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Background— The incretin hormone, glucagon-like peptide-1, promotes myocardial glucose uptake and may improve myocardial tolerance to ischemia. Endogenous glucagon-like peptide-1 (7–36) is augmented by pharmacological inhibition of dipeptidyl peptidase-4. We investigated whether chronic dipeptidyl peptidase-4 inhibition by sitagliptin protected against ischemic left ventricular dysfunction during dobutamine stress in patients with type 2 diabetes mellitus and coronary artery disease. Methods and Results— A total of 19 patients with type 2 diabetes mellitus underwent dobutamine stress echocardiography with tissue Doppler imaging on 2 separate occasions: the first (control) while receiving oral hypoglycemic agents, and the second after the addition of sitagliptin (100 mg once daily) for ≈4 weeks. Sitagliptin increased plasma glucagon-like peptide-1 (7–36) levels and, at peak stress, enhanced both global (ejection fraction, 70.5±7.0 versus 65.7±8.0%; P P =0.01) and regional left ventricular function, assessed by peak systolic velocity and strain rate in 12 paired, nonapical segments. This was predominantly because of a cardioprotective effect on ischemic segments (strain rate in ischemic segments, −2.27±0.65 versus −1.98±0.58 s −1 ; P =0.001), whereas no effect was seen in nonischemic segments (−2.19±0.48 versus −2.18±0.54 s −1 ; P =0.87). At 30 minutes recovery, dipeptidyl peptidase-4 inhibition mitigated the postischemic stunning seen in the control scan. Conclusions— The addition of dipeptidyl peptidase-4 inhibitor therapy with sitagliptin to the treatment regime of patients with type 2 diabetes mellitus and coronary artery disease is associated with a sustained improvement in myocardial performance during dobutamine stress and a reduction in postischemic stunning. Clinical Trial Registration— URL: http://www.isrctn.org . Unique identifier ISRCTN61646154.

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 Electronic supplementary material The online version of this article (doi:10.1186/s12933-016-0416-3) contains supplementary material, which is available to authorized users.

Coronary collaterals preserve left ventricular (LV) function during coronary occlusion by reducing myocardial ischemia and may directly influence LV compliance. We aimed to re-evaluate the relationship between coronary collaterals, measured quantitatively with a pressure wire, and simultaneously recorded LV contractility from conductance catheter data during percutaneous coronary intervention (PCI) in humans. Twenty-five patients with normal LV function awaiting PCI were recruited. Pressure-derived collateral flow index (CFI p): CFI p = (P w − P v)/(P a − P v) was calculated from pressure distal to coronary balloon occlusion (P w), central venous pressure (P v), and aortic pressure (P a). CFI p was compared with the changes in simultaneously recorded LV end-diastolic pressure (ΔLVEDP), end-diastolic volume, maximum rate of rise in pressure (ΔLVdP/dtmax; systolic function), and time constant of isovolumic relaxation (ΔLV τ; diastolic function), measured by a LV cavity conductance catheter. Measurements were recorded at baseline and following a 1-min coronary occlusion and were duplicated after a 30-min recovery period. There was significant LV diastolic dysfunction following coronary occlusion (ΔLVEDP: +24.5%, P < 0.0001; and ΔLV τ: +20.0%, P < 0.0001), which inversely correlated with CFI p (ΔLVEDP vs. CFI p: r = −0.54, P < 0.0001; ΔLV τ vs. CFI p: r = −0.46, P = 0.0009). Subjects with fewer collaterals had lower LVEDP at baseline (r = 0.33, P = 0.02). CFI p was inversely related to the coronary stenosis pressure gradient at rest (r = −0.31, P = 0.03). Collaterals exert a direct hemodynamic effect on the ventricle and attenuate ischemic LV diastolic dysfunction during coronary occlusion. Vessels with lesions of greater hemodynamic significance have better collateral supply.

Objectives This study sought to assess the impact of targeted left ventricular (LV) lead placement on outcomes of cardiac resynchronization therapy (CRT). Background Placement of the LV lead to the latest sites of contraction and away from the scar confers the best response to CRT. We conducted a randomized, controlled trial to compare a targeted approach to LV lead placement with usual care. Methods A total of 220 patients scheduled for CRT underwent baseline echocardiographic speckle-tracking 2-dimensional radial strain imaging and were then randomized 1:1 into 2 groups. In group 1 (TARGET [Targeted Left Ventricular Lead Placement toGuide Cardiac Resynchronization Therapy]), the LV lead was positioned at the latest site of peak contraction with an amplitude of >10% to signify freedom from scar. In group 2 (control) patients underwent standard unguided CRT. Patients were classified by the relationship of the LV lead to the optimal site as concordant (at optimal site), adjacent (within 1 segment), or remote (≥2 segments away). The primary endpoint was a ≥15% reduction in LV end-systolic volume at 6 months. Secondary endpoints were clinical response (≥1 improvement in New York Heart Association functional class), all-cause mortality, and combined all-cause mortality and heart failure–related hospitalization. Results The groups were balanced at randomization. In the TARGET group, there was a greater proportion of responders at 6 months (70% vs. 55%, p = 0.031), giving an absolute difference in the primary endpoint of 15% (95% confidence interval: 2% to 28%). Compared with controls, TARGET patients had a higher clinical response (83% vs. 65%, p = 0.003) and lower rates of the combined endpoint (log-rank test, p = 0.031). Conclusions Compared with standard CRT treatment, the use of speckle-tracking echocardiography to the target LV lead placement yields significantly improved response and clinical status and lower rates of combined death and heart failure–related hospitalization. (Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy [TARGET] study); ISRCTN19717943 )

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. (PACE 2011; 34:1527–1536)

Glucagon-like peptide-1 (GLP-1) is an incretin hormone which has been shown to promote myocardial glucose uptake. Its pharmacological properties as a cardioprotective agent are attractive because it has a short half-life and there is minimal risk of hypoglycaemia.To assess the hypothesis that intravenous infusion of GLP-1 would protect the heart from ischaemic left ventricular (LV) dysfunction during dobutamine stress echocardiography (DSE) in patients with coronary artery disease (CAD).Randomised crossover study.14 patients with CAD and good LV function awaiting revascularisation underwent two DSE scans in a randomised order. GLP-1 was infused intravenously at 1.2 pmol/kg/min starting 30 min before the DSE for one of the scans and the other scan acted as a control.Global and regional wall LV function assessed using tissue Doppler imaging at rest, peak stress and 30 min into recovery.Global LV function was greater at peak stress during GLP-1 infusion compared with control (ejection fraction 77.0±4.4 vs 70.8±5.0%, p0.0001; mitral annular systolic velocity 12.18±3.10 vs 11.31±3.11 cm/s, p=0.0004). GLP-1 infusion improved regional wall LV function in 12 non-apical segments assessed by velocity, strain and strain rate. This beneficial effect was predominantly seen in ischaemic segments. In recovery, infusion of GLP-1 mitigated the post-ischaemic stunning seen in the control scan.Intravenous infusion of GLP-1 protects the heart from ischaemic LV dysfunction induced by dobutamine stress in patients with CAD.URL: http://isrctn.org.ISRCTN 69686930.

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.

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. (PACE 2011; 34:467–474)

Objectives We aimed to investigate whether left ventricular (LV) stunning could be detected late after coronary occlusion when coronary flow has normalized. Background Stunning and cumulative LV dysfunction after ischemia reperfusion has been clearly demonstrated in animal models but has been refuted in several angioplasty models in humans. However, these studies have assessed LV function early, during the reactive hyperemic phase, which might have augmented LV function. Methods We recruited 20 male subjects with single-vessel, type A coronary disease, and normal ventricular function. We simultaneously measured LV function with a conductance catheter and coronary flow velocity with a Combowire (Volcano Therapeutics, Inc., Rancho Cordova, California) at baseline (BL), for 30 s after a low-pressure coronary balloon occlusion for 1 min and again after 30 min, before a second balloon occlusion. Results Stunning was detected at 30 min after a 1-min balloon occlusion: stroke volume (ml) BL1: 88.4 (22.8) versus BL2: 79.4 (24.0), p = 0.04; τ (ms) BL1: 49.8 (9.0) versus BL2: 52.5 (8.9), p = 0.02, despite full recovery of coronary average peak velocity (p = 0.62). A second balloon occlusion caused cumulative LV dysfunction: stroke volume (ml) BO1: 77.3 (34.6) versus BO2 64.9 (22.9), p = 0.01. Reactive hyperemia significantly augmented early recovery systolic function: dP/dt max 30 s: +5.8% versus 30 min − 5.4%, p = 0.0009. Conclusions Coronary occlusion for 1-min results in late stunning and cumulative LV dysfunction after 30 min. Reactive hyperemia augments stunned LV systolic function in early recovery.

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.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) by15%. 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, P0.001). A 20% increase in acute CO following CRT predicted LVESV reduction of15% 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, P0.01) and for VV delay in 39 of 47 patients (83%, r = 0.89, P0.01).Non-invasive cardiac output monitoring is a simple, reliable, and portable alternative to echocardiography to program CRT devices.

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)

Introduction Glucagon-like Peptide-1 (GLP-1) protects against left ventricular (LV) stunning but the mechanism is unclear. Two protocols (P1 and P2) investigated whether blockade of mitochondrial K-ATP channels (responsible for ischaemic conditioning) with glibenclamide abrogates GLP-1 cardioprotection in humans. Methods P1. Patients attending for elective PCI to their LAD were assigned to 4 groups (Figure 1). Pressure-volume loops, allowing systolic/diastolic assessment, were recorded at baseline (BL1) and after 1-minute LAD balloon occlusion (BO1). GLP-1 or saline infusion was started after BO1, with loops repeated (BL2 and BO2) at 30mins. P2. Patients awaiting PCI underwent serial dobutamine stress echos (DSE) with tissue Doppler, to assess impact of GLP-1 and glibenclamide on global and regional systolic function. Results P1. BO1 reduced LV function in all groups. Recovery from stunning (BL2) and cumulative dysfunction (BO2) improved with GLP-1 alone, and when glibenclamide was added. P2. At peak stress and recovery there was additional improvement in systolic function with GLP-1 versus control. However, systolic function was unchanged, with and without glibenclamide. Conclusion Glibenclamide did not abrogate GLP-1-mediated cardioprotection, suggesting GLP-1 acts through a non-KATP-dependent pathway in humans.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the gut in response to the oral ingestion of nutrients. GLP-1 has a number of extrapancreatic functions, including enhancing myocardial glucose uptake, that may improve myocardial tolerance to ischemia. The degradation of the active

This study sought to assess the impact of targeted left ventricular (LV) lead placement on outcomes of cardiac resynchronization therapy (CRT).Placement of the LV lead to the latest sites of contraction and away from the scar confers the best response to CRT. We conducted a randomized, controlled trial to compare a targeted approach to LV lead placement with usual care.A total of 220 patients scheduled for CRT underwent baseline echocardiographic speckle-tracking 2-dimensional radial strain imaging and were then randomized 1:1 into 2 groups. In group 1 (TARGET [Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy]), the LV lead was positioned at the latest site of peak contraction with an amplitude of10% to signify freedom from scar. In group 2 (control) patients underwent standard unguided CRT. Patients were classified by the relationship of the LV lead to the optimal site as concordant (at optimal site), adjacent (within 1 segment), or remote (≥2 segments away). The primary endpoint was a ≥15% reduction in LV end-systolic volume at 6 months. Secondary endpoints were clinical response (≥1 improvement in New York Heart Association functional class), all-cause mortality, and combined all-cause mortality and heart failure-related hospitalization.The groups were balanced at randomization. In the TARGET group, there was a greater proportion of responders at 6 months (70% vs. 55%, p = 0.031), giving an absolute difference in the primary endpoint of 15% (95% confidence interval: 2% to 28%). Compared with controls, TARGET patients had a higher clinical response (83% vs. 65%, p = 0.003) and lower rates of the combined endpoint (log-rank test, p = 0.031).Compared with standard CRT treatment, the use of speckle-tracking echocardiography to the target LV lead placement yields significantly improved response and clinical status and lower rates of combined death and heart failure-related hospitalization. (Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy [TARGET] study); ISRCTN19717943).

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.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.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.Device optimization using noninvasive measures of CO is associated with better clinical and echocardiographic response compared to empiric settings.

Background— The incretin hormone glucagon-like peptide-1 (GLP-1) has been shown to have cardioprotective properties in animal models of ischemia and infarction due to promotion of myocardial glucose uptake and suppression of apoptosis. We investigated whether GLP-1 protected the heart from dysfunction caused by supply ischemia during percutaneous coronary intervention (PCI). Methods and Results— Twenty patients with normal left ventricular (LV) function and single-vessel coronary disease within the left anterior descending artery undergoing elective PCI were studied. A conductance catheter was placed into the LV through the femoral artery, and pressure-volume loops were recorded at baseline and during a 1-minute low-pressure balloon occlusion at the site of the stenosis. The patients were randomized to receive an infusion of either GLP-1(7–36) amide at 1.2 pmol/kg per minute or saline immediately after the first balloon occlusion. Coronary balloon occlusion caused LV stunning in the control group with cumulative LV dysfunction on subsequent occlusion that was not seen in the GLP-1 group. GLP-1 improved recovery of LV systolic and diastolic function at 30 minutes after balloon occlusion compared with control (delta dP/dt max from baseline, −1.6% versus −12.2%; P =0.02) and reduced the LV dysfunction after the second balloon occlusion (delta dP/dt max , −13.1% versus −25.3%; P =0.01). Conclusions— In this pilot study, infusion of GLP-1 has been demonstrated to reduce ischemic LV dysfunction after supply ischemia during coronary balloon occlusion in humans and mitigates stunning. The findings require confirmation in a larger scale clinical trial. Clinical Trial Registration— URL: http://www.isrctn.org . Unique identifier: ISRCTN 77442023.

Category: 28. Cardiac PacingSession-Poster Board Number: 1089-397Authors: Fakhar Z. Khan, Munmohan S. Virdee, David Begley, John Hutchinson, Beverley Smith, Philip A. Read, Peter J. Pugh, Simon P. Fynn, David P. Dutka, Addenbrooke’s Hospital, Cambridge, United Kingdom, Papworth Hospital, Cambridge, United Kingdom Background: We aimed to assess to what extent acute changes in non invasive cardiac output measurements (NICOM) are related to longer term outcomes following cardiac resynchronization therapy (CRT).Methods: In 196 patients (69±9yrs, EF 23±7%, QRS 154±12ms, NYHA III/IV 183/13) CO recordings were made within 1 day of CRT at baseline (CRT OFF) and during optimized settings (CRT ON). Response was defined by >15% reduction in left ventricular end systolic volume (LVESV) at 6 months.Results: There was a significant difference in CO readings during CRT between responders (n=112) and non responders (6.23±1.21 vs 5.19±0.96L/min, p 20% in CO, 1 day after CRT implant had greater survival than those patients with

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.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.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%, P0.001). There were no differences in outcomes in patients with a concordant or discordant LV lead according to the RV lead location.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.

Results: The mean reduction in LVESV from baseline at follow up in the RVS group was greater than in the RVA group (22.7% vs. 13.5%, p=0.03), as was the rate of responders (69.7% vs. 44.1%, p=0.03). In the concordant group (n=28), there were no differences between the RVS (n=17) and RVA (n=11) groups in the extent of LVESV reduction (29.1 vs. 26.4%, p =0.91) and CRT response rates (71.3 vs. 81.8%, p=0.22) In patients with a discordant LV lead, there were significant differences between the RVS (n=16) and RVA (n=23) groups in the extent of LVESV reduction (15.8 vs. 4.7%, p=0.05) and in response rates (28.3 vs. 12.8%, p

Background— Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted postprandially that promotes myocardial glucose uptake. The active amide GLP-1 (7-36) is degraded by the enzyme DPP-4, and drugs that inhibit this enzyme (such as sitagliptin) have been introduced to treat type 2 diabetes. We assessed the hypothesis that increasing the plasma concentration of GLP-1 by DPP-4 inhibition would protect the heart from ischemic left ventricular (LV) dysfunction during dobutamine stress echocardiography in patients with coronary artery disease. Methods and Results— Fourteen patients with coronary artery disease and preserved LV function awaiting revascularization were studied. After either a single dose of 100 mg sitagliptin or placebo, 75 g of glucose was given orally to promote GLP-1 secretion and dobutamine stress echocardiography was conducted with tissue Doppler imaging at rest, peak stress, and 30 minutes. After sitagliptin, plasma GLP-1 (7-36) was increased at peak stress (16.5�10.7 versus 9.7�8.7 pg/mL; P =0.003) and in recovery (12.4�5.5 versus 9.0�5.5 pg/mL; P =0.01), and the LV response to stress was enhanced (ejection fraction, 72.6�7.2 versus 63.9�7.9%, P =0.0001; mitral annular systolic velocity, 12.54�3.18 versus 11.49�2.52 cm/s; P =0.0006). DPP-4 inhibition also improved LV regional function in the 12 paired nonapical segments assessed by peak systolic tissue Doppler (velocity, 10.56�4.49 versus 9.81�4.26 cm/s, P =0.002; strain, −15.9�6.3 versus −14.6�6.6%, P =0.01; strain rate, −2.04�1.04 versus −1.75�0.98 s −1 , P =0.0003). This was predominantly due to a cardioprotective effect on ischemic segments (velocity in ischemic segments, 9.77�4.18 versus 8.74�3.87, P =0.007; velocity in nonischemic segments, 11.51�4.70 versus 11.14�4.38, P =0.14). In recovery, sitagliptin attenuated the postischemic stunning seen after the control study. Conclusions— The augmentation of GLP-1 (7-36) by inhibition of DPP-4 improves global and regional LV performance in response to stress and mitigates postischemic stunning in humans with coronary artery disease. Clinical Trial Registration— URL: http://www.isrctn.org. Unique identifier: ISRCTN78649100.

Left ventricular (LV) lead placement to areas of scar has detrimental effects on response to cardiac resynchronization therapy (CRT). Speckle-tracking radial two-dimensional strain offers assessment of the extent of regional myocardial deformation. The aim of this study was to assess the impact of LV lead placement at areas of low-amplitude strain on CRT response.The optimal cutoff of radial strain amplitude at the LV pacing site associated with an unfavorable CRT response was determined in a derivation group (n = 65) and then tested in a second consecutive validation group (n = 75) of patients with heart failure. Patients had concordant LV leads if placed at the most delayed site, and dyssynchrony was defined as anteroseptal to posterior delay ≥ 130 msec. CRT response was defined as a ≥15% reduction in LV end-systolic volume at 6 months.In the derivation group, a derived cutoff for radial strain amplitude of9.8% defined low-amplitude segments (LAS) and had a high specificity but low sensitivity for predicting LV reverse remodeling, suggesting a strong negative predictive value. In the validation group, compared with patients without LAS at the LV pacing site, in patients with LAS (n = 16), CRT response was significantly lower (62.7% vs 31.3%, P.05). By multivariate analysis, LV lead concordance and the absence of an LAS at the LV pacing site but not dyssynchrony were significantly related to CRT response.LV lead placement over segments with two-dimensional radial strain amplitudes9.8% is associated with poor outcomes of CRT.

We aimed to investigate whether left ventricular (LV) stunning could be detected late after coronary occlusion when coronary flow has normalized.Stunning and cumulative LV dysfunction after ischemia reperfusion has been clearly demonstrated in animal models but has been refuted in several angioplasty models in humans. However, these studies have assessed LV function early, during the reactive hyperemic phase, which might have augmented LV function.We recruited 20 male subjects with single-vessel, type A coronary disease, and normal ventricular function. We simultaneously measured LV function with a conductance catheter and coronary flow velocity with a Combowire (Volcano Therapeutics, Inc., Rancho Cordova, California) at baseline (BL), for 30 s after a low-pressure coronary balloon occlusion for 1 min and again after 30 min, before a second balloon occlusion.Stunning was detected at 30 min after a 1-min balloon occlusion: stroke volume (ml) BL1: 88.4 (22.8) versus BL2: 79.4 (24.0), p = 0.04; tau (ms) BL1: 49.8 (9.0) versus BL2: 52.5 (8.9), p = 0.02, despite full recovery of coronary average peak velocity (p = 0.62). A second balloon occlusion caused cumulative LV dysfunction: stroke volume (ml) BO1: 77.3 (34.6) versus BO2 64.9 (22.9), p = 0.01. Reactive hyperemia significantly augmented early recovery systolic function: dP/dt max 30 s: +5.8% versus 30 min - 5.4%, p = 0.0009.Coronary occlusion for 1-min results in late stunning and cumulative LV dysfunction after 30 min. Reactive hyperemia augments stunned LV systolic function in early recovery.

Although monoamine oxidase inhibitors (MAOIs) have had their clinical obituary written on many occasions in the 33 years since they were first introduced to clinical practice they remain very much alive. Although their prescription has fallen understandably with the introduction of many other drugs for the treatment of affective disorders they still have a place in the treatment of anxiety and depression. This is because they are often effective when other types of antidepressants have failed, because they are effective against disorders that are otherwise very difficult to treat, and because they have energizing properties that are possessed by virtually no other compounds. Their main clinical use is in mixed anxiety-depressive syndromes although in the United States they are also promoted for the treatment of panic disorder. Their main handicaps, potentially serious food and drug interactions, remain a serious deterrent to prescription but have been reduced by the introduction of new reversible compound...

Background Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the gut in response to the oral ingestion of nutrients. Through augmentation of myocardial glucose uptake and subsequent reduction in fatty acid oxidation, GLP-1 modulation therapy has emerged as a potential target for improving myocardial oxygen efficiency at times of ischaemic stress, such as occurs in obstructive coronary artery disease (CAD). Sitagliptin is a DDP-4 inhibitor licensed for the treatment of Type 2 Diabetes Mellitus (T2DM) that reduces degradation of plasma GLP-1 (7–36). We investigated whether sitagliptin improved myocardial performance during dobutamine stress echocardiography (DSE) in patients with T2DM and CAD. Methods 12 patients (aged 69±9 years, 9 men) with T2DM on oral hypoglycaemic therapy (OHT), obstructive CAD and preserved left ventricular (LV) systolic function were studied. Each subject underwent DSE on two separate occasions after an overnight fast; the first (control) while receiving standard OHT and the second after the addition of sitagliptin (100 mg od) for 4 weeks. Tissue Doppler imaging was acquired in three apical views at rest, peak stress and 30 min recovery. Global function was assessed by ejection fraction (EF) using the Simpson's biplane method and mitral annular peak systolic velocity (MASV) averaged over six sites. Regional LV wall motion was assessed using a 12-segment model comprising the base and mid-level of six regional walls. Peak systolic tissue velocity (Vs), strain (S) and strain rate (SR) were calculated for each region from tissue Doppler velocity data averaged over three consecutive beats using an off-line workstation (EchoPac, GE Medical Systems). Results At rest, all parameters of both global and regional LV performance were unchanged after sitagliptin. At peak stress, the rate-pressure product attained was the same for both DSE studies but those after sitagliptin demonstrated significantly enhanced myocardial performance in both global (LVEF 69.9±6.5 vs 63.9±6.2%, p=0.001; MASV 12.69±3.0 vs 11.65±3.5 cm/s, p=0.003) and regional parameters (data for 12 segments; vs 10.8±4.4 vs 9.9±4.4 cm/s, p 50% stenosis than in those supplied by a non-obstructed artery. At 30 min recovery, ischaemic LV dysfunction did not occur after sitagliptin (LVEF 55.6±3.5 vs 49.7±2.6%, p=0.0001; MASV 5.55±1.2 vs 5.20±1.0 cm/s, p=0.003). Conclusion In patients with CAD and T2DM receiving OHT, DPP-4 inhibition by sitagliptin improves both global and regional myocardial performance during demand ischaemia (with greater benefit seen in ischaemic vs non-ischaemic segments), and mitigates post-ischaemic stunning.

Background Cardiac resynchronisation therapy (CRT) offers improved morbidity and mortality in patients with left ventricular dysfunction and intraventricular conduction delay. Up to 30% of CRT recipients fail to derive any clinical benefit. Left ventricular (LV) lead placement to the latest areas of activation (concordant LV lead) are associated with better clinical outcomes, greater LV reverse remodelling and lower mortality compared to a discordant lead position. However, there is little known about the effect of the RV lead position on CRT response. We investigated the relationship between the RV lead position and CRT response in patients with and without a concordant LV lead position. Methods In this prospective non randomised study, a total of 67 patients successfully underwent CRT (69±9 years, EF 23±7%, QRS 157±21 ms, and NYHA III/IV 63/4). The LV lead was positioned preferentially in a lateral or posterolateral vein. The RV lead was positioned according to operator preference to either the RV septum (RVS n=33) or RV apex (RVA, n=34). The latest site of activation was determined with 2D speckle tracking radial strain imaging (pre-implant), and the LV lead position from biplane fluoroscopy. Patients were regarded as having a concordant LV lead position if the LV lead was pacing the latest segment, and discordant if not. Response was defined as >15% reduction in LV end systolic volume (LVESV) at 6 months follow-up. Results The baseline characteristics between the RVS and RVA groups were similar. The mean reduction in LVESV from baseline at follow up in the RVS group was greater than in the RVA group (22.7% vs 13.5%, p=0.03). Similarly there was a higher rate of responders in the RVS group (69.7% vs 44.1%, p=0.03). In the concordant group (n=28), there were no differences between the RVS (n=17) and RVA (n=11) groups in the extent of LVESV reduction (29.1 vs 26.4%, p =0.91) and CRT response rates (71.3 vs 81.8%, p=0.22) In patients with a discordant LV lead, there were significant differences between the RVS (n=16) and RVA (n=23) groups in the extent of LVESV reduction (15.8 vs 4.7%, p=0.05) and in response rates (28.3 vs 12.8%, p Conclusion In patients with a concordant LV lead position, the RV lead position appears to make no difference in the response to CRT. However in patients with a discordant LV lead position, an RVS lead position is associated with better LV reverse remodelling. These findings suggest an important role for the RV lead position particularly in patients with a suboptimal LV lead position.

Introduction In selecting patients that may benefit from cardiac resynchronisation therapy (CRT), dyssynchrony assessment by echocardiography based only upon the timing of regional contraction is limited by being inherently independent of underlying myocardial contractility. We hypothesised that patient selection may be enhanced using a strain-based parameter based not only the timing of myocardial segmental motion, but also on the amplitude of contraction, a potential measure of contractile reserve. We assessed a combined early and late strain index (ELSI) to predict CRT response. Methods Speckle tracking radial strain was performed in 67 heart failure patients scheduled for CRT (age 69±9 years, ischaemic 56%, QRS 154±12 ms, NYHA III/IV—63/4, ejection fraction 23±7%). The ELSI was calculated as the sum for each of the 12 non apical segments of the difference in peak radial strain and strain at aortic valve closure. CRT response was defined as a >15% reduction from baseline in LV end systolic volume (LVESV) at 6 months. The predictive value of the ELSI was compared to previously reported dyssynchrony measures including the SD of time to peak myocardial longitudinal velocity of the 12 non apical segments (Ts SD12), the anteroseptal–posterior wall radial strain delay (AS-P delay) and the SD of time to peak radial strain of 12 segments (Rs-SD12). Results Response to CRT occurred in 38/67 (57%) patients. Significant differences were seen between responders and non responders in the ELSI (91±45 vs 27±14%, p Conclusion A combined early and late strain parameter based on both the timing and amplitude of segmental strain has a stronger predictive value in determining CRT response compared to widely reported dyssynchrony parameters based on segmental timing alone.

Category: Cardiac PacingPresentation Number: 1024-130Authors: Fakhar Z. Khan, Munmohan S. Virdee, Philip A. Read, Peter J. Pugh, Simon P. Fynn, David P. Dutka, Addenbrooke’s Hospital, Cambridge, United Kingdom, Papworth Hospital, Cambridge, United Kingdom Background: Left ventricular (LV) lead placement is an important determinant of response to cardiac resynchronization therapy (CRT). We aimed to investigate the relationship between LV lead proximity to the latest site of activation and CRT response.Methods: Sixty seven patients (age 69 +/- 8 yrs, NYHA III 92%, EF 23 +/- 7%, QRS width 154 +/- 9 ms) were assessed before and 3 months after CRT. The latest site of activation was determined with speckle tracking radial strain prior to CRT and the LV lead position defined by biplane fluoroscopy as either anterior, lateral, posterior or inferior. Patients were classified into one of three groups according to the relation of the LV lead position to the latest site: Concordant (C - lead position at latest site), Adjacent (A - within one segment) or Remote (R - 2 or more segments away from latest site). CRT response was defined as a >15% reduction in LV end systolic volume (LVESV) at 3 months.Results: The proportions of patients in group C, A and R were 42% (n=28), 31% (21) and 27% (18) respectively. The baseline characteristics between all three groups were similar. There were no differences in either the extent of LVESV reduction from baseline between groups C and A (23.1 vs 20.4%, p=0.49) or response rates (78.6 vs 61.9%, p=0.20). There were significant differences between groups C and R and groups A and R in both the extent of reduction of LVESV (C vs R: 23.1 vs 6.8%, p

The design of a modified cathode follower circuit which possesses an extremely linear response and a voltage gain of essentially unity is presented. Analysis of the circuit shows that, in principle, the harmonic distortion may be made arbitrarily small, and at the same time the voltage gain may be made arbitrarily close to unity. The modification is applied to a White cathode follower where the increase in linearity and gain is accompanied by a decrease in the output impedance. A practical modified White follower having a measured intermodulation distortion of 2×10−5%, a calculated voltage gain of (1−10−6), and a calculated output impedance of 2×10−3 ohms is given.

Improvements in a semi-empirical correlation of the energy and mass yield data for U236 fission are presented. The available mass, energy, and neutron emission data are correlated with each other within the accuracy of the input data. A simple model of the U236 fragments at scission is presented. This model, together with some experimental data, is used to predict the surface tension parameters of the fragments and kinetic energies of the fragment pairs. The calculated kinetic energies agree reasonably well with experiment. The surface tension parameters of the fragments show strong shell effects, as indicated in other studies. The shapes of the fragments at scission are estimated from the model. (Author)