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.

Coronary microvascular dysfunction is associated with poor glycemic control amongst female diabetics with chest pain and non-obstructive coronary artery disease.

BACKGROUND: Patients with type 2 diabetes mellitus are at an increased risk of adverse cardiovascular events compared to those without diabetes. The timing, relative to disease onset, and degree of glycemic control that reduces the risk of adverse cardiovascular events remains uncertain. Coronary microvascular dysfunction is prevalent in patients with type 2 diabetes mellitus and is linked to adverse cardiovascular events. We assessed the association between endothelial-dependent and endothelial-independent coronary microvascular dysfunction and glycemic control in patients presenting with chest pain and nonobstructive coronary disease at angiography. METHODS: Patients presenting with chest pain and found to have non-obstructive CAD (stenosis < 40%) at angiography underwent an invasive assessment of endothelial-independent and endothelial -dependent microvascular function. Endothelial-independent microvascular function was assessed by comparing the coronary flow velocity, measured using a Doppler guidewire, in response to intracoronary infusion of adenosine to calculate the coronary flow reserve ratio in response to adenosine (CFRAdn Ratio). A CFRAdn Ratio ≤ 2.5 was considered abnormal. Endothelial-dependent microvascular function was assessed by measuring the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), and microvascular endothelial dysfunction defined as a %ΔCBFAch of ≤ 50%. Patients were classified by normal versus abnormal CFRAdn Ratio and %ΔCBFAch. Measurements of HbA1c and fasting serum glucose were obtained prior to catheterization and compared between groups. RESULTS: Between 1993 and 2012, 1469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing for coronary microvascular dysfunction, of which 129 (8.8%) had type 2 diabetes. Fifty-one (39.5%) had an abnormal %ΔCBFAch and 49 (38.0%) had an abnormal CFRAdn Ratio. Conventional cardiovascular risk factors and cardiovascular or diabetic medication use did not vary significantly between groups. Females with an abnormal CFRAdn Ratio or abnormal %ΔCBFAch had a significantly higher HbA1c compared to patients with a normal CFRAdn Ratio or %ΔCBFAch respectively: HbA1c % (standard deviation) 7.4 (2.1) vs. 6.5 (1.1), p = 0.035 and 7.3 (1.9) vs. 6.4 (1.2), p = 0.022, respectively. Female patients with an abnormal CFRAdn Ratio had significantly higher fasting serum glucose concentrations compared to those with a normal CFRAdn Ratio: fasting serum glucose mg/dL (standard deviation) 144.4 (55.6) vs. 121.9 (28.1), p = 0.035. This was not observed in men. Amongst female diabetics, a higher HbA1c was significantly associated with any coronary microvascular dysfunction both in a univariate and multivariate analysis: odds ratio (95% confidence interval) 1.69 (1.01-2.86) p = 0.049; and a fasting serum glucose > 140 mg/dL was significantly associated with an abnormal CFRAdn Ratio, 4.28 (1.43-12.81). CONCLUSION: Poor glycemic control is associated with coronary microvascular dysfunction amongst female diabetics presenting with chest pain and non-obstructive CAD. These findings highlight the importance of sex specific risk stratification models and treatment strategies when managing cardiovascular risk amongst diabetics. Further studies are required to identify additional risk prevention tools and therapies targeting microvascular dysfunction as an integrated index of cardiovascular risk.

[DIABETES AND RAMADAN FASTING - UPDATE 2019].

INTRODUCTION: Fasting during the month of Ramadan and other religious fasting days presents a challenging issue for healthcare practitioners (HCP). Education and instructions for patients with diabetes who intend to fast is mandatory during the pre-Ramadan period. This period represents a golden opportunity to evaluate the general health status of the patients including their risk associated with fasting. Furthermore, it allows HCP to revise and adapt suitable changes for their anti- diabetic therapy before initiating fasting. Therapy with high safety profile agents such as incretin-based therapy is more favorable than therapy with moderate-low safety profile agents such as sulphonylureas(SUs) and insulin to be administrated during the month of Ramadan. Patients already receiving treatment with sodium glucose co-transporter 2 inhibitors (SGLT2i) need thorough medical evaluation during the pre-Ramadan period in order to enable them to fast safely during the month of Ramadan using this class of agents. The aim of this review is to provide HCP in Israel with instructions and recommendations for better management of diabetic patients during Ramadan, while taking into consideration the recently published data and therapies available in Israel.

Management of cystic prolactinomas: a review.

INTRODUCTION: Cystic prolactinoma is a variant of prolactin-secreting pituitary adenoma. The strategies for the management of cystic prolactinoma have not been addressed thoroughly in clinical guidelines. METHODS: A literature search was performed using Pubmed to review the current approaches to the treatment of cystic prolactinoma. RESULTS: Transsphenoidal resection is an effective and relatively safe approach for the treatment of cystic prolactinoma, however, morbidity of surgery is dependent on the skill of the surgeon. Emerging studies allude to the efficacy and safety of dopamine agonists in the management of cystic prolactinoma. Dopamine agonists are associated with considerable rates of clinical improvement and tumor shrinkage, hence reducing the need for surgical intervention. CONCLUSIONS: Recent studies suggest that dopamine agonist therapy may be an effective and safe treatment option in a considerable portion of patients with cystic prolactinomas. We suggest that dopamine agonists should be considered as a first-line therapy for cystic prolactinoma in the absence of indications for early surgical intervention.

Sodium-glucose cotransporter-2-induced euglycemic diabetic ketoacidosis unmasks latent autoimmune diabetes in a patient misdiagnosed with type 2 diabetes mellitus: a case report.

BACKGROUND: Euglycemic diabetic ketoacidosis is an uncommon but life-threatening complication associated with the use of sodium-glucose cotransporter 2 inhibitors that causes lower than expected blood glucose levels typically seen in diabetic ketoacidosis. CASE PRESENTATION: We present a case of 64-year-old Caucasian male patient previously diagnosed with type 2 diabetes treated with a sodium-glucose cotransporter 2 inhibitor who developed severe ketoacidosis. Serum glucose levels on initial presentation were slightly above normal baseline level. The patient was revealed to have latent autoimmune diabetes in adults. CONCLUSION: This case highlights the importance of prescribing sodium-glucose cotransporter 2 inhibitors to the correct patient population and the significance of accurately differentiating between various types of diabetes.

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.

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.

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.

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.

Assessment of peripheral endothelial function predicts future risk of solid-tumor cancer.

AIMS: Cardiovascular health metrics predict the risk not only of cardiovascular diseases but also of several types of cancers. Microvascular endothelial dysfunction can predict future cardiovascular adverse events, but the predictive value of microvascular endothelial dysfunction for future risk of solid-tumor cancer has not been characterized. METHODS: A total of 488 patients who underwent microvascular endothelial function assessment using reactive hyperemia peripheral arterial tonometry were included in this study. Microvascular endothelial dysfunction was defined as a reactive hyperemia peripheral arterial tonometry index ≤2.0. RESULTS: Of 221 patients with a baseline reactive hyperemia peripheral arterial tonometry index ≤2.0, 21 patients (9.5%) were diagnosed with incident solid-tumor cancer during follow-up, whereas of 267 patients with a baseline reactive hyperemia peripheral arterial tonometry index >2.0, 10 patients (3.7%) were diagnosed with incident solid-tumor cancer during follow-up (p = 0.009). Patients with a reactive hyperemia peripheral arterial tonometry index ≤2.0 had lower solid-tumor cancer-free survival compared to patients with a reactive hyperemia peripheral arterial tonometry index >2.0 (log-rank p = 0.017) (median follow-up 6.0 (3.0-9.1) years). Cox proportional hazard analyses showed that a reactive hyperemia peripheral arterial tonometry index ≤2.0 predicted the incidence of solid-tumor cancer, with a hazard ratio of 2.52 (95% confidence interval 1.17-5.45; p = 0.019) after adjusting for age, sex, and coronary artery disease, 2.83 (95% confidence interval 1.30-6.17; p = 0.009) after adjusting for diabetes mellitus, hypertension, smoking status, and body mass index >30 kg/m2, 2.79 (95% confidence interval 1.21-6.41; p = 0.016) after adjusting for fasting plasma glucose, systolic blood pressure, smoking status (current or former), and body mass index, and 2.43 (95% confidence interval 1.10-5.34; p = 0.028) after adjusting for Framingham risk score. CONCLUSION: Microvascular endothelial dysfunction, as defined by a reactive hyperemia peripheral arterial tonometry index ≤2.0, was associated with a greater than two-fold increased risk of solid-tumor cancer. Microvascular endothelial dysfunction may be a useful marker to predict the future risk of solid-tumor cancer, in addition to its known ability to predict cardiovascular disease. Further research is necessary to develop adequate cancer screening strategies for patients with microvascular endothelial dysfunction.

Metabolic syndrome is associated with peripheral endothelial dysfunction amongst men.

Purpose: Metabolic syndrome (MetS) and peripheral endothelial dysfunction (PED) are both independently associated with an increased risk of cardiovascular disease (CVD). PED provides prognostic information beyond that provided by conventional risk factors. However, the association between MetS and PED remains uncertain. We evaluated the association between MetS and PED. Patients and methods: We performed a retrospective analysis of patients who were referred to Mayo Clinic between 2006 and 2014 for evaluation of chest pain and/or an assessment of CVD risk that included an assessment of PED measured with reactive hyperemia peripheral arterial tonometry. MetS was defined as the presence of at least 3 of the following: body mass index≥25 kg/m2, impaired fasting glucose or diabetes, high blood pressure or hypertension, hypertriglyceridemia, or low high-density lipoprotein cholesterol. Results: Six hundred seventy-eight patients were included (mean age 51.9±13.5 years, 418 (61.6%) women), of which 293 (43.2%) had PED, and 249 (36.7%) had MetS. In multivariable analyses adjusted for age, sex, CVD, smoking status, and elevated low-density lipoprotein, MetS was significantly associated with PED (Odds Ratio (OR) 2.06; P=0.0090). Of the individual MetS components, only being overweight and MetS range high-density lipoprotein had a similar association. After stratifying by sex, the association between MetS and PED persisted only in men (OR 3.16, P=0.0094). Conclusions: MetS is associated with PED in men undergoing an assessment of chest pain and/or CVD risk. Identifying PED in individuals with MetS could provide an abridged assessment of risk, potentially allowing for earlier and more intensive management of risk factors.

Elevated serum uric acid is associated with peripheral endothelial dysfunction in women.

BACKGROUND AND AIMS: Both elevated serum uric acid (SUA) and peripheral endothelial dysfunction (PED) are associated independently with cardiovascular disease (CVD). However, the association between SUA and PED is yet to be established. We hypothesized that high normal range of SUA is associated with PED. METHODS: 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). A high UA was defined as ≥5 mg/dL, in keeping with previous studies evaluating the link between SUA and CVD outcomes. RESULTS: One hundred forty patients were included (mean age 50.7 ±â€¯12.9 years, 86 (61.4%) female). Twenty four patients (17.1%) had pre-existing CVD (8 (9.3%) in females). Thirty patients (21.6%) had a Framingham score > 10% (8 (9.4%) in females). Fifty eight (41.4%) had PED and 77 (55.0%) had an elevated SUA. SUA levels were higher in patients with PED compared to those without (5.5 ±â€¯1.4 vs 4.8 ±â€¯1.2 mg/dL; p = 0.004). In an univariate analysis, elevated SUA levels were associated with PED (Odds Ratio (OR): 2.7; 95% confidence interval [CI] 1.33-5.48; p = 0.005). In a multivariate analysis adjusting for age, sex, presence of obstructive CVD and Framingham score>10, elevated SUA levels were associated with PED (OR 2.45; 95% CI 1.08-5.52; p = 0.031). After stratifying by sex, this association persisted in females only. CONCLUSIONS: High normal SUA levels are associated with PED in women who are otherwise at low risk for CVD. Thus, SUA is a promising circulating biomarker that could be used to assist in risk stratification in female patients with chest pain and/or those undergoing evaluation of CVD risk.

Predictors and Clinical Outcomes of Vasoplegia in Patients Bridged to Heart Transplantation With Continuous-Flow Left Ventricular Assist Devices.

Background The presence of a durable left ventricular assist device (LVAD) is associated with increased risk of vasoplegia in the early postoperative period following heart transplantation (HT). However, preoperative predictors of vasoplegia and its impact on survival after HT are unknown. We sought to examine predictors and outcomes of patients who develop vasoplegia after HT following bridging therapy with an LVAD. Methods and Results We identified 94 patients who underwent HT after bridging with continuous-flow LVAD from 2008 to 2018 at a single institution. Vasoplegia was defined as persistent low vascular resistance requiring ≥2 intravenous vasopressors within 48 hours after HT for >24 hours to maintain mean arterial pressure >70 mm Hg. Overall, 44 patients (46.8%) developed vasoplegia after HT. Patients with and without vasoplegia had similar preoperative LVAD, echocardiographic, and hemodynamic parameters. Patients with vasoplegia were significantly older; had longer LVAD support, higher preoperative creatinine, longer cardiopulmonary bypass time, and higher Charlson comorbidity index; and more often underwent combined organ transplantation. In a multivariate logistic regression model, older age (odds ratio: 1.08 per year; P=0.010), longer LVAD support (odds ratio: 1.06 per month; P=0.007), higher creatinine (odds ratio: 3.9 per 1 mg/dL; P=0.039), and longer cardiopulmonary bypass time (odds ratio: 1.83 per hour; P=0.044) were independent predictors of vasoplegia. After mean follow-up of 4.0 years after HT, vasoplegia was associated with increased risk of all-cause mortality (hazard ratio: 5.20; 95% CI, 1.71-19.28; P=0.003). Conclusions Older age, longer LVAD support, impaired renal function, and prolonged intraoperative CPB time are independent predictors of vasoplegia in patients undergoing HT after LVAD bridging. Vasoplegia is associated with worse prognosis; therefore, detailed assessment of these predictors can be clinically important.