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

AIMS: 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). METHODS AND RESULTS: 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. CONCLUSION: 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.

Coronary Reactivity Assessment Is Associated With Lower Health Care-Associated Costs in Patients Presenting With Angina and Nonobstructive Coronary Artery Disease.

BACKGROUND: The financial burden linked to the diagnosis and treatment of patients with chest pain on the health care system is considerable. Angina and nonobstructive coronary artery disease (ANOCA) is common, associated with adverse cardiovascular events, and may lead to repeat testing or hospitalizations. Diagnostic certainty can be achieved in patients with ANOCA using coronary reactivity testing (CRT); however, its financial effect on the patient has not been studied. Our goal was to assess the effect of CRT on health care-related cost in patients with ANOCA. METHODS: Patients with ANOCA who underwent diagnostic coronary angiography (CAG) and CRT (CRT group) were matched to controls who had similar presentation but only underwent a CAG without CRT (CAG group). Standardized inflation-adjusted costs were collected and compared between the 2 groups on an annual basis for 2 years post the index date (CRT or CAG). RESULTS: Two hundred seven CRT and 207 CAG patients were included in the study with an average age of 52.3±11.5 years and 76% females. The total cost was significantly higher in the CAG group as compared with the CRT group ($37 804 [$26 933-$48 674] versus $13 679 [$9447-$17 910]; P<0.001). When costs are itemized and divided based on the Berenson-Eggers Type of Service categorization, the largest cost difference occurred in imaging (any type, including CAG; P<0.001), procedures (eg, percutaneous coronary intervention/coronary artery bypass grafting/thrombectomy) (P=0.001), and test (eg, blood tests, EKG; P<0.001). CONCLUSIONS: In this retrospective observational study, assessment of CRT in patients with ANOCA was associated with significantly reduced annual total costs and health care utilization. Therefore, the study may support the integration of CRT into clinical practice.

Coronary microvascular dysfunction is an independent predictor of developing cancer in patients with non-obstructive coronary artery disease.

AIMS: Cardiovascular disease and cancer share common pathogenesis and risk factors. Coronary microvascular dysfunction (CMD), reflecting impaired coronary microvascular dilation in response to stress, is related to a higher risk of major cardiovascular events; however, its association with cancer has not been explored. METHODS AND RESULTS: A retrospective study on 1042 patients with non-obstructive coronary artery diseases (NOCADs) was performed. Data regarding demographic, clinical history, diagnostic coronary reactivity test, and cancer occurrence were collected. Coronary microvascular dysfunction was defined as coronary flow reserve (the ratio of hyperaemic blood flow to resting blood flow) ≤2.5. Thirty-four per cent had CMD (67.4% female and the average age was 52.4 ± 12.2 years). Of 917 patients with no history of cancer, 15.5% developed cancer during follow-up [median of 9 (4, 16) years]. Kaplan-Meier analysis showed that CMD patients had lower cancer-free survival compared with those without CMD (log-rank P = 0.005). Cox proportional hazard analyses showed that after adjusting for age, sex, hypertension, diabetes, smoking, and glomerular filtration rate, CMD is independently associated with cancer [hazard ratio, 1.4; 95% confidence interval (CI), 1.09-2.04; P = 0.04]. The rate of major adverse cardiovascular events (MACE) was significantly higher in CMD patients compared with that in non-CMD patients who had a previous history of cancer [odds ratio (OR), 2.5; 95% CI, 1-6.2; P = 0.04] and those with no history of cancer (OR, 1.4; 95% CI, 1.01-1.9; P = 0.044). CONCLUSION: Coronary microvascular dysfunction is associated with cancer incidence in patients presenting with NOCADs. This study emphasizes follow-up in patients with CMD to evaluate the risk of MACE as well as potential malignant diseases.

Impact of Peripheral Microvascular Endothelial Dysfunction on White Matter Hyperintensity.

Background White matter hyperintensity (WMH), characterized by hyperintensities on T2-weighted fluid-attenuated inversion recovery brain magnetic resonance imaging, has been linked to an increased risk of ischemic stroke (IS). Endothelial dysfunction is an indicator of vascular dysfunction, predicting the risk of IS. This study aimed to investigate the association between endothelial dysfunction and regional WMH, and its impact on future risk of IS. Methods and Results We enrolled 219 patients (mean age, 53.1±14.1 years; 34.7% men) who underwent peripheral endothelial function assessment using reactive hyperemia peripheral arterial tonometry and brain magnetic resonance imaging without any history of IS. Volumetric WMH segmentation was automatically extrapolated using a validated automated digital tool. Total and juxtacortical WMH volume/intracranial volume (%) increased with aging and became more prominent in patients aged >50 years (n=131) than those aged ≤50 years (n=88) (total WMH: ≤50 years, Pearson r=0.24, P=0.03; >50 years, Pearson r=0.62, P<0.0001; juxtacortical WMH: ≤50 years, Pearson r=0.09, P=0.40; >50 years, Pearson r=0.55, P<0.0001). Reactive hyperemia peripheral arterial tonometry index was negatively associated with total and juxtacortical WMH volume/intracranial volume (%) in patients aged >50 years after adjustment for other covariates (reactive hyperemia peripheral arterial tonometry index, standardized ß coefficient -0.17, P=0.04). Juxtacortical WMH volume/intracranial volume (%) was associated with an increased risk of IS during median follow-up of 6.5 years (hazard ratio, 1.47; 95% CI, 1.05-1.92; P=0.03). Conclusions Peripheral endothelial dysfunction is associated with an increased volume of juxtacortical WMH in patients aged >50 years, which is a potential marker to predict future risk of IS.

Anxiety Disorders Are Associated With Coronary Endothelial Dysfunction in Women With Chest Pain and Nonobstructive Coronary Artery Disease.

Background Anxiety disorders are the most prevalent mental disorders and are an emerging risk factor for coronary artery disease and its complications. We determine the relationship between having a clinical diagnosis of an anxiety disorder and coronary endothelial dysfunction (CED) using invasive coronary reactivity testing across both sexes. Methods and Results Patients presenting with chest pain and nonobstructive coronary artery disease (stenosis <40%) at coronary angiography underwent an invasive assessment of CED. Patients were categorized as having a clinical diagnosis of an anxiety disorder at the time of coronary angiography by chart review. The frequency of CED was compared between patients with versus without an anxiety disorder and after stratifying patients by sex. Between 1992 and 2020, 1974 patients (mean age, 51.3 years; 66.2% women) underwent invasive coronary reactivity testing, of which 550 (27.9%) had a documented anxiety disorder at the time of angiography. There was a significantly higher proportion of patients with any type of CED in those with an anxiety disorder in all patients (343 [62.7%] versus 790 [56.4%]; P=0.011) that persisted in women but not in men. After adjusting for covariables, anxiety was significantly associated with any CED among all patients (odds ratio [95% CI], 1.36 [1.10-1.68]; P=0.004), and after stratifying by sex in women but not in men. Conclusions Anxiety disorders are significantly associated with CED in women presenting with chest pain and nonobstructive coronary artery disease. Thus, CED may represent a mechanism underpinning the association between anxiety disorders and coronary artery disease and its complications, highlighting the role of anxiety as a potential therapeutic target to prevent cardiovascular events.

Risk Stratification of Patients With NonObstructive Coronary Artery Disease Using Resistive Reserve Ratio.

Background Resistive reserve ratio (RRR), or the ratio of baseline to hyperemic microvascular resistance, has prognostic implications in predicting clinical outcomes in patients with obstructive coronary artery disease. However, its value in patients with angina or ischemia with nonobstructive coronary artery disease is unknown. Methods and Results We included 1692 patients with nonobstructive coronary artery disease who underwent invasive coronary vasoreactivity testing. Abnormal coronary flow reserve (CFR, the ratio of hyperemic and baseline resting flow velocities) and RRR were defined as <2.5 and <2.62, respectively. The mortality rate was marginally higher in patients with abnormal CFR (428 patients [25%]) than those with normal CFR (38 [9%] versus 81 [6%]; P=0.08), and was significantly higher in patients with abnormal RRR (716 patients [42%]) than those with normal RRR (70 [10%] versus 49 [5%], P=0.0002) over the median follow-up of 11.3 years. Patients with abnormal CFR had marginally lower survival than those with normal CFR (log-rank P=0.08). In contrast, patients with abnormal RRR had significantly lower survival than those with normal RRR (log-rank P=0.001). Abnormal RRR was associated with shorter time to death even after adjustment for other covariates (adjusted hazard ratio, 1.63; 95% CI, 1.11-2.38; P=0.01). Conclusions In patients with no obstructive coronary artery disease, RRR was superior to CFR in predicting long-term survival. An RRR <2.62 was associated with 1.6 times increased risk of death in patients with nonobstructive coronary artery disease. Indices of coronary microcirculatory resistive reserve comprising flow- and pressure-derived values may reflect underlying microvascular pathology more faithfully than flow-alone indices like CFR.

Compositional change of gut microbiome and osteocalcin expressing endothelial progenitor cells in patients with coronary artery disease.

Osteogenic endothelial progenitor cells (EPCs) contribute to impaired endothelial repair and promote coronary artery disease (CAD) and vascular calcification. Immature EPCs expressing osteocalcin (OCN) has been linked to unstable CAD; however, phenotypic regulation of OCN-expressing EPCs is not understood. We hypothesized that gut-microbiome derived pro-inflammatory substance, trimethylamine N-oxide (TMAO) might be associated with mobilization of OCN-expressing EPCs. This study aimed to investigate the association between dysbiosis, TMAO, and circulating mature and immature OCN-expressing EPCs levels in patients with and without CAD. We included 202 patients (CAD N = 88; no CAD N = 114) who underwent assessment of EPCs using flow cytometry and gut microbiome composition. Mature and immature EPCs co-staining for OCN were identified using cell surface markers as CD34+/CD133-/kinase insert domain receptor (KDR)+ and CD34-/CD133+/KDR+ cells, respectively. The number of observed operational taxonomy units (OTU), index of microbial richness, was used to identify patients with dysbiosis. The number of immature OCN-expressing EPCs were higher in patients with CAD or dysbiosis than patients without. TMAO levels were not associated with circulating levels of OCN-expressing EPCs. The relative abundance of Ruminococcus gnavus was moderately correlated with circulating levels of immature OCN-expressing EPCs, especially in diabetic patients. Gut dysbiosis was associated with increased levels of TMAO, immature OCN-expressing EPCs, and CAD. The relative abundance of Ruminococcus gnavus was correlated with immature OCN-expressing EPCs, suggesting that the harmful effects of immature OCN-expressing EPCs on CAD and potentially vascular calcification might be mediated by gut microbiome-derived systemic inflammation.

Machine learning aids clinical decision-making in patients presenting with angina and non-obstructive coronary artery disease.

Aims: The current gold standard comprehensive assessment of coronary microvascular dysfunction (CMD) is through a limited-access invasive catheterization lab procedure. We aimed to develop a point-of-care tool to assist clinical guidance in patients presenting with chest pain and/or an abnormal cardiac functional stress test and with non-obstructive coronary artery disease (NOCAD). Methods and results: This study included 1893 NOCAD patients (<50% angiographic stenosis) who underwent CMD evaluation as well as an electrocardiogram (ECG) up to 1-year prior. Endothelial-independent CMD was defined by coronary flow reserve (CFR) ≤2.5 in response to intracoronary adenosine. Endothelial-dependent CMD was defined by a maximal percent increase in coronary blood flow (%ΔCBF) ≤50% in response to intracoronary acetylcholine infusion. We trained algorithms to distinguish between the following outcomes: CFR ≤2.5, %ΔCBF ≤50, and the combination of both. Two classes of algorithms were trained, one depending on ECG waveforms as input, and another using tabular clinical data. Mean age was 51 ± 12 years and 66% were females (n = 1257). Area under the curve values ranged from 0.49 to 0.67 for all the outcomes. The best performance in our analysis was for the outcome CFR ≤2.5 with clinical variables. Area under the curve and accuracy were 0.67% and 60%. When decreasing the threshold of positivity, sensitivity and negative predictive value increased to 92% and 90%, respectively, while specificity and positive predictive value decreased to 25% and 29%, respectively. Conclusion: An artificial intelligence-enabled algorithm may be able to assist clinical guidance by ruling out CMD in patients presenting with chest pain and/or an abnormal functional stress test. This algorithm needs to be prospectively validated in different cohorts.

Prognostic impact and clinical outcomes of coronary flow reserve and hyperaemic microvascular resistance.

BACKGROUND: Most studies dichotomise indices of coronary microvascular function to assess their prognostic values. AIMS: We aimed to investigate whether coronary flow reserve (CFR) and hyperaemic microvascular resistance (HMR) as continua predict major adverse cardiovascular events (MACE), comprising all-cause death, myocardial infarction, revascularisation, and stroke in patients with ischaemia and non-obstructive coronary artery disease. METHODS: A total of 610 patients were included and followed up over a median of 8.0 years (199 individual MACE in 174 patients). RESULTS: Both CFR and HMR as continua predicted MACE with an odds ratio (OR) of 0.70 (per 1-unit increase, 95% confidence interval [CI]: 0.53, 0.92; p=0.01) and 1.63 (per 1 mmHg/cm/s, 95% CI: 1.20, 2.21; p=0.002), respectively. This relationship remained significant after adjustment for age and sex with an adjusted OR of 0.66 (per 1 unit increase, 95% CI: 0.49, 0.89; p=0.01) and 1.42 (per 1 mmHg/cm/s, 95% CI: 1.03, 1.94; p=0.03). HMR added prognostic value to CFR in predicting MACE (net reclassification index 0.17, 95% CI: 0.02, 0.31; p=0.03; integrated discrimination improvement 0.01, 95% CI: 0.0001, 0.02; p=0.046). CONCLUSIONS: Both CFR and HMR as continuous variables predict future risk of MACE.

Clinical decision-making: Challenging traditional assumptions.

Clinical decision-making that best serves the interests of our patients requires the synthesis of evidence-based medicine, sound clinical judgment and guidelines. However, a relatively low percentage of clinical guidelines are based on well-designed prospective randomized clinical trials. Thus the foundation on which good clinical outcomes can be reasonably expected should be based on i) data derived from the most applicable and highest quality clinical studies available, and ii) 'tried and tested' clinical maxims acquired through experience that are, in turn, those ideas that are in keeping with a reasonable body of medical opinion. It follows that poor decision-making and unfavorable clinical outcomes can be linked to inappropriate or inferior quality evidence, or incorrectly conceived or implemented clinical judgment. Here we review selected areas of recent controversy in clinical cardiology, highlighting the critical role of evidence-based medicine when making informed clinical decisions to help avoid harm in our patients.

Coronary microvascular dysfunction is associated with exertional haemodynamic abnormalities in patients with heart failure with preserved ejection fraction.

AIMS: This study uniquely explored the relationship between coronary microvascular function and exercise haemodynamics using concurrent invasive testing. METHODS AND RESULTS: Fifty-one consecutive patients with unexplained cardiac exertion symptoms, non-obstructive coronary artery disease and normal left ventricular ejection fraction (>50%) underwent haemodynamic exercise assessment and concurrent coronary reactivity testing. Heart failure with preserved ejection fraction (HFpEF) was defined as a pulmonary arterial wedge pressure (PAWP) ≥15 mmHg at rest and/or ≥25 mmHg at peak exercise. Endothelium-independent coronary microvascular dysfunction (CMD) was defined as a coronary flow reserve (CFR) ≤2.5, while endothelium-dependent CMD was defined as ≤50% increase in coronary blood flow (CBF) in response to intracoronary acetylcholine infusions. Patients with HFpEF (n = 22) had significantly lower CFR (2.5 ± 0.6 vs. 3.2 ± 0.7; P = 0.0003) and median %CBF increase in response to intracoronary acetylcholine [1 (-35; 34) vs. 64 (-4; 133); P = 0.002] compared to patients without HFpEF (n = 29). PAWP was significantly higher in patients with endothelium-independent CMD compared to controls during both rest and exercise. This significant elevation was only present during exercise in patients with endothelium-dependent CMD compared to controls. CFR had significant inverse correlations with PAWP at rest (r = -0.31; P = 0.03) and peak exercise (r = -0.47, P = 0.001). CFR also had positive correlations with maximal exercise capacity (in W/kg) (r = 0.33, P = 0.02). CONCLUSIONS: Coronary microvascular function is inversely associated with filling pressures, particularly during exercise. Both types of CMD are associated with higher filling pressures at peak exercise. These findings underscore the potential mechanism and therapeutic target for CMD and HFpEF.

Coronary Microvascular Endothelial Dysfunction in Patients With Angina and Nonobstructive Coronary Artery Disease Is Associated With Elevated Serum Homocysteine Levels.

Background Elevated levels of serum homocysteine, via impaired nitric oxide production, and coronary microvascular dysfunction are associated with increased risk of major adverse cardiovascular events. However, whether serum homocysteine levels and coronary microvascular endothelial dysfunction (CMED) are linked remains unknown. Methods and Results This study included 1418 patients with chest pain or an abnormal functional stress test and with nonobstructive coronary artery disease (<40% angiographic stenosis), who underwent CMED evaluation with functional angiography and had serum homocysteine levels measured. Patients were classified as having normal microvascular function versus CMED. Patients in the CMED group (n=743; 52%) had higher mean age (52.1±12.2 versus 50.0±12.4 years; P<0.0001), higher body mass index (29.1 [25.0-32.8] versus 27.5 [24.2-32.4]; P=0.001), diabetes mellitus (12.5% versus 9.4%; P=0.03), and fewer women (63.5% versus 68.7%; P=0.04) compared with patients in the normal microvascular function group. However, they had lower rates of smoking history, and mildly lower low-density lipoprotein cholesterol levels. Serum homocysteine levels were significantly higher in patients with CMED, and the highest quartile of serum homocysteine level (>9 µmol/L) was an independent predictor of CMED (odds ratio, 1.34 [95% CI, 1.03-1.75]; P=0.03) after adjustment for age; sex; body mass index; chronic kidney disease (CKD); diabetes mellitus; smoking exposure; low-density lipoprotein cholesterol; high-density lipoprotein cholesterol and triglycerides; and aspirin, statin, and B vitamin use. Conclusions Patients with CMED have significantly higher levels of serum homocysteine. Elevated serum homocysteine levels were associated with a significantly increased odds of an invasive diagnosis of CMED. The current study supports a potential role for homocysteine for diagnosis and target treatment in the patients with early coronary atherosclerosis.

Peripheral endothelial dysfunction is a novel risk factor for systolic dysfunction and heart failure progression.

BACKGROUND: ACC/AHA guidelines recognize the progressive nature of heart failure (HF). Patients with risk factors (Stage A) are at risk for developing asymptomatic cardiac dysfunction (Stage B), which may then lead to symptomatic HF (Stage C). As such, therapies targeting abnormalities in stages A and B may protect against development of symptomatic HF. peripheral endothelial dysfunction (PED) is an independent predictor of adverse outcomes in patients with stage C HF. The aim of the current study was to evaluate whether PED might be associated with Stage B HF, where therapeutic interventions to prevent progression might be more efficacious. METHODS: We performed a retrospective cross-sectional analysis of patients who were referred for routine cardiovascular evaluation that included an assessment of peripheral endothelial function with reactive hyperemia-peripheral arterial tonometry. Individuals in this study underwent routine clinically indicated echocardiography within 2 months of testing for PED. Patients with clinical HF were excluded. RESULTS: The study included 355 patients (mean age 51.5 ± 14.6 years, 231 (65.1%) female). There was a significant association between PED and Stage B HF (Odds Ratio (OR) 6.38; P < 0.0001) that persisted after stratifying by sex. In multivariate analyses PED was significantly associated with Stage B HF (OR 5.33; P = 0.0038), and was also associated with progression to overt stage C HF (OR 4.63; P = 0.033). CONCLUSION: Peripheral endothelial dysfunction is risk factor for Stage B HF, even in low risk individuals. Further study is warranted to better understand the mechanistic basis of PED in HF to reduce the risk of symptomatic progression.

Secondary Raynaud's phenomenon is associated with microvascular peripheral endothelial dysfunction.

Previous studies in patients with Raynaud's phenomenon (RP) have found an association between microvascular abnormalities assessed by nail fold capillaroscopy and macrovascular peripheral endothelial dysfunction (PED), but the association between RP and nitric oxide related (NO) microvascular PED is not yet established. We performed a retrospective cross-sectional analysis of patients who were referred to Mayo Clinic between 2006 and 2014 for routine cardiovascular evaluation and who underwent evaluation of Reactive Hyperemia Peripheral Arterial Tonometry (index <2 consistent with PED). Identification of the presence of RP was determined by retrospective chart review. Six hundred sixty six individuals were included in this study (mean age 51.9 ± 13.5 years, 411 (61.3%) women), 637 (95.1%) individuals did not have RP (control group), and 29 (4.3%) had secondary RP. Only 4 patients had primary RP and were thus excluded from the final analyses. In a multivariate analysis adjusting for age, sex, smoking status, and use of statins we found a significant association between secondary RP and microvascular PED in all patients (Odds ratio: 2.45; 95% confidence interval 1.13-5.34; P = 0.0236) that remained significant in women after stratifying by sex. Secondary RP is associated with microvascular PED, detected using a non-invasive NO-dependent method. Early detection of microvascular PED could help in identifying individuals with secondary RP who are at risk for developing connective tissue disease as well as CVD.

Non-invasive assessment of endothelial function in patients with spontaneous coronary artery dissection: A case-control study.

BACKGROUND: The physiopathology underlying spontaneous coronary artery dissection remains largely unknown. Endothelial dysfunction is an early feature of many vascular disorders. We sought to determine the endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) in patients with SCAD and compare it to that of non-SCAD patients with similar cardiovascular risk profile. METHODS: This is a case-control study with the participation of 2 centers. Patients (cases) were diagnosed with SCAD between 2008 and 2018. Control subjects were individually matched 2:1 to SCAD cases from a cohort recruited for assessment with RH-PAT between 2006 and 2013. The primary measure variable was the mean difference in the log-transformed reactive hyperemia index (LnRH-PAT Index) between groups. RESULTS: LnRH-PAT data from 23 patients with SCAD and 46 matched controls were analyzed. No significant differences were noted in the matching variables (overall, 95.7% female with mean age 52.7 years). In the SCAD group, more patients reported migraine (61 vs. 21%) and more patients were on betablockers (70 vs 28%), ACE inhibitors (65 vs. 13%) and statins (70 vs. 28%), all differences statistically significant. The mean LnRH-PAT value was 0.55 ± 0.22 in patients with SCAD and 0.77 ± 0.23 in controls (mean difference: 0.22, p < 0.001). CONCLUSIONS: In this observational study, patients with SCAD had a poorer endothelial function than similar subjects without prior SCAD. This finding opens a new venue in the research of the physio pathologic mechanisms underlying SCAD.

Asymptomatic Left Ventricle Systolic Dysfunction.

Heart failure is a common debilitating illness, associated with significant morbidity and mortality, rehospitalisation and societal costs. Current guidelines and position statements emphasise the management of patients with overt symptomatic disease, but the increasing prevalence of congestive heart failure underscores the need to identify and manage patients with early left ventricular dysfunction prior to symptom onset. Asymptomatic left ventricular systolic dysfunction (ALVSD), classified as stage B heart failure, is defined as depressed left ventricular systolic function in the absence of clinical heart failure. Early initiation of therapies in patients with presumed ALVSD has been shown to lead to better outcomes. In this article, the authors clarify issues surrounding the definition and natural history of ALVSD, outline clinical tools that may be of value in identifying patients with ALVSD and highlight potential opportunities for future investigations to better address aspects of our understanding of this complex syndrome.

Incremental Prognostic Impact of Peripheral Microvascular Endothelial Dysfunction on the Development of Ischemic Stroke.

Background Peripheral microvascular endothelial dysfunction (PMED) has been linked to an increased risk of cardiovascular events, but there is a lack of information characterizing the predictive value of PMED for future risk of ischemic stroke (IS). Methods and Results This retrospective observational cohort study enrolled 637 patients who underwent non-invasive microvascular endothelial function assessment using reactive hyperemia peripheral arterial tonometry. Reactive hyperemia peripheral arterial tonometry index ≤2 was defined as PMED. Of 280 patients with PMED, 12 (4.3%) patients developed IS, compared with only 4 (1.1%) of 357 patients without PMED during a median follow-up of 5.3 years. Patients with PMED had lower IS-free survival compared with patients without PMED (log-rank P=0.03). Cox proportional hazard ratio (HR) analyses showed that PMED predicted the incidence of IS, with a HR of 3.43, 95% CI, 1.10-10.63 (P=0.03); adjusted HR of 3.70, 95% CI, 1.18-11.59 (P=0.02) after adjusting for sex, smoking history, and atrial fibrillation; adjusted HR of 3.45, 95% CI, 1.11-10.72 (P=0.03) after adjusting for CHA2DS2-VASc score; adjusted HR of 5.70, 95% CI, 1.40-23.29 (P=0.02) after adjusting for revised Framingham Stroke Risk Score. Reactive hyperemia peripheral arterial tonometry index improved discrimination of risk for IS after adding reactive hyperemia peripheral arterial tonometry index to CHA2DS2-VASc score and revised Framingham Stroke Risk Score. Conclusions PMED was associated with a >3-fold increased risk of IS. These findings underscore the concept of the systemic nature of endothelial dysfunction, which could act as a potential marker to predict future risk of IS.

Elevated plasma homocysteine levels are associated with impaired peripheral microvascular vasomotor response.

BACKGROUND: Hyperhomocysteinemia (HHcy) has been proposed as an important cardiovascular risk factor (cRF). However, little is known about the association between plasma homocysteine levels and peripheral microvascular endothelial dysfunction (PMED), which is an integrated index of vascular health. METHODS: This cross-sectional and retrospective cohort study included patients who underwent non-invasive PMED assessment using reactive hyperemia peripheral arterial tonometry (RH-PAT). The association between HHcy and PMED, and its impact on MACE (all-cause mortality and atherosclerotic cardiovascular events) was investigated. RESULTS: A total of 257 patients were enrolled (HHcy > 10.0 µmol/L, N = 51; lower levels of homocysteine [LHcy] ≤ 10 µmol/L, N = 206). Patients with HHcy were older, predominantly males, and with more comorbidities than patients with LHcy (p < 0.05 for all). RH-PAT index was lower in patients with HHcy versus LHcy (p = 0.01). A significant association between HHcy and PMED was observed in older (≥60 years), obese (≥30 kg/m2), present/past smokers and hypertensive patients. HHcy was significantly associated with PMED even after adjusting for other cRF and B-vitamins supplementation. HHcy was associated with an increased risk of MACE with a hazard ratio of 3.65 (95% CI 1.41-9.48, p = 0.01) and an adjusted hazard ratio of 2.44 (95% CI 0.91-6.51, p = 0.08) after adjustment for age (≥60 years). CONCLUSION: HHcy was independently associated with PMED after adjusting for cRF and B-vitamins supplementation. Thus, the link between homocysteine and MACE could be mediated by endothelial dysfunction, and will require further clarification with future studies.