Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies.

BACKGROUND: Glucagon-like peptide-1 (7-36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans. METHODS: Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure-volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment. RESULTS: GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ % dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 % (p = 0.02) and GLP-1 + glibenclamide: -0.8 ± 9.0 % (p = 0.04) compared to control: -11.5 ± 10.0 %. GLP-1 also reduced cumulative stunning after BO2: -12.8 ± 10.5 % (p = 0.02) as did GLP-1 + glibenclamide: -14.9 ± 9.2 % (p = 0.02) compared to control: -25.7 ± 9.6 %. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74). CONCLUSIONS: Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia. Trial registration Clinicaltrials.gov Unique Identifier: NCT02128022.

Glucagon-like peptide-1 protects against ischemic left ventricular dysfunction during hyperglycemia in patients with coronary artery disease and type 2 diabetes mellitus.

BACKGROUND: Enhancement of myocardial glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7-36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM). METHODS: In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)-one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments. RESULTS: In study 1, the HHC (compared with control) increased glucose (13.0 ± 1.9 versus 4.8 ± 0.5 mmol/l, p < 0.0001) and insulin (1,212 ± 514 versus 114 ± 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 ± 175 versus 1,001 ± 333 µmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 ± 5.0 versus 71.3 ± 4.3%, p = 0.004) and regional (peak systolic strain -18.1 ± 6.6 versus -15.5 ± 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia. CONCLUSIONS: In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM. TRIAL REGISTRATION: http://www.isrctn.org . Unique identifier ISRCTN69686930.

Optimising cardioprotection during myocardial ischaemia: targeting potential intracellular pathways with glucagon-like peptide-1.

Coronary heart disease and type-2 diabetes are both major global health burdens associated with an increased risk of myocardial infarction (MI). Following MI, ischaemia-reperfusion injury (IRI) remains a significant contributor to myocardial injury at the cellular level. Research has focussed on identifying a strategy or intervention to minimise IRI to optimise reperfusion therapy, with the aim of delivering a superior clinical outcome. The incretin hormone glucagon-like peptide-1, already an established basis for the treatment of type-2 diabetes, also has the potential to protect against IRI. We explain the physiology and cellular processes involved in IRI, and the intracellular pathways activated by GLP-1, which could intercept IRI and deliver cardioprotection. The review also examines the current preclinical and clinical evidence for GLP-1 in cardioprotection and future directions for research as we look for an effective adjunctive treatment to minimise IRI.

Utility of speckle tracking echocardiography to characterize dysfunctional myocardium in patients with ischemic cardiomyopathy referred for cardiac resynchronization therapy.

BACKGROUND: Assessment of transmural scar at the site of latest mechanical activation is relevant to maximize outcomes in cardiac resynchronization therapy (CRT). Few studies have assessed the ability of speckle tracking echocardiography (STE)-derived short-axis strain to identify segmental myocardial scar, defined by contrast-enhanced cardiac magnetic resonance imaging (CMR), in patients referred for CRT. METHODS: A total of 26 patients with ischemic cardiomyopathy who underwent preprocedure echocardiography and CMR were studied. Extent of transmural scar was assessed using contrast-enhanced CMR and corresponding peak segmental radial and circumferential strains were derived using two-dimensional (2D) STE. Total left ventricle (LV) scar volume was compared with parameters of global strain. CRT response was defined as >15% reduction in LV end systolic volume (LVESV) at 6 months. RESULTS: Speckle tracking short-axis strain analysis was technically possible in over 90% of LV segments. Applying a segmental radial strain cutoff value of 10% distinguished segments with >50% scar area with a high negative predictive value (98%). Global longitudinal strain <-5% predicted CRT response. CONCLUSIONS: Two-dimensional STE offers potential to characterize dysfunctional myocardium and define segmental scar offering an integrated imaging approach to guide LV lead placement for CRT.

Impact of VV optimization in relation to left ventricular lead position: an acute haemodynamic study.

AIMS: Left ventricular (LV) lead placement to the most delayed segment offers the greatest potential benefit to cardiac resynchronization therapy (CRT). We assessed the impact of interventricular (VV) optimization on acute changes in cardiac output (CO) in patients with and without LV pacing of the most delayed segment. METHODS AND RESULTS: In 124 patients, the most delayed segment was defined by speckle tracking radial strain and the LV lead position by biplane fluoroscopy. Patients were classified as either a concordant (LV lead at latest site), adjacent (within one segment), or remote (two or more segments away) LV lead. Atrioventricular (AV) and VV delays were optimized by echocardiography. Cardiac output was measured non-invasively and a >20% increase in CO from baseline (intrinsic) defined acute response. Changes in CO in patients with concordant, adjacent, or remote LV leads were recorded following atrioventricular optimization alone (AV OPT) and after combined AV and VV optimization (AV/VV OPT). Compared with AV OPT pacing, AV/VV OPT produced a greater rise in CO (5.45 ± 1.1 vs. 5.76 ± 1.2 L/min, P< 0.001) and higher acute response rates (48.4 vs. 61.3%, P= 0.041). In adjacent patients, compared with AV OPT pacing, AV/VV OPT settings increased the response rate from 36.4 to 63.6% (P= 0.037). VV optimization had no effect on acute response rates in patients with remote (26.7 vs. 33.3%, P = 0.581) or concordant LV leads (65.6 vs. 72.1%, P = 0.438). CONCLUSION: VV optimization overcomes some but not all of the deleterious effects of a suboptimal LV lead position.

Cardiac resynchronization therapy optimization using noninvasive cardiac output measurement.

AIMS: Noninvasive cardiac output (CO) measurement (NICOM) is a novel method to assess ventricular function and offers a potential alternative for optimization of cardiac resynchronization therapy (CRT) devices. We compared the effect of NICOM-based optimization to no optimization (empiric settings) on CRT outcomes. METHODS: Two hundred and three patients undergoing CRT were assessed in two consecutive nonrandomized groups; an empiric group (n = 54) was programmed to "out of the box" settings with a fixed AV delay of 120 ms and a VV delay of 0 ms; and the optimization group (n = 149) underwent adjustments of both the AV and VV delays according to the greatest improvement in resting CO. The primary endpoints were improvements in left ventricular (LV) volumes and function from baseline at 6 months. Secondary endpoints were change in New York Heart Association (NYHA) class, quality of life score, and 6-minute walk test (6 MWT) performance. RESULTS: After 6 months of CRT, the optimization group had a better clinical response with lower NYHA class (2.1 ± 0.8 vs 2.4 ± 0.8, P = 0.048) and quality of life scores (35 ± 18 vs 42 ± 20, P = 0.045) but no differences in 6-MWT performance (269 ± 110 vs 277 ± 114 m, P = 0.81). Echocardiographic response was also better in the optimization group with lower LV end systolic volume (108 ± 51 vs 126 ± 60 mL, P = 0.048) and higher ejection fraction (30 ± 7 vs 27 ± 8, P = 0.01) compared to empiric settings. CONCLUSION: Device optimization using noninvasive measures of CO is associated with better clinical and echocardiographic response compared to empiric settings.

The impact of the right ventricular lead position on response to cardiac resynchronization therapy.

INTRODUCTION: Left ventricular (LV) lead placement to the latest contracting area (concordant LV lead) is associated with better response to cardiac resynchronization therapy (CRT) compared to a discordant LV lead. However, the effect of the right ventricular (RV) lead site on CRT response is unclear. We investigated the relationship of the RV and LV lead positions on CRT response. METHODS: In 131 CRT patients, the LV lead was positioned preferentially in a lateral or posterolateral vein and the RV lead to either the RV septum (RVS, n = 55) or RV apex (RVA, n = 76). The latest site of contraction was determined with two-dimensional speckle tracking radial strain imaging and patients had a concordant LV lead position if pacing the latest segment, and discordant if not. Response was defined as ≥15% reduction in LV end systolic volume (LVESV) at 6-month follow-up. RESULTS: There were no significant differences in mean reduction of LVESV at follow-up (RVS vs RVA: -23.3 ± 16% vs 22.1 ± 18%, P = 0.70) or rate of responders (58.2% vs 57.9%, P = 0.97) between the two groups. In patients with a concordant LV lead (n = 71), the response rate was significantly higher than those with a discordant lead (76.1% vs 36.7%, P < 0.001). There were no differences in outcomes in patients with a concordant or discordant LV lead according to the RV lead location. CONCLUSION: The extent of LV reverse remodeling following CRT is not related to the RV lead position, but is significantly higher in patients with a concordant LV lead.

Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective, randomized control trial.

BACKGROUND: Myocyte necrosis as a result of elective percutaneous coronary intervention (PCI) occurs in approximately one third of cases and is associated with subsequent cardiovascular events. This study assessed the ability of remote ischemic preconditioning (IPC) to attenuate cardiac troponin I (cTnI) release after elective PCI. METHODS AND RESULTS: Two hundred forty-two consecutive patients undergoing elective PCI with undetectable preprocedural cTnI were recruited. Subjects were randomized to receive remote IPC (induced by three 5-minute inflations of a blood pressure cuff to 200 mm Hg around the upper arm, followed by 5-minute intervals of reperfusion) or control (an uninflated cuff around the arm) before arrival in the catheter laboratory. The primary outcome was cTnI at 24 hours after PCI. Secondary outcomes included renal dysfunction and major adverse cardiac and cerebral event rate at 6 months. The median cTnI at 24 hours after PCI was lower in the remote IPC compared with the control group (0.06 versus 0.16 ng/mL; P=0.040). After remote IPC, cTnI was <0.04 ng/mL in 44 patients (42%) compared with 24 in the control group (24%; P=0.01). Subjects who received remote IPC experienced less chest discomfort (P=0.0006) and ECG ST-segment deviation (P=0.005) than control subjects. At 6 months, the major adverse cardiac and cerebral event rate was lower in the remote IPC group (4 versus 13 events; P=0.018). CONCLUSIONS: Remote IPC reduces ischemic chest discomfort during PCI, attenuates procedure-related cTnI release, and appears to reduce subsequent cardiovascular events.

Hyperinsulinemia improves ischemic LV function in insulin resistant subjects.

BACKGROUND: Glucose is a more efficient substrate for ATP production than free fatty acid (FFA). Insulin resistance (IR) results in higher FFA concentrations and impaired myocardial glucose use, potentially worsening ischemia. We hypothesized that metabolic manipulation with a hyperinsulinemic euglycemic clamp (HEC) would affect a greater improvement in left ventricular (LV) performance during dobutamine stress echo (DSE) in subjects with IR. METHODS: 24 subjects with normal LV function and coronary disease (CAD) awaiting revascularization underwent 2 DSEs. Prior to one DSEs they underwent an HEC, where a primed infusion of insulin (rate 43 mU/m 2/min) was co-administered with 20% dextrose at variable rates to maintain euglycemia. At steady-state the DSE was performed and images of the LV were acquired with tissue Doppler at each stage for offline analysis. Segmental peak systolic velocities (Vs) were recorded, as well as LV ejection fraction (EF). Subjects were then divided into two groups based on their insulin sensitivity during the HEC. RESULTS: HEC changed the metabolic environment, suppressing FFAs and thereby increasing glucose use. This resulted in improved LV performance at peak stress, measured by EF (IS group mean difference 5.3 (95% CI 2.5-8) %, p = 0.002; IR group mean difference 8.7 (95% CI 5.8-11.6) %, p < 0.0001) and peak V s in ischemic segments (IS group mean improvement 0.7(95% CI 0.07-1.58) cm/s, p = 0.07; IR group mean improvement 1.0 (95% CI 0.54-1.5) cm/s, p < 0.0001) , that was greater in the subjects with IR. CONCLUSIONS: Increased myocardial glucose use induced by HEC improves LV function under stress in subjects with CAD and IR. Cardiac metabolic manipulation in subjects with IR is a promising target for future therapy.

Elective coronary stenting increases fractional flow reserve in other arteries due to an increase in microvascular resistance: clinical implications for assessment of multivessel disease.

INTRODUCTION: Fractional flow reserve (FFR) can guide percutaneous coronary intervention (PCI) in multivessel disease (MVD). However, the effect of target vessel (TV) stenting on subsequent FFR measurements in remote non-TVs (NTVs) is unknown. We investigated the effect of TV stenting on NTV FFR in patients with MVD. METHODS: Patients with MVD (>50% stenosis, ≥2 vessels >2.5 mm diameter; n = 51) undergoing elective PCI were studied. NTV distal pressure, aortic pressure, and saline-bolus thermodilution transit time (Tmn) were measured at baseline and during maximal hyperemia to derive FFR, index of myocardial resistance (IMR), and coronary flow reserve (CFR). PCI was then performed to the TV and the measurements repeated. Collaterals were assessed by modified Rentrop score before and after TV stenting. RESULTS: Mean FFR increased in the NTV after stenting the TV (0.79 ± 0.02 vs. 0.81 ± 0.02; P < 0.01), particularly in patients with normal baseline IMR (0.77 ± 0.02 vs. 0.80 ± 0.02; P = 0.001; n = 41). In this group, PCI to the TV increased remote microvascular resistance (NTV IMR increased from 12.5 ± 0.7 to 16.3 ± 1.4; P = 0.007; and CFR decreased from 3.0 ± 0.2 to 2.4 ± 0.2; P = 0.008). This change was independent of angiographic loss of coronary collaterals from the NTV. CONCLUSION: Elective TV PCI increases NTV FFR due to an increase in remote coronary microvascular resistance in patients with normal microvascular function. The effect of stent deployment on subsequent FFR measurements in other arteries should be considered.

Remote ischaemic pre-conditioning does not attenuate ischaemic left ventricular dysfunction in humans.

AIMS: Remote ischaemic pre-conditioning (RIPC) reduces distant tissue ischaemia reperfusion injury. We tested the hypothesis that RIPC would protect the left ventricle (LV) from ischaemic dysfunction and stunning. METHODS AND RESULTS: Forty-two patients with single vessel coronary disease and normal LV function were prospectively recruited. Twenty patients had repeated conductance catheter assessment of LV function during serial coronary occlusions with/without RIPC and a further 22 patients underwent serial dobutamine stress echocardiography and tissue Doppler analysis with/without RIPC. Remote ischaemic pre-conditioning was induced by three 5 min inflations of a blood pressure cuff around the upper arm. RIPC did not diminish the degree of ischaemic LV dysfunction during coronary balloon occlusion (Tau, ms: 59.2 (2.8) vs. 62.8 (2.8), P = 0.15) and there was evidence of cumulative LV dysfunction despite RIPC [ejection fraction (EF), %: 54.3 (5.8) vs. 44.9 (3.7), P = 0.03]. Remote ischaemic pre-conditioning did not improve contractile recovery during reperfusion (EF, %: 51.7 (3.6) vs. 51.5 (5.7), P = 0.88 and Tau, ms: 55.6 (2.8) vs. 56.0 (2.0), P = 0.85). A neutral effect of RIPC on LV function was confirmed by tissue Doppler analysis of ischaemic segments at peak dobutamine (V(s), cm s(-1) control: 8.2 (0.4) vs. RIPC 8.1 (0.4), P = 0.43) and in recovery. CONCLUSION: RIPC does not attenuate ischaemic LV dysfunction in humans.

Non-invasive cardiac output measurements based on bioreactance for optimization of atrio- and interventricular delays.

AIMS: Non-invasive cardiac output monitoring (NICOM) based on bio-reactance offers a portable method to assess ventricular function. Optimization of cardiac resynchronization therapy (CRT) by echocardiography is labour-intensive. We compared the ability of NICOM and echocardiography to facilitate optimum CRT device programming. METHODS AND RESULTS: Forty-seven patients in sinus rhythm were evaluated within 14 days of CRT implantation. The atrio- (AV) and interventricular (VV) delay intervals were incrementally adjusted and at each setting, NICOM and echocardiographic data were recorded. Left ventricular (LV) volumes and function were assessed by echocardiography at baseline and 3 months. Response to CRT was defined as a reduction in LV end-systolic volume (LVESV) by >15%. In all patients, cardiac output (CO) increased significantly at optimized settings compared with baseline (5.66 +/- 1.4 vs. 4.35 +/- 1.1 L/min, P < 0.001). A 20% increase in acute CO following CRT predicted LVESV reduction of >15% with a sensitivity of 81% and specificity of 92% (AUC 0.86). The optimum AV delay determined by NICOM was confirmed by echocardiography in 40 of 47 patients (85%, r = 0.89, P < 0.01) and for VV delay in 39 of 47 patients (83%, r = 0.89, P < 0.01). CONCLUSION: Non-invasive cardiac output monitoring is a simple, reliable, and portable alternative to echocardiography to program CRT devices.

Insulin resistance and heart failure.

Despite recent therapeutic advances, heart failure remains a leading cause of morbidity and mortality. The prevalence of heart failure continues to rise, and the importance of cardiac energetics underlying myocardial dysfunction is increasingly recognized. The rise in obesity and type 2 diabetes with associated insulin resistance results in abnormal glucose and fatty acid metabolism of the myocardium and the entire body, serving to highlight the fact that deranged metabolism may provide a therapeutic target beyond existing neuroendocrine inhibition. Evidence from clinical studies often conflict, but it appears that the association between heart failure and insulin resistance is interdependent and complex. Drugs that improve glucose metabolism may harm myocardial performance under stress, and the use of metabolic treatment in patients with heart failure must be targeted on the individual and based on evidence from carefully designed clinical trials.

Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial.

BACKGROUND: Myocardial and renal injury commonly contribute to perioperative morbidity and mortality after abdominal aortic aneurysm repair. Remote ischemic preconditioning (RIPC) is a phenomenon whereby brief periods of ischemia followed by reperfusion in one organ provide systemic protection from prolonged ischemia. To investigate whether remote preconditioning reduces the incidence of myocardial and renal injury in patients undergoing elective open abdominal aortic aneurysm repair, we performed a randomized trial. METHOD AND RESULTS; Eighty-two patients were randomized to abdominal aortic aneurysm repair with RIPC or conventional abdominal aortic aneurysm repair (control). Two cycles of intermittent crossclamping of the common iliac artery with 10 minutes ischemia followed by 10 minutes reperfusion served as the RIPC stimulus. Myocardial injury was assessed by cardiac troponin I (>0.40 ng/mL), myocardial infarction by the American College of Cardiology/American Heart Association definition and renal injury by serum creatinine (>177 micromol/L) according to American Heart Association guidelines for risk stratification in major vascular surgery. The groups were well matched for baseline characteristics. RIPC reduced the incidence of myocardial injury by 27% (39% versus 12% [95% CI: 8.8% to 45%]; P=0.005), myocardial infarction by 22% (27% versus 5% [95% CI: 7.3% to 38%]; P=0.006), and renal impairment by 23% (30% versus 7%; [95% CI: 6.4 to 39]; P=0.009). Multivariable analysis revealed the protective effect of RIPC on myocardial injury (OR: 0.22, 95% CI: 0.07 to 0.67; P=0.008), myocardial infarction (OR: 0.18, 95% CI: 0.04 to 0.75; P=0.006) and renal impairment were independent of other covariables. CONCLUSIONS: In patients undergoing elective open abdominal aortic aneurysm repair, RIPC reduces the incidence of postoperative myocardial injury, myocardial infarction, and renal impairment.

Left Atrial Function Is Associated with Earlier Need for Cardiac Surgery in Moderate to Severe Mitral Regurgitation: Usefulness in Targeting for Early Surgery.

BACKGROUND: The aim of this study was to determine whether assessment of left atrial (LA) function helps identify patients at risk for early deterioration during follow-up with mitral valve prolapse and mitral regurgitation. METHODS: Patients with moderate to severe mitral regurgitation but no guideline-based indications for surgery were retrospectively identified from a dedicated clinical database. Maximal and minimal LA volumes were used to derive total LA emptying fraction ([maximal LA volume - minimal LA volume]/maximal L volume × 100%). Average values of peak contractile, conduit, and reservoir strain were obtained using two-dimensional speckle-tracking imaging. The study outcome was time to mitral surgery. RESULTS: One hundred seventeen patients were included; median follow-up was 18 months. Sixty-eight patients underwent surgery. Receiver operating characteristic curves were used to derive optimal cutoffs for TLAEF (>50.7%) and strain (reservoir, >28.5%; contractile, >12.5%). Using Cox analysis, TLAEF and contractile, reservoir, and conduit strain were univariate predictors of time to event. After multivariate analysis, TLAEF (hazard ratio, 2.59; P = .001), reservoir strain (hazard ratio, 3.06; P < .001), and contractile strain (hazard ratio, 2.01; P = .022) remained independently associated with events, but conduit strain did not. Using Kaplan-Meier curves, event-free survival was considerably improved in patients with values above the derived thresholds (TLAEF: 1-year survival, 78 ± 5% vs 28 ± 8%; 3-year survival, 68 ± 6% vs 13 ± 5%; P < .001 for both; reservoir strain: 1-year survival, 79 ± 5% vs 29 ± 7%; 3-year survival, 67 ± 6% vs 15 ± 6%; P < .001 for both; contractile strain: 1-year survival, 80 ± 5% vs 41 ± 7%; 3-year survival, 69 ± 6% vs 24 ± 6%; P < .001 for both). CONCLUSION: LA function is independently associated with surgery-free survival in patients with mitral valve prolapse and moderate to severe mitral regurgitation. Quantitative assessment of LA function may have clinical utility in guiding early surgical intervention in these patients.

Glucagon-Like Peptide-1: A Promising Agent for Cardioprotection During Myocardial Ischemia.

Glucagon-like peptide-1-(7-36) amide (GLP-1) is a human incretin hormone responsible for the release of insulin in response to food. Pre-clinical and human physiological studies have demonstrated cardioprotection from ischemia-reperfusion injury. It can reduce infarct size, ischemic left ventricular dysfunction, and myocardial stunning. GLP-1 receptor agonists have also been shown to reduce infarct size in myocardial infarction. The mechanism through which this protection occurs is uncertain but may include hijacking the subcellular pathways of ischemic preconditioning, modulation of myocardial metabolism, and hemodynamic effects including peripheral, pulmonary, and coronary vasodilatation. This review will assess the evidence for each of these mechanisms in turn. Challenges remain in successfully translating cardioprotective interventions from bench-to-bedside. The window of cardioprotection is short and timing of cardioprotection in the appropriate clinical setting is critically important. We will emphasize the need for high-quality, well-designed research to evaluate GLP-1 as a cardioprotective agent for use in real-world practice.

Mechanisms of coronary microcirculatory dysfunction in patients with aortic stenosis and angiographically normal coronary arteries.

BACKGROUND: Development of left ventricular hypertrophy in aortic stenosis (AS) is accompanied by coronary microcirculatory dysfunction, demonstrated by an impaired coronary vasodilator reserve (CVR). However, evidence for regional abnormalities in myocardial blood flow (MBF) and the potential mechanisms is limited. The aims of this study were to quantitatively demonstrate differences in subendocardial and subepicardial microcirculation and to investigate the relative contribution of myocyte hypertrophy, hemodynamic load, severity of AS, and coronary perfusion to impairment in microcirculatory function. METHODS AND RESULTS: Twenty patients with isolated moderate to severe AS were studied using echocardiography to assess severity of AS, cardiovascular magnetic resonance to measure left ventricular mass (LVM), and PET to quantify resting and hyperemic (dipyridamole 0.56 mg/kg) MBF and CVR in both the subendocardium and subepicardium. In the patients with most severe AS (n=15), the subendocardial to subepicardial MBF ratio decreased from 1.14+/-7 at rest to 0.92+/-7 during hyperemia (P<0.005), and subendocardial CVR (1.43+/-3) was lower than subepicardial CVR (1.78+/-35; P=0.01). Resting total LV blood flow was linearly related to LVM, whereas CVR was not. Increase of total LV blood flow during hyperemia (mean value, 89.6+/-6%; range, 17% to 233%) was linearly related to aortic valve area. The decrease in CVR was related to severity of AS, increase in hemodynamic load, and reduction in diastolic perfusion time, particularly in the subendocardium. CONCLUSIONS: CVR was more severely impaired in the subendocardium in patients with LVH attributable to severe AS. Severity of impairment was related to aortic valve area, hemodynamic load imposed, and diastolic perfusion rather than to LVM.

Absolute blood flow and oxygen consumption in stunned myocardium in patients with coronary artery disease.

OBJECTIVES: In patients with coronary artery disease (CAD), we sought to demonstrate normal myocardial blood flow (MBF) and myocardial oxygen consumption (MMRO(2)) to post-ischemic myocardium that exhibited reversible dysfunction and the relation between the severity of the dysfunction and the preceding ischemia. BACKGROUND: In animal models of stunning, MBF and MMRO(2) are normal or near normal, and the severity of stunning is related to the degree of the preceding ischemia. METHODS: Myocardial blood flow and MMRO(2) were measured using positron emission tomography and oxygen 15-labelled water (H(2)(15)O) and oxygen 15-labelled oxygen ((15)O(2)), respectively, in 14 patients with CAD and normal left ventricular (LV) function. Global ejection fraction and regional LV systolic function (SF) were measured using quantitative echocardiography during and after dobutamine-induced ischemia. RESULTS: Ejection fraction and SF were reduced 30 min after dobutamine (both: p < 0.01) but recovered by 120 min. Myocardial blood flow (ml/min per g) to regions with reversible LV dysfunction was normal at baseline and during dysfunction (0.88 [0.82 to 0.99] and 1.09 [0.75 to 1.37], respectively, p = NS) as was MMRO(2) (ml/min per 100 g) (16.64 [10.16 to 16.18] and 11.68 [8.43 to 15.30] respectively, p = NS). Left ventricular dysfunction was related to stenosis severity and peak MBF. Regions were divided into those subtended by a stenosis of <50%, 50% to 80% and >80% luminal diameter. Systolic function 30 min after dobutamine was 93.9% (83.4% to 104.4%) (p = NS), 85.4% (80.0% to 90.9%) and 67.4% (56.2% to 78.7%) (both: p < 0.001), respectively. Peak MBF was 2.0 (1.71 to 2.31), 1.75 (1.65 to 1.85) (p = 0.01 compared with <50%) and 1.47 (1.33 to 1.60) (p = 0.03 compared with 50% to 80% and p = 0.002 compared with <50%), respectively. CONCLUSIONS: In patients with CAD, dobutamine produces prolonged, but reversible, LV dysfunction when MBF is normal, confirming stunning. This stunning is related to the severity of the coronary stenosis and the reduction in peak MBF. Myocardial oxygen consumption to stunned myocardium is normal.

Pre-treatment with glucagon-like Peptide-1 protects against ischemic left ventricular dysfunction and stunning without a detected difference in myocardial substrate utilization.

OBJECTIVES: This study sought to determine whether pre-treatment with intravenous glucagon-like peptide-1 (GLP-1)(7-36) amide could alter myocardial glucose use and protect the heart against ischemic left ventricular (LV) dysfunction during percutaneous coronary intervention. BACKGROUND: GLP-1 has been shown to have favorable cardioprotective effects, but its mechanisms of action remain unclear. METHODS: Twenty patients with preserved LV function and single-vessel left anterior descending coronary artery disease undergoing elective percutaneous coronary intervention were studied. A conductance catheter was placed into the LV, and pressure-volume loops were recorded at baseline, during 1-min low-pressure balloon occlusion (BO), and at 30-min recovery. Patients were randomized to receive an infusion of either GLP-1(7-36) amide at 1.2 pmol/kg/min or saline immediately after baseline measurements. Simultaneous coronary artery and coronary sinus blood sampling was performed at baseline and after BO to assess transmyocardial glucose concentration gradients. RESULTS: BO caused both ischemic LV dysfunction and stunning in the control group but not in the GLP-1 group. Compared with control subjects, the GLP-1 group had a smaller reduction in LV performance during BO (delta dP/dTmax, -4.3 vs. -19.0%, p = 0.02; delta stroke volume, -7.8 vs. -26.4%, p = 0.05), and improved LV performance at 30-min recovery. There was no difference in transmyocardial glucose concentration gradients between the 2 groups. CONCLUSIONS: Pre-treatment with GLP-1(7-36) amide protects the heart against ischemic LV dysfunction and improves the recovery of function during reperfusion. This occurs without a detected change in myocardial glucose extraction and may indicate a mechanism of action independent of an effect on cardiac substrate use. (Effect of Glucgon-Like-Peptide-1 [GLP-1] on Left Ventricular Function During Percutaneous Coronary Intervention [PCI]; ISRCTN77442023).

Atrial function as a guide to timing of intervention in mitral valve prolapse with mitral regurgitation.

OBJECTIVES: The purpose of this study was to determine the clinical utility of left atrial (LA) functional indexes in patients with mitral valve prolapse (MVP) and mitral regurgitation (MR). BACKGROUND: Timing of surgery for MVP remains challenging. We hypothesized that assessment of LA function may provide diagnostic utility in these patients. METHODS: We studied 192 consecutive patients in sinus rhythm with MVP, classified into 3 groups: moderate or less MR (MOD group, n = 54); severe MR without surgical indication (SEV group, n = 52); and severe MR with ≥1 surgical indication (SURG group, n = 86). Comparison was made with 50 control patients. Using 2D speckle imaging, average peak contractile, conduit, and reservoir atrial strain was recorded. Using Simpson's method we recorded maximal left atrial volume (LAVmax) and minimal left atrial volume (LAVmin), from which the total left atrial emptying fraction (TLAEF) was derived: (LAVmax-LAVmin)/LAVmax × 100%. RESULTS: TLAEF was similar in the MOD and control groups (61% vs. 57%; p = NS), was reduced in the SEV group (55%; p < 0.001 vs. control group), and markedly lower in the SURG group (40%; p < 0.001 vs. other groups). Reservoir strain demonstrated a similar pattern. Contractile strain was similarly reduced in the MOD and SEV groups (MOD 15%; SEV 14%; p = NS; both p < 0.05 vs. control group 20%) and further reduced in the SURG group (8%; p < 0.001 vs. other groups). By multivariate analysis, TLAEF (odds ratio [OR]: 0.78; p < 0.001), reservoir strain (OR: 0.91; p = 0.028), and contractile strain (OR: 0.86; p = 0.021) were independent predictors of severe MR requiring surgery. Using receiver-operating characteristic analysis, TLAEF <50% demonstrated 91% sensitivity and 92% specificity for predicting MVP with surgical indication (area under the curve: 0.96; p < 0.001). CONCLUSIONS: We report the changes in left atrial function in humans with MVP and the relationship of LA dysfunction to clinical indications for mitral valve surgery. We propose that the findings support the utility of quantitative assessment of atrial function by echocardiography as an additional tool to guide the optimum timing of surgery for MVP.