Mitral valve-in-valve with 4D intracardiac echocardiography: Procedural and imaging technique.

Transcatheter mitral valve-in-valve (ViV) has emerged as a safe and effective therapeutic option for patients with a degenerated mitral bioprosthesis. As procedural techniques mature and operator experience improve, there is a push to adopt a "minimalist" approach of using conscious sedation instead of general anesthesia for faster recovery. The heavy reliance on fluoroscopy for ViV deployment makes feasible the use of intracardiac echocardiography (ICE) instead of transesophageal echocardiography for other procedural imaging requirements. We hereby use a case example to illustrate a step-by-step approach of using four-dimensional ICE to guide transcatheter mitral ViV under conscious sedation.

Transfemoral tricuspid valve replacement and one-year outcomes: the TRISCEND study.

BACKGROUND AND AIMS: For patients with symptomatic, severe tricuspid regurgitation (TR), early results of transcatheter tricuspid valve (TV) intervention studies have shown significant improvements in functional status and quality of life associated with right-heart reverse remodelling. Longer-term follow-up is needed to confirm sustained improvements in these outcomes. METHODS: The prospective, single-arm, multicentre TRISCEND study enrolled 176 patients to evaluate the safety and performance of transcatheter TV replacement in patients with ≥moderate, symptomatic TR despite medical therapy. Major adverse events, reduction in TR grade and haemodynamic outcomes by echocardiography, and clinical, functional, and quality-of-life parameters are reported to one year. RESULTS: Enrolled patients were 71.0% female, mean age 78.7 years, 88.0% ≥ severe TR, and 75.4% New York Heart Association classes III-IV. Tricuspid regurgitation was reduced to ≤mild in 97.6% (P < .001), with increases in stroke volume (10.5 ± 16.8 mL, P < .001) and cardiac output (0.6 ± 1.2 L/min, P < .001). New York Heart Association class I or II was achieved in 93.3% (P < .001), Kansas City Cardiomyopathy Questionnaire score increased by 25.7 points (P < .001), and six-minute walk distance increased by 56.2 m (P < .001). All-cause mortality was 9.1%, and 10.2% of patients were hospitalized for heart failure. CONCLUSIONS: In an elderly, highly comorbid population with ≥moderate TR, patients receiving transfemoral EVOQUE transcatheter TV replacement had sustained TR reduction, significant increases in stroke volume and cardiac output, and high survival and low hospitalization rates with improved clinical, functional, and quality-of-life outcomes to one year. Funded by Edwards Lifesciences, TRISCEND ClinicalTrials.gov number, NCT04221490.

6-Minute walk test predicts prolonged hospitalization in patients undergoing transcatheter mitral valve repair by MitraClip.

BACKGROUND: The 6-minute walk test (6MWT) is a simple functional test that can predict exercise capacity and is widely employed to assess treatment outcomes. Although mortality with transcatheter mitral valve repair (TMVr) using the MitraClip (Abbott Vascular, Menlo Park, CA) is significantly less than for open mitral valve surgery in high-risk patients, identifying which patient will benefit the most from TMVr remains a concern. There are limited prognostic metrics guiding patient selection and, no studies have reported relationship between prolonged hospitalization and 6MWT. This study aimed to determine if the 6MWT can predict prolonged hospitalization in patients undergoing TMVr by MitraClip. METHODS: We retrospectively reviewed 162 patients undergoing 6MWT before TMVr. Patients were divided into three groups according to the 6MWT distance (6MWTD) using the median (6MWTD ≥219 m, 6MWTD <219 m, and Unable to Walk). Multivariate logistic regression model was applied to select the demographic characteristics that were associated with the prolonged hospitalization defined as total length of stay ≥4 days in the study. RESULTS: We found that 6MWT (odds ratio 3.64, 95% confidence interval 2.03-6.52, P < 0.001) was independently associated with prolonged hospitalization after adjustment in multivariate analysis. Area under the curve of 6MWT for predicting prolonged hospitalization was 0.79 (95% confidence interval 0.72-0.85). CONCLUSIONS: Our study demonstrates that 6MWT was independently associated with prolonged hospitalization in patients with TMVr, and has a good discriminatory performance for predicting prolonged hospitalization.

GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans.

Muscle microvascular surface area determines substrate and hormonal exchanges between plasma and muscle interstitium. GLP-1 (glucagon-like peptide-1) regulates glucose-dependent insulin secretion and has numerous extrapancreatic effects, including a salutary vascular action. To examine whether GLP-1 recruits skeletal and cardiac muscle microvasculature in healthy humans, 26 overnight-fasted healthy adults received a systemic infusion of GLP-1 (1.2 pmol/kg of body mass per min) for 150 min. Skeletal and cardiac muscle MBV (microvascular blood volume), MFV (microvascular flow velocity) and MBF (microvascular blood flow) were determined at baseline and after 30 and 150 min. Brachial artery diameter and mean flow velocity were measured and total blood flow was calculated before and at the end of the GLP-1 infusion. GLP-1 infusion raised plasma GLP-1 concentrations to the postprandial levels and suppressed plasma glucagon concentrations with a transient increase in plasma insulin concentrations. Skeletal and cardiac muscle MBV and MBF increased significantly at both 30 and 150 min (P<0.05). MFV did not change in skeletal muscle, but decreased slightly in cardiac muscle. GLP-1 infusion significantly increased brachial artery diameter (P<0.005) and flow velocity (P=0.05) at 150 min, resulting in a significant increase in total brachial artery blood flow (P<0.005). We conclude that acute GLP-1 infusion significantly recruits skeletal and cardiac muscle microvasculature in addition to relaxing the conduit artery in healthy humans. This could contribute to increased tissue oxygen, nutrient and insulin delivery and exchange and therefore better prandial glycaemic control and tissue function in humans.

Echocardiographic Outcomes With Transcatheter Edge-to-Edge Repair for Degenerative Mitral Regurgitation in Prohibitive Surgical Risk Patients.

BACKGROUND: The CLASP IID randomized trial (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial) demonstrated the safety and effectiveness of the PASCAL system for mitral transcatheter edge-to-edge repair (M-TEER) in patients at prohibitive surgical risk with significant symptomatic degenerative mitral regurgitation (DMR). OBJECTIVES: This study describes the echocardiographic methods and outcomes from the CLASP IID trial and analyzes baseline variables associated with residual mitral regurgitation (MR) ≤1+. METHODS: An independent echocardiographic core laboratory assessed echocardiographic parameters based on American Society of Echocardiography guidelines focusing on MR mechanism, severity, and feasibility of M-TEER. Factors associated with residual MR ≤1+ were identified using logistic regression. RESULTS: In 180 randomized patients, baseline echocardiographic parameters were well matched between the PASCAL (n = 117) and MitraClip (n = 63) groups, with flail leaflets present in 79.2% of patients. Baseline MR was 4+ in 76.4% and 3+ in 23.6% of patients. All patients achieved MR ≤2+ at discharge. The proportion of patients with MR ≤1+ was similar in both groups at discharge but diverged at 6 months, favoring PASCAL (83.7% vs 71.2%). Overall, patients with a smaller flail gap were significantly more likely to achieve MR ≤1+ at discharge (adjusted OR: 0.70; 95% CI: 0.50-0.99). Patients treated with PASCAL and those with a smaller flail gap were significantly more likely to sustain MR ≤1+ to 6 months (adjusted OR: 2.72 and 0.76; 95% CI: 1.08-6.89 and 0.60-0.98, respectively). CONCLUSIONS: The study used DMR-specific echocardiographic methodology for M-TEER reflecting current guidelines and advances in 3-dimensional echocardiography. Treatment with PASCAL and a smaller flail gap were significant factors in sustaining MR ≤1+ to 6 months. Results demonstrate that MR ≤1+ is an achievable benchmark for successful M-TEER. (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial [CLASP IID]; NCT03706833).

1-Year Outcomes of Transcatheter Tricuspid Valve Repair.

BACKGROUND: Surgical management of isolated tricuspid regurgitation (TR) is associated with high morbidity and mortality, thereby creating a significant need for a lower-risk transcatheter solution. OBJECTIVES: The single-arm, multicenter, prospective CLASP TR (Edwards PASCAL TrAnScatheter Valve RePair System in Tricuspid Regurgitation [CLASP TR] Early Feasibility Study) evaluated 1-year outcomes of the PASCAL transcatheter valve repair system (Edwards Lifesciences) to treat TR. METHODS: Study inclusion required a previous diagnosis of severe or greater TR and persistent symptoms despite medical treatment. An independent core laboratory evaluated echocardiographic results, and a clinical events committee adjudicated major adverse events. The study evaluated primary safety and performance outcomes, with echocardiographic, clinical, and functional endpoints. Study investigators report 1-year all-cause mortality and heart failure hospitalization rates. RESULTS: Sixty-five patients were enrolled: mean age of 77.4 years; 55.4% female; and 97.0% with severe to torrential TR. At 30 days, cardiovascular mortality was 3.1%, the stroke rate was 1.5%, and no device-related reinterventions were reported. Between 30 days and 1 year, there were an additional 3 cardiovascular deaths (4.8%), 2 strokes (3.2%), and 1 unplanned or emergency reintervention (1.6%). One-year postprocedure, TR severity significantly reduced (P < 0.001), with 31 of 36 (86.0%) patients achieving moderate or less TR; 100% had at least 1 TR grade reduction. Freedom from all-cause mortality and heart failure hospitalization by Kaplan-Meier analyses were 87.9% and 78.5%, respectively. Their New York Heart Association functional class significantly improved (P < 0.001) with 92% in class I or II, 6-minute walk distance increased by 94 m (P = 0.014), and overall Kansas City Cardiomyopathy Questionnaire scores improved by 18 points (P < 0.001). CONCLUSIONS: The PASCAL system demonstrated low complication and high survival rates, with significant and sustained improvements in TR, functional status, and quality of life at 1 year. (Edwards PASCAL TrAnScatheter Valve RePair System in Tricuspid Regurgitation [CLASP TR] Early Feasibility Study [CLASP TR EFS]; NCT03745313).

1-Year Outcomes of Cardioband Tricuspid Valve Reconstruction System Early Feasibility Study.

BACKGROUND: Tricuspid regurgitation (TR) is prevalent and undertreated, with mortality and morbidity increasing with TR severity. Given poor outcomes with medical therapy and high in-hospital mortality for isolated tricuspid valve surgery, emerging transcatheter repair devices offer a promising alternative. OBJECTIVES: The Edwards Cardioband Tricuspid Valve Reconstruction System Early Feasibility study (NCT03382457) evaluates the treatment of functional TR via annular reduction with the Cardioband Tricuspid Valve Reconstruction System (Edwards Lifesciences). METHODS: Patients with ≥ moderate functional TR were eligible for this prospective, single-arm multicenter study. At 1 year, patients were evaluated for echocardiographic parameters, clinical and quality-of-life measures, and major adverse events. RESULTS: The 37 patients enrolled had a mean age of 78 years; 76% were female; and they had ≥ severe functional (97.3%) or mixed (2.7%) TR, atrial flutter/fibrillation (97%), and New York Heart Association functional class III/IV (65%). At 1 year, 73.0% achieved ≤ moderate TR (P < 0.0001), and 73.1% had ≥2 grade reductions. Echocardiography showed significant reductions in the tricuspid annulus diameter (P < 0.0001), mean vena contracta (P < 0.0001), proximal isovelocity surface area effective regurgitant orifice area (P < 0.0001), right ventricular end-diastolic diameter (P < 0.0001), and inferior vena contracta (P = 0.0006). New York Heart Association functional class improved significantly (P < 0.0001), with 92.3% achieving class I/II, and Kansas City Cardiomyopathy Questionnaire scores improved by 19.0 points (P < 0.0001). One-year cardiovascular mortality was 8.1%, reinterventions were necessary in 5.4%, major access site complications occurred in 8.1%, and severe bleeding was noted in 35.1% of patients. Kaplan-Meier estimates of survival and freedom from heart failure rehospitalization were 85.9% and 88.7%, respectively. CONCLUSIONS: One-year experience using the Cardioband system for tricuspid valve repair shows high survival and low rehospitalization rates with durable outcomes in TR reduction and echocardiographic, clinical, and quality-of-life outcomes.

Feasibility Study of the Transcatheter Valve Repair System for Severe Tricuspid Regurgitation.

BACKGROUND: Tricuspid regurgitation (TR) is a prevalent disease with limited treatment options. OBJECTIVES: This is the first 30-day report of the U.S. single-arm, multicenter, prospective CLASP TR early feasibility study of the PASCAL transcatheter valve repair system in the treatment of TR. METHODS: Patients with symptomatic TR despite optimal medical therapy, reviewed by the local heart team and central screening committee, were eligible for the study. Data were collected at baseline, discharge, and the 30-day follow-up and were reviewed by an independent clinical events committee and echocardiographic core laboratory. Feasibility endpoints included safety (composite major adverse event [MAE] rate), echocardiographic, clinical, and functional endpoints. RESULTS: Of the 34 patients enrolled in the study, the mean age was 76 years, 53% were women, the mean Society of Thoracic Surgeons score was 7.3%, 88% had atrial fibrillation/flutter, 97% had severe or greater TR, and 79% had New York Heart Association (NYHA) functional class III/IV symptoms. Twenty-nine patients (85%) received implants; at 30 days, 85% of them achieved a TR severity reduction of at least 1 grade, with 52% with moderate or less TR (p < 0.001). The MAE rate was 5.9%, and none of the patients experienced cardiovascular mortality, stroke, myocardial infarction, renal complication, or reintervention. Eighty-nine percent of the patients improved to NYHA functional class I/II (p < 0.001), the mean 6-min walk distance improved by 71 m (p < 0.001), and the mean Kansas City Cardiomyopathy Questionnaire score improved by 15 points (p < 0.001). CONCLUSIONS: In this early experience, the repair system performed as intended, with substantial TR reduction, favorable safety results with a low MAE rate, no mortality or reintervention, and significant improvements in functional status, exercise capacity, and quality of life. (Edwards CLASP TR EFS [CLASP TR EFS]; NCT03745313).

Early Feasibility Study of Cardioband Tricuspid System for Functional Tricuspid Regurgitation: 30-Day Outcomes.

OBJECTIVES: The study reports for the first time the 30-day outcomes of the first U.S. study with the Cardioband tricuspid valve reconstruction system for the treatment of functional tricuspid regurgitation (TR). BACKGROUND: Increasing severity of TR is associated with progressively higher morbidity and mortality; however, treatment options for isolated significant disease are limited. METHODS: In this single-arm, multicenter, prospective Food and Drug Administration-approved early feasibility study (EFS), 30 patients with severe or greater symptomatic functional TR were enrolled who were deemed candidates for transcatheter tricuspid repair with the Cardioband tricuspid system by the local heart team and multidisciplinary screening committee. RESULTS: The mean patient age was 77 years, 80% were women, 97% had atrial fibrillation, 70% were in New York Heart Association functional class III to IV with mean left ventricular ejection fraction of 58%, and 27% had severe, 20% massive, and 53% torrential TR. Device success was 93% and all patients were alive at 30 days. Between baseline and 30 days, septolateral tricuspid annular diameter was reduced by 13% (p < 0.001), 85% of patients had ≥1 grade TR reduction and 44% had ≤moderate TR, 75% were in New York Heart Association functional class I to II (p < 0.001), and overall Kansas City Cardiomyopathy Questionnaire score improved by 16 points (p < 0.001). CONCLUSIONS: In patients with severe symptomatic functional TR, this is the first study in the United States with the Cardioband tricuspid system for direct transcatheter annular reduction. This early feasibility study demonstrates high procedural feasibility with no 30-day mortality. There is significant reduction of functional TR with clinically significant improvements in functional status and quality of life. (Edwards Cardioband Tricuspid Valve Reconstruction System Early Feasibility Study; NCT03382457).

GLP-1 and Insulin Recruit Muscle Microvasculature and Dilate Conduit Artery Individually But Not Additively in Healthy Humans.

CONTEXT: Glucagon-like peptide-1 (GLP-1) and insulin increase muscle microvascular perfusion, thereby increasing tissue endothelial surface area and nutrient delivery. OBJECTIVE: To examine whether GLP-1 and insulin act additively on skeletal and cardiac microvasculature and conduit artery. DESIGN: Healthy adults underwent three study protocols in random order. SETTING: Clinical Research Unit at the University of Virginia. METHODS: Overnight-fasted participants received an intravenous infusion of GLP-1 (1.2 pmol/kg/min) or normal saline for 150 minutes with or without a 2-hour euglycemic insulin clamp (1 mU/kg/min) superimposed from 30 minutes onward. Skeletal and cardiac muscle microvascular blood volume (MBV), flow velocity, and flow; brachial artery diameter, flow velocity, and blood flow; and pulse wave velocity (PWV) were measured. RESULTS: GLP-1 significantly increased skeletal and cardiac muscle MBV and microvascular blood flow (MBF) after 30 minutes; these remained elevated at 150 minutes. Insulin also increased skeletal and cardiac muscle MBV and MBF. Addition of insulin to GLP-1 did not further increase skeletal and cardiac muscle MBV and MBF. GLP-1 and insulin increased brachial artery diameter and blood flow, but this effect was not additive. Neither GLP-1, insulin, nor GLP-1 and insulin altered PWV. Combined GLP-1 and insulin infusion did not result in higher whole-body glucose disposal. CONCLUSION: GLP-1 and insulin at physiological concentrations acutely increase skeletal and cardiac muscle microvascular perfusion and dilate conduit artery in healthy adults; these effects are not additive. Thus, GLP-1 and insulin may regulate skeletal and cardiac muscle endothelial surface area and nutrient delivery under physiological conditions.

Predictive Value of Age-Adjusted Charlson Co-Morbidity Index for 1-, 3-, and 5-Year Mortality in Patients Requiring Transcatheter Mitral Valve Repair.

Co-morbidities increase markedly with aging, and they often negatively affect its prognosis. Although mortality with transcatheter mitral valve repair (TMVr) is significantly less than for open mitral valve surgery in patients at high surgical risk, it remains a concern to identify which patients will benefit from this treatment. Some prognostic metrics have been reported to guide better patient selection; however, universal risk stratification measures have not been established. This study aimed to determine if age-adjusted Charlson co-morbidity index (CCI) could predict mortality in patients who underwent TMVr and to assess its discriminatory performance in long-term outcomes. We retrospectively reviewed 222 patients who underwent TMVr, and 7 who died in hospital was excluded. Cox proportional hazard models were applied to select the demographic characteristics that were associated with cumulative mortality. Receiver-operating characteristic analyses were performed for predicting all-cause mortality, and discriminatory performance was assessed. We found that the age-adjusted CCI (hazard ratio 1.33, 95% confidence interval 1.16 to 1.51, p <0.001), New York Heart Association classification, and atrial fibrillation were independently associated with mortality. The age-adjusted CCI demonstrated good discriminative performance for predicting mortality at 3 and 5 years (area under the curve 0.71 and 0.77, respectively) and were greater than those of the Society of Thoracic Surgeons score in receiver-operating characteristic analysis. Kaplan-Meier curve demonstrated that the age-adjusted CCI ≥ 8 had poor prognosis after TMVr. In conclusions, the age-adjusted CCI could predict mortality and had a good discriminative performance for predicting longer term outcomes in patients who underwent TMVr.

Early Feasibility Study of a Transcatheter Tricuspid Valve Annuloplasty: SCOUT Trial 30-Day Results.

BACKGROUND: The SCOUT (Percutaneous Tricuspid Valve Annuloplasty System for Symptomatic Chronic Functional Tricuspid Regurgitation) trial is a prospective, single-arm, multicenter, early feasibility study of a novel transcatheter device to plicate the tricuspid annulus (TA) and reduce tricuspid regurgitation (TR). OBJECTIVES: This study tested the feasibility and safety of a novel transcatheter device and assessed its early performance and functional outcomes. METHODS: Between November 2015 and June 2016, 15 patients with New York Heart Association (NYHA) functional class ≥II and moderate or greater functional TR were enrolled. Primary performance and safety endpoint outcomes were technically successful at 30 days with no reintervention. Echocardiographic measurements (TA diameter, effective regurgitant orifice area [EROA], left ventricular stroke volume [LVSV]) and quality-of-life (QoL) measurements (NYHA functional class, Minnesota Living with Heart Failure Questionnaire [MLHFQ], and 6-min walk test [6MWT]) were performed at baseline and 30 days. RESULTS: All patients (mean 73.2 ± 6.9 years of age, 87% female) underwent successful device implantation with no deaths, strokes, bleeding, tamponade, or valve reintervention. Technical success rate at 30 days was 80%, with 3 single-pledget annular detachments without reintervention. In the remaining 12 patients, there were significant reductions in TA (12.3 ± 3.1 cm2 to 11.3 ± 2.7 cm2, respectively; p = 0.019) and EROA (0.51 ± 0.18 cm2 vs. 0.32 ± 0.18 cm2, respectively; p = 0.020), with significant increase in LVSV (63.6 ± 17.9 ml vs. 71.5 ± 25.7 ml, respectively; p = 0.021). In the intention-to-treat cohort, there were significant improvements in NYHA functional class (≥1 class, p = 0.001), MLHFQ (47.4 ± 17.6 to 20.9 ± 14.8; p < 0.001), and 6MWT (245.2 ± 110.1 to 298.0 m ± 107.6 m; p = 0.008). CONCLUSIONS: The 30-day results of the SCOUT trial confirmed the safety of the novel transcatheter device, which reduced TA and EROA, increased LVSV, and improved QoL. (Early Feasibility of the Mitralign Percutaneous Tricuspid Valve Annuloplasty System (PTVAS) Also Known as TriAlign [SCOUT]; NCT02574650.).

Progressive Mitral Stenosis After MitraClip Implantation in a Patient With Systemic Inflammatory Disease.

We describe a patient at high surgical risk who was successfully treated with a MitraClip (Abbott Vascular, Menlo Park, CA) without transmitral gradient. She received corticosteroid therapy for systemic lupus erythematosus, and progressive mitral stenosis developed late after MitraClip implantation. It gradually increased and reached 23 mm Hg at 28 months after the procedure; during the same period, her dose of prednisone had to be increased owing to lupus flare. Systemic inflammatory disease has the potential to result in mitral valve inflammation and fibrosis, ultimately causing thickening of the tissue bridge and worsening of the mitral valve obstruction. Preprocedural counseling regarding durability may help in this population.

The cardiovascular response in sepsis: proposed mechanisms of the beneficial effect of adrenomedullin and its binding protein (review).

Sepsis and its complications are leading causes of morbidity and mortality. A better understanding of the mechanisms responsible for the shift from the early, hyperdynamic phase of sepsis to the late hypodynamic phase could lead to novel therapies that might improve the outcome of the septic patient. Adrenomedullin is a vasodilatory peptide which shows sustained elevation starting early in sepsis and is important in initiating the hyperdynamic response. As sepsis progresses, however, the vascular response to adrenomedullin is blunted and this decreased sensitivity is important in producing the shift to the late, hypodynamic phase. The decline in the vascular response to adrenomedullin is related to a sepsis-induced decrease in the binding protein for adrenomedullin (i.e., adrenomedullin binding protein-1) rather than a change in gene expression of the components of adrenomedullin receptors. Treatment of septic animals with the combination of adrenomedullin and its binding protein prevents the transition to the late phase of sepsis, maintains cardiovascular stability, and reduces sepsis-induced mortality. We propose that the mechanisms responsible for the beneficial effect of adrenomedullin and adrenomedullin binding protein-1 in sepsis are associated with downregulation of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), maintainence of endothelial constitutive nitric oxide synthase, and reduction of vascular endothelial cell apoptosis.

Candesartan acutely recruits skeletal and cardiac muscle microvasculature in healthy humans.

CONTEXT: Angiotensin II type 1 receptor (AT(1)R) tone restricts muscle microvascular blood volume (MBV) and decreases muscle insulin delivery and glucose use. OBJECTIVE: The objective of the study was to examine whether acute AT(1)R blockade alters microvascular perfusion in skeletal and cardiac muscle in humans. SETTING: The study was conducted at the General Clinical Research Center at the University of Virginia. METHODS: Eight overnight-fasted healthy young adults were studied thrice in random order. In study 1, each subject received candesartan (32 mg) orally at time 0. In study 2, each subject received placebo at time 0 and a 1 mU/min · kg euglycemic insulin clamp from time 240 to 360 min. In study 3, each subject received candesartan (32 mg) orally at time 0 and insulin infusion from 240 to 360 min. Forearm skeletal and cardiac muscle MBV, microvascular flow velocity, and microvascular blood flow (MBF) were determined at baseline and at 240 and 360 min. RESULTS: Candesartan treatment acutely recruited microvasculature in both skeletal and cardiac muscle by significantly increasing MBV (P < 0.03 and P = 0.02, respectively) and MBF (P < 0.03 for both) without altering microvascular flow velocity. Insulin infusion significantly increased cardiac MBV (P = 0.02) and MBF (P < 0.02). Superimposing insulin infusion 4 h after candesartan ingestion did not further recruit microvasculature. Insulin-mediated whole-body glucose disposal did not differ with or without candesartan pretreatment. CONCLUSIONS: Acute AT(1)R blockade with candesartan recruits skeletal as well as cardiac muscle microvasculature in healthy humans without altering insulin-mediated whole-body glucose disposal. This may contribute to the observed improvement in the cardiovascular outcomes in patients receiving prolonged treatment with AT(1)R blockers.

Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans.

OBJECTIVE: Insulin recruits muscle microvasculature, thereby increasing endothelial exchange surface area. Free fatty acids (FFAs) cause insulin resistance by activating inhibitor of κB kinase ß. Elevating plasma FFAs impairs insulin's microvascular and metabolic actions in vivo. Whether salsalate, an anti-inflammatory agent, prevents FFA-induced microvascular and/or metabolic insulin resistance in humans is unknown. RESEARCH DESIGN AND METHODS: Eleven healthy, young adults were studied three times in random order. After an overnight fast, on two occasions each subject received a 5-h systemic infusion of Intralipid ± salsalate pretreatment (50 mg/kg/day for 4 days). On the third occasion, saline replaced Intralipid. A 1 mU/kg/min euglycemic insulin clamp was superimposed over the last 2-h of each study. Skeletal and cardiac muscle microvascular blood volume (MBV), microvascular flow velocity (MFV), and microvascular blood flow (MBF) were determined before and after insulin infusion. Whole body glucose disposal rates were calculated from glucose infusion rates. RESULTS: Insulin significantly increased skeletal and cardiac muscle MBV and MBF without affecting MFV. Lipid infusion abolished insulin-mediated microvascular recruitment in both skeletal and cardiac muscle and lowered insulin-stimulated whole body glucose disposal (P<0.001). Salsalate treatment rescued insulin's actions to recruit muscle microvasculature and improved insulin-stimulated whole body glucose disposal in the presence of high plasma FFAs. CONCLUSIONS: High plasma concentrations of FFAs cause both microvascular and metabolic insulin resistance, which can be prevented or attenuated by salsalate treatment. Our data suggest that treatments aimed at inhibition of inflammatory response might help alleviate vascular insulin resistance and improve metabolic control in patients with diabetes.

Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans.

CONTEXT: Insulin recruits microvasculature in both cardiac and skeletal muscle, which increases the endothelial exchange surface area. Plasma concentrations of free fatty acids (FFAs) are elevated in patients with diabetes, which impairs insulin-mediated skeletal muscle microvascular recruitment. OBJECTIVE: The objective of the study was to examine whether elevated FFAs likewise cause insulin resistance in cardiac muscle microvasculature. SETTING: The study was conducted at the General Clinical Research Center at the University of Virginia. METHODS: Twenty-two healthy, young adults were studied twice in random order after an overnight fast. Each subject received a 5-h systemic infusion of either saline or Intralipid/heparin with a 1 mU/min · kg euglycemic insulin clamp superimposed for the last 2 h. Cardiac and forearm skeletal muscle microvascular blood volume (MBV) and flow velocity were measured and microvascular blood flow (MBF) calculated before and at the end of the insulin infusion. RESULTS: Insulin significantly increased MBV and MBF in both cardiac (P < 0.0001 for both) and skeletal (P = 0.008 and < 0.03, respectively) muscle. Microvascular flow velocity increased slightly but significantly in the skeletal (P = 0.04) but not in cardiac muscle. Lipid infusion lowered insulin-stimulated whole-body glucose disposal and abolished insulin-mediated increases in MBV and MBF in both cardiac and skeletal muscle. Whole-body insulin sensitivity predicted skeletal but not cardiac muscle microvascular responses to insulin. Insulin even decreased skeletal muscle MBV during lipid infusion in subjects who were moderately sensitive to insulin metabolically. CONCLUSIONS: In conclusion, high plasma concentrations of FFAs cause insulin resistance in cardiac as well as skeletal muscle microvasculature in healthy humans. This may contribute to the association of cardiac complications with metabolic insulin resistance in diabetes.