Anna C. Kydd

Chronic Dipeptidyl Peptidase-4 Inhibition With Sitagliptin Is Associated With Sustained Protection Against Ischemic Left Ventricular Dysfunction in a Pilot Study of Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease

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<0.0001; mitral annular systolic velocity, 11.7±2.6 versus 10.9±2.3 cm/s; 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.

Prognostic Benefit of Optimum Left Ventricular Lead Position in Cardiac Resynchronization Therapy : Follow-Up of the TARGET Study Cohort (Targeted Left Ventricular Lead Placement to guide Cardiac Resynchronization Therapy)

OBJECTIVESnThis study was conducted to assess the impact of left ventricular (LV) lead position on longer-term survival after cardiac resynchronization therapy (CRT).nnnBACKGROUNDnAn optimal LV lead position in CRT is associated with improved clinical outcome. A strategy of speckle-tracking echocardiography can be used to guide the implanter to the site of latest activation and away from segments of low strain amplitude (scar). Long-term, prospective survival data according to LV lead position in CRT are limited.nnnMETHODSnData from a follow-up registry of 250 consecutive patients receiving CRT between June 2008 and July 2010 were studied. The study population comprised patients recruited to the derivation group and the subsequent TARGET (Targeted Left Ventricular Lead Placement to guide Cardiac Resynchronization Therapy) randomized, controlled trial. Final LV lead position was described, in relation to the pacing site determined by pre-procedure speckle-tracking echocardiography, as optimal (concordant/adjacent) or suboptimal (remote). All-cause mortality was recorded at follow-up.nnnRESULTSnAn optimal LV lead position (n = 202) conferred LV remodeling response superior to that of a suboptimal lead position (change in LV end-systolic volume: -24 ± 15% vs. -12 ± 17% [p < 0.001]; change in ejection fraction: +7 ± 8% vs. +4 ± 7% [p = 0.02]). During long-term follow-up (median: 39 months; range: <1 to 61 months), an optimal LV lead position was associated with improved survival (log-rank p = 0.003). A suboptimal LV lead placement independently predicted all-cause mortality (hazard ratio: 1.8; p = 0.024).nnnCONCLUSIONSnAn optimal LV lead position at the site of latest mechanical activation, avoiding low strain amplitude (scar), was associated with superior CRT response and improved survival that persisted during follow-up.

Radial Strain Delay Based on Segmental Timing and Strain Amplitude Predicts Left Ventricular Reverse Remodeling and Survival After Cardiac Resynchronization Therapy

Background— Dyssynchrony assessment based on the timing of regional contraction is inherently independent of underlying myocardial contractility. We tested the hypothesis that patient selection for cardiac resynchronization therapy (CRT) would be enhanced using a parameter derived from the net radial strain delay (RSD) for the 12 basal and mid–left ventricular segments (calculated radial strain delay RSD [RSDc]), based on not only timing but also amplitude of segmental strain. Methods and Results— Echocardiographic data were analyzed in 240 patients with symptomatic heart failure undergoing CRT (New York Heart Association class III/IV; QRS >120 milliseconds; ejection fraction, 23±7%). RSDc was calculated as the sum of difference between peak radial strain and radial strain at aortic valve closure before CRT implantation. CRT response was defined as >15% reduction in left ventricular end-systolic volume at 6 months. In a derivation group (n=102), RSDc was higher in responders compared with nonresponders (74±39% versus 29±15%; P<0.001) and related to the change in left ventricular end-systolic volume (r=−0.53; P<0.001). RSDc >40% predicted remodeling (sensitivity, 87%; specificity, 88%). In the validation group (n=108), RSDc similarly predicted response (sensitivity, 89%; specificity, 84%). Survival at long-term follow-up was greater in patients with RSDc >40% (P<0.0001). Conclusions— RSDc, based on both the timing and the amplitude of segmental strain, has a strong predictive value for CRT remodeling response and long-term survival.

Atrial Function as a Guide to Timing of Intervention in Mitral Valve Prolapse With Mitral Regurgitation

OBJECTIVESnThe 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).nnnBACKGROUNDnTiming of surgery for MVP remains challenging. We hypothesized that assessment of LA function may provide diagnostic utility in these patients.nnnMETHODSnWe studied 192 consecutive patients in sinus rhythm with MVP, classified into 3 groups: moderate or less MR (MOD group, nxa0= 54); severe MR without surgical indication (SEV group, nxa0= 52); and severe MR with ≥1 surgical indication (SURG group, nxa0= 86). Comparison was made with 50 control patients. Using 2D speckle imaging, average peak contractile, conduit, and reservoir atrial strain was recorded. Using Simpsons method we recorded maximal left atrial volume (LAVmax) and minimal leftxa0atrial volume (LAVmin), from which the total left atrial emptying fraction (TLAEF) was derived: (LAVmax-LAVmin)/LAVmaxxa0× 100%.nnnRESULTSnTLAEF was similar in the MOD and control groups (61% vs. 57%; pxa0= 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%; pxa0= 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; pxa0= 0.028), and contractile strain (OR: 0.86; pxa0= 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).nnnCONCLUSIONSnWe 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.

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

AbstractBackgroundEnhancement of myocardial nglucose 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).MethodsIn 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 1.2xa0pmol/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.ResultsIn study 1, the HHC (compared with control) increased glucose (13.0xa0±xa01.9 versus 4.8xa0±xa00.5xa0mmol/l, pxa0<xa00.0001) and insulin (1,212xa0±xa0514 versus 114xa0±xa047xa0pmol/l, pxa0=xa00.01) concentrations, and reduced FFA levels (249xa0±xa0175 versus 1,001xa0±xa0333xa0μmol/l, pxa0<xa00.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5xa0±xa05.0 versus 71.3xa0±xa04.3%, pxa0=xa00.004) and regional (peak systolic strain −18.1xa0±xa06.6 versus −15.5xa0±xa05.4%, pxa0<xa00.0001) myocardial performance at peak stress and at 30xa0min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia.ConclusionsIn 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

Development of a multiparametric score to predict left ventricular remodelling and prognosis after cardiac resynchronization therapy

Optimal delivery of CRT requires appropriate patient selection and device implantation. Echocardiographic predictors of CRT response individually appear to enhance patient selection, but do not fully reflect the complex underlying myocardial dysfunction. We hypothesized that a multiparametric approach would offer greater predictive value and sought to derive a score incorporating baseline characteristics including: dyssynchrony, LV function, and LV lead position.

119 DEFINING PATENT FORAMEN OVALE MORPHOLOGY USING THREE-DIMENSIONAL TRANSOESOPHAGEAL ECHOCARDIOGRAPHY AND RELATIONSHIP TO SHUNT SIZE

Background Three dimensional transoesophageal echocardiography (3D TOE) has allowed better understanding of atrial septal anatomy and patent foramen ovale (PFO) morphology. Anatomical variations seen in patients undergoing transcatheter device closure may influence device choice and procedural success. Currently there is no standardised approach to 3D TOE imaging of a PFO. The aim of this study was to utilise a 3D imaging protocol to describe/quantify PFO morphological features of clinically important PFOs and relate our findings to shunt size. Methods We examined 3D TOE images of the atrial septum in consecutive patients with otherwise structurally normal hearts undergoing TOE assessment prior to PFO closure. Datasets were obtained using Philips iE33 and then analysed offline (QLab 3DQ, Philips Healthcare). Linear measurements recorded included: tunnel dimensions, fossa ovalis dimensions, and septal sway. Other characteristics assessed included left atrial opening morphology, right atrial anatomy and presence of an atrial septal aneurysm (>10u2005mm septal excursion from the midline). Morphological features were categorised as either simple or complex. Complex defects were those with one or more of the following: long tunnel length (>8u2005mm), multiple openings into the left atrium, atrial septal aneurysm, hybrid defect (additional small defect(s) in fossa ovalis), thick secundum septum (>8u2005mm), Eustachian ridge (ER), Eustachian valve or Chiari network. The size of right-to-left shunt either at rest or with Valslava manoeuvre was assessed by transthoracic contrast echocardiography and graded according to the number of bubbles seen in a single still frame in the left atrium as: small-to-moderate (<25 bubbles), large (25–50 bubbles) and very large (>50 bubbles). Results 3D datasets were available for analysis in 73 patients. Mean age of the population was 47±12.7u2005years. and 62% were male. The most frequent indication for PFO closure was stroke (48%). Linear dimensions recorded from 3D datasets are presented (table). Left atrial opening was categorised as high, opening onto the left atrial roof, in 18% of patients and presence of multiple left atrial openings was observed in 8%. Atrial septal aneurysm was present in 12%. A prominent Eustachean ridge was seen in 78% patients and was positioned high on fossa ovalis in 32% cases. The majority of patients (88%) had one or more complex morphological features. There was no clear association observed between shunt size and size of PFO. Conclusions 3D transoesophageal echocardiography allows a practical, qualitative, and quantitative assessment of PFO morphology. In our cohort of patients a variety of complex anatomical features are demonstrated. Shunt size did not correlate with PFO dimensions. Figure 1

Optimizing benefit from CRT: role of speckle tracking echocardiography, the importance of LV lead position and scar.

Cardiac resynchronization therapy is demonstrated to be effective in patients with advanced heart failure. Correcting mechanical dyssynchrony is proposed as the predominant mechanism of response. Achieving optimum left ventricular lead position, at the site of maximal mechanical dyssynchrony but away from transmural scar, is identified as one of the main determinants of both symptomatic and prognostic benefit. Strategies employing multimodality cardiac imaging techniques have been used to identify this optimal pacing site, in addition to any potential anatomical limitations to successful implantation. Speckle tracking echocardiography offers prospective lead targeting, incorporating pathophysiological determinants of cardiac resynchronization therapy response. This review considers the key factors in defining optimum left ventricular lead location, emphasizing the role of myocardial scar. The use of speckle tracking echocardiography and the potential for this technique to be incorporated into routine practice to guide the implant strategy in an individual patient is discussed.

149 ATRIAL FUNCTION AS A GUIDE TO INTERVENTION IN MITRAL VALVE PROLAPSE

Introduction Timing of surgery for patients with mitral valve prolapse and severe mitral regurgitation (MR) remains problematic. In the absence of symptoms, current guidelines emphasise the importance of left ventricular (LV) size and function, pulmonary artery pressures and the development of AF in helping to determine the need for intervention in these individuals. Little is known regarding the impact of chronic mitral regurgitation on atrial physiology, nor has the association between atrial function and the timing of mitral valve surgery been investigated. Methods We included consecutive patients reviewed in our specialist valve service. All underwent clinical and echocardiographic assessment. We divided patients according to the severity of MR and whether they had accepted indications for surgery. Echo data recorded included: LV dimensions, LV function, pulmonary artery pressure, and MR severity using the PISA method. Additionally, we measured maximal and minimal left atrial volume (LAV) using the Simpsons biplane method, from which we derived the atrial volume change (AVC), defined as: Finally, using 2D speckle imaging from the apical 2- and 4-chamber views, we recorded the three components of atrial strain: peak negative (contractile), peak positive (conduit), and total (reservoir). Results We included 160 patients, divided into 4 groups: severe MR with an indication for surgery (surgical; n=77); severe MR with no surgical indication (non-surgical; n=26); patients with moderate or less MR (moderate; n=32) and 25 controls. AVC correlated strongly to total atrial strain (r=0.86; p<0.0001). AVC was similar in the control, moderate and non-surgical groups, but was significantly lower in the surgical cohort (see Graph 1: AVC surgical 34±10%; non-surgical 55±9%; moderate 57±11%; controls 62±6%; p<0.001 surgical vs other groups), with a similar pattern seen for total atrial strain. The contractile component of atrial function was highest in controls, was reduced similarly in moderate and non-surgical patients, and was reduced further in the surgical group (Graph 2: negative strain surgical −4.5±5.2; non-surgical −14.8±8.0; moderate −14.6±9.3; controls −20.8±5.6). Receiver-operator curve analysis demonstrated that an AVC of <50% is 97% sensitive and 87% specific for severe MR requiring surgical intervention. Conclusions The atrium adapts to chronic mitral regurgitation by increasing conduit function at the expense of the contractile component of atrial strain. With ongoing MR the atrium loses overall reservoir capacity and develops a reduced AVC. Loss of normal atrial volume change accurately predicts the need for surgical intervention in these patients and may be useful in guiding surgery in asymptomatic individuals. Figure 1 Figure 2

001 OPTIMISING OUTCOMES IN CARDIAC RESYNCHRONISATION THERAPY (CRT): GUIDING LEFT VENTRICULAR LEAD POSITION AND DEFINING MECHANISM OF RESPONSE

Background Cardiac resynchronisation therapy (CRT) is an effective treatment for advanced heart failure. However, up to one-third of patients fail to exhibit a clinical response. We have recently demonstrated that directing the left ventricular (LV) lead to the region of latest mechanical activation, in viable myocardium, using speckle tracking radial strain echocardiography enhances clinical response and improves prognosis. The correction of mechanical dyssynchrony is proposed as one of the major mechanisms underlying the effect of CRT. A novel radial strain delay parameter derived from the net radial strain delay for the 12 basal and mid left ventricular (LV) segments (RSDc), based not only on timing but also amplitude of segmental strain may enhance understanding of CRT remodelling response. We present 4u2005year follow-up data according to LV lead location and relate the use of RSDc to LV remodelling response. Methods We obtained follow-up mortality data for all 250 patients who received CRT between June 2008–June 2010 and were enrolled in the TARGET study or derivation group. The optimum site for the LV lead was defined using speckle tracking radial strain at baseline, prior to CRT. Final LV lead position was determined by fluoroscopy as concordant (CON, optimal segment), adjacent (ADJ, within one segment of optimal site) or remote (REM, >1 segment from optimal site). Response to CRT was defined as ≥15% reduction in end systolic volume. RSDc was calculated at baseline and 6u2005months following CRT, as the difference between peak and end-systolic radial strain (%) summed for each of the 12 non-apical segments. Results In the 250 patients (median age 72u2005years; 88% NYHA class 3; QRS 157u2005ms; EF 23.3%; 53% ischaemic aetiology) lead position was CON 55%, ADJ 25% and REM 19%. The CON or ADJ LV lead position conferred a more favourable prognosis than REM up to maximum of 4u2005years follow-up (p=0.001, see figure). Patients with a concordant or adjacent LV lead demonstrated greater remodelling response than patients with a remote LV lead (LV end systolic volume reduction −24.3±15 vs −12.17±17). CRT responders had a higher baseline RSDc than non-responders (79%±33 vs 32%±20 p<0.001). There was a greater reduction in RSDc at 6u2005months in responders, compared with non-responders (−40%±35 vs −3.3%±26 p=0.001). Conclusions Speckle tracking echocardiography can be used to define the optimum placement of the LV lead during CRT and to predict response. Optimum LV lead placement confers a survival benefit whereas pacing inappropriately appears to increase mortality risk. RSDc may provide a valuable tool for further understanding mechanisms of CRT response. Figure 1