Fakhar Z. Khan

Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial.

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 to Guide 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).

DPP-4 Inhibition by Sitagliptin Improves the Myocardial Response to Dobutamine Stress and Mitigates Stunning in a Pilot Study of Patients With Coronary Artery Disease

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.

A Pilot Study to Assess Whether Glucagon-Like Peptide-1 Protects the Heart From Ischemic Dysfunction and Attenuates Stunning After Coronary Balloon Occlusion in Humans

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/dtmax from baseline, −1.6% versus −12.2%; P=0.02) and reduced the LV dysfunction after the second balloon occlusion (delta dP/dtmax, −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.

Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease

Background 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. Objective 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). Design Randomised crossover study. Patients and Interventions 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. Main outcome measurements Global and regional wall LV function assessed using tissue Doppler imaging at rest, peak stress and 30 min into recovery. Results 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%, p<0.0001; 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. Conclusion Intravenous infusion of GLP-1 protects the heart from ischaemic LV dysfunction induced by dobutamine stress in patients with CAD. Clinical trial registration URL: http://isrctn.org. Registration number ISRCTN 69686930.

A Comprehensive Study of Clinical, Biochemical, Radiological, Vascular, Cardiac, and Sleep Parameters in an Unselected Cohort of Patients With Acromegaly Undergoing Presurgical Somatostatin Receptor Ligand Therapy

CONTEXT Attainment of safe GH and IGF-1 levels is a central goal of acromegaly management. OBJECTIVE The aim of this study was to determine the extent to which reductions in GH and IGF-1 concentrations correlate with amelioration of radiological, metabolic, vascular, cardiac, and respiratory sequelae in a single unselected patient cohort. STUDY DESIGN This was a prospective, within-subject comparison in 30 patients with newly diagnosed acromegaly (15 women and 15 men: mean age, 54.3 years; range, 23-78 years) before and after 24 weeks of lanreotide Autogel (ATG) therapy. RESULTS Reductions in GH and IGF-1 concentrations and tumor volume were observed in all but 2 patients (median changes [Δ]: GH, -6.88 μg/L [interquartile range -16.78 to -3.32, P = .000001]; IGF-1, -1.95 × upper limit of normal [-3.06 to -1.12, P = .000002]; and pituitary tumor volume, -256 mm(3) [-558 to -72.5, P = .0002]). However, apnea/hypopnea index scores showed highly variable responses (P = .11), which were independent of ΔGH or ΔIGF-1, but moderately correlated with Δweight (R(2) = 0.42, P = .0001). Although systolic (P = .33) and diastolic (P = .76) blood pressure were unchanged, improvements in arterial stiffness (aortic pulse wave velocity, -0.4 m/s [-1.2 to +0.2, P = .046]) and endothelial function (flow mediated dilatation, +1.73% [-0.32 to +6.19, P = .0013]) were observed. Left ventricular mass index regressed in men (-11.8 g/cm(2) [-26.6 to -1.75], P = .019) but not in women (P = .98). Vascular and cardiac changes were independent of ΔGH or ΔIGF-1 and also showed considerable interindividual variation. Metabolic parameters were largely unchanged. CONCLUSIONS Presurgical ATG therapy lowers GH and IGF-1 concentrations, induces tumor shrinkage, and ameliorates/reverses cardiac, vascular, and sleep complications in many patients with acromegaly. However, responses vary considerably between individuals, and attainment of biochemical control cannot be assumed to equate to universal complication control.

The accuracy of central SBP determined from the second systolic peak of the peripheral pressure waveform.

Background Recent evidence suggests that central aortic blood pressure may be a better predictor of cardiovascular risk than peripheral blood pressure. The central SBP (cSBP) can be estimated from the late systolic shoulder of the radial pulse waveform. We compared the second systolic peak of the radial waveform (pSBP2) with the central systolic pressure derived by a generalized transfer function in a large cohort, across a wide age range, of patients from the Anglo-Cardiff Collaborative Trial. We also compared pSBP2 with the true cSBP measured by cardiac catheterization [invasively measured cSBP (cSBPi)]. Methods Noninvasive measurements were made by applanation tonometry using the SphygmoCor device. The aortic pressure waveform was derived from the radial waveform using a validated transfer function. Invasive measures of cSBPi were carried out in a group of 38 patients undergoing diagnostic cardiac angiography, and radial artery pressure waveforms were simultaneously recorded using the SphygmoCor device. Results Overall, there was a strong correlation (r = 0.99, P < 0.001) and good agreement between pSBP2 and the derived cSBP (mean difference ± SD 1 ± 4 mmHg). However, there was a systematic bias with a greater difference between these measures at lower average pressures. There was also a strong correlation and good agreement between the invasively measured cSBPi and pSBP2 (r = 0.92, P < 0.001, mean difference 2 ± 6 mmHg). Conclusion The second systolic shoulder of the peripheral pressure waveform approximates the cSBP in a large cohort of patients across a wide age range, but this may be inaccurate at low SBP values.

Left ventricular lead placement in cardiac resynchronization therapy: where and how?

Cardiac resynchronization therapy (CRT) offers proven benefit to patients with refractory symptomatic chronic heart failure (New York Heart Association Class III or IV), severe left ventricular (LV) systolic dysfunction (LV ejection fraction <35%), and LV dyssynchrony (QRS width >120 ms). Cardiac resynchronization therapy has the potential to improve survival and functional capacity, reduce hospital admissions, and promote LV reverse remodelling. Although difficult to truly evaluate, up to 30% of patients do not attain symptomatic benefit. Factors associated with a poor outcome include inappropriate patient selection, inadequate device programming, presence of myocardial scar, and suboptimal LV lead placement. Left ventricular dyssynchrony is an important determinant of CRT response, although at present no reliable single measure to identify patients beyond QRS width has been identified. In this review, we discuss the effect of LV lead placement to pace the region of maximal dyssynchrony, the impact of total scar burden on response, and the relationship between LV lead position and localized scar. Consideration is also given to prospectively defining placement of the LV lead including surgical epicardial lead positioning.

Effect of Low-Amplitude Two-Dimensional Radial Strain at Left Ventricular Pacing Sites on Response to Cardiac Resynchronization Therapy

BACKGROUND 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. METHODS 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. RESULTS In the derivation group, a derived cutoff for radial strain amplitude of <9.8% 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. CONCLUSION LV lead placement over segments with two-dimensional radial strain amplitudes <9.8% is associated with poor outcomes of CRT.

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.

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)

OBJECTIVES This study was conducted to assess the impact of left ventricular (LV) lead position on longer-term survival after cardiac resynchronization therapy (CRT). BACKGROUND An 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. METHODS Data 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. RESULTS An 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). CONCLUSIONS An 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.