 72% of patients <50 years, 82% of 50-70 years, and 86% of ≥70 years. Blood pressure was not correlated with VRI. In this largest registry of peripheral microvascular function measurements, suboptimal scores were highly frequent among on-treatment patients, possibly suggesting a significant residual risk. Prospective studies are warranted to validate microvascular dysfunction as an indicator of residual risk.

Peripheral microvascular dysfunction is also present in patients with ischemia and no obstructive coronary artery disease (INOCA).

In patients with ischemia and no obstructive coronary artery disease (INOCA), coronary microvascular dysfunction is associated with higher rate of major adverse cardiovascular events. To demonstrate if microvascular dysfunction present in coronary microcirculation of patients with INOCA may be detected noninvasively in their peripheral circulation. 25 patients with INOCA and 25 apparently healthy individuals (controls) were subjected to nailfold videocapillaroscopy (NVC) and venous occlusion plethysmography (VOP) to evaluate peripheral microvascular function and blood collection for biomarkers analysis, including soluble vascular cell adhesion molecule-1 (sVCAM-1), endothelin-1 (ET-1) and C-reactive protein (CRP). Red blood cell velocity (RBCV) before and after ischemia (RBCVmax) were significantly lower in patients with INOCA (p = 0.0001). Time to reach maximal red blood cell velocity (TRBCVmax) was significantly longer in INOCA group (p = 0.0004). Concerning VOP, maximal blood flow (p = 0.004) and its relative increment were significantly lower in patients with INOCA (p = 0.0004). RBCVmax showed significant correlations with sVCAM-1 (r = -0.38, p < 0.05), ET-1 (r = -0.73, p < 0.05) and CRP (r = -0.33, p < 0.05). Relative increment of maximal post-ischemic blood flow was significantly correlated with sVCAM-1 (r = -0.42, p < 0.05) and ET-1 (r = -0.48, p < 0.05). The impairment of microvascular function present in coronary microcirculation of patients with INOCA can be also detected in peripheral microcirculation.

Locomotor Muscle Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction.

[Figure: see text].

Peripheral microvascular dysfunction is associated with plaque progression and adverse long-term outcomes in heart transplant patients.

AimsCardiac allograft vasculopathy (CAV) is the major cause of increased morbidity and mortality after heart transplantation. Peripheral endothelial dysfunction (PED) is associated with early atherosclerosis and future risk of major adverse cardiovascular events (MACE) in non‐heart transplant population. We aimed to investigate the association of PED with future MACE, and plaque progression assessed by intravascular ultrasound (IVUS) after heart transplantation.Methods and resultsWe included 66 transplant patients who underwent serial IVUS surveillance for CAV and baseline assessment of peripheral endothelial function using reactive hyperaemia peripheral arterial tonometry. PED was defined as reactive hyperaemia index < 2. The primary endpoint of the study was to investigate the association of PED with CAV progression assessed by intravascular ultrasound (IVUS). CAV progression was assessed as the change (Δ) in plaque volume divided by segment length, and Δ plaque index (plaque volume/vessel volume), adjusted for the time between IVUS measurements (median 3.0 [2.2, 3.1] years). The secondary endpoint was to investigate the association between PED and future MACE, which was defined as any incident of revascularization, heart failure hospitalization, stroke, myocardial infarction, re‐transplantation, and death. Patients with PED (n = 27) had more yearly plaque progression (0.50 ± 0.66 vs. 0.15 ± 0.50 mm3/mm/year, P = 0.02) and a higher Δ plaque index (2.41 ± 2.53% vs. 0.69 ± 2.22%, P = 0.01). Patients with PED were more likely to experience MACE during a median follow‐up of 8.2 years (interquartile range [7.6, 8.4]), after adjustment for potential cofounders such as age, high‐density lipoprotein cholesterol levels, total rejection score, baseline International Society for Heart & Lung Transplantation CAV grade, and indication of transplantation. (hazard ratio 2.15, 95% confidence interval [1.09, 4.23], P = 0.03).ConclusionsPeripheral endothelial dysfunction is associated with increased plaque progression and adverse long‐term cardiovascular outcomes in transplant patients. PED assessment might be a useful clinical tool for risk stratification after heart transplantation.