Pacing therapy for atrioventricular dromotropathy: a combined computational-experimental-clinical study.

AIMS: Investigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational-experimental-clinical study. METHODS AND RESULTS: Computer simulations were performed in the CircAdapt model of the normal and failing human heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical study, left ventricular (LV) pressure and volume were measured in 22 heart failure (HF) patients (LV ejection fraction <35%) with prolonged PR interval (>230 ms) and narrow or non-left bundle branch block QRS complex. Computer simulations and animal studies in normal hearts showed that restoring of AV-coupling with unchanged ventricular activation sequence significantly increased LV filling, mean arterial pressure, and cardiac output by 10-15%. In computer simulations of failing hearts and in HF patients, reducing PR interval by biventricular (BiV) pacing (patients: from 300 ± 61 to 137 ± 30 ms) resulted in significant increases in LV stroke volume and stroke work (patients: 34 ± 40% and 26 ± 31%, respectively). However, worsening of ventricular dyssynchrony by using right ventricular (RV) pacing abrogated the benefit of restoring AV-coupling. In model simulations, animals and patients, the increase of LV filling and associated improvement of LV pump function coincided with both larger mitral inflow (E- and A-wave area) and reduction of diastolic mitral regurgitation. CONCLUSION: Restoration of AV-coupling by BiV pacing in normal and failing hearts with prolonged AV conduction leads to considerable haemodynamic improvement. These results indicate that BiV or physiological pacing, but not RV pacing, may improve cardiac function in patients with HF and prolonged PR interval.

Interim Analysis of the Phase II Study: Noninferiority Study of Doxorubicin with Upfront Dexrazoxane plus Olaratumab for Advanced or Metastatic Soft-Tissue Sarcoma.

PURPOSE: To report the interim analysis of the phase II single-arm noninferiority trial, testing the upfront use of dexrazoxane with doxorubicin on progression-free survival (PFS) and cardiac function in soft-tissue sarcoma (STS). PATIENTS AND METHODS: Patients with metastatic or unresectable STS who were candidates for first-line treatment with doxorubicin were deemed eligible. An interim analysis was initiated after 33 of 65 patients were enrolled. Using the historical control of 4.6 months PFS for doxorubicin in the front-line setting, we tested whether the addition of dexrazoxane affected the efficacy of doxorubicin in STS. The study was powered so that a decrease of PFS to 3.7 months would be considered noninferior. Secondary aims included cardiac-related mortality, incidence of heart failure/cardiomyopathy, and expansion of cardiac monitoring parameters including three-dimensional echocardiography. Patients were allowed to continue on doxorubicin beyond 600 mg/m2 if they were deriving benefit and were not demonstrating evidence of symptomatic cardiac dysfunction. RESULTS: At interim analysis, upfront use of dexrazoxane with doxorubicin demonstrated a PFS of 8.4 months (95% confidence interval: 5.1-11.2 months). Only 3 patients were removed from study for cardiotoxicity, all on > 600 mg/m2 doxorubicin. No patients required cardiac hospitalization or had new, persistent cardiac dysfunction with left ventricular ejection fraction remaining below 50%. The median administered doxorubicin dose was 450 mg/m2 (interquartile range, 300-750 mg/m2). CONCLUSIONS: At interim analysis, dexrazoxane did not reduce PFS in patients with STS treated with doxorubicin. Involvement of cardio-oncologists is beneficial for the monitoring and safe use of high-dose anthracyclines in STS.See related commentary by Benjamin and Minotti, p. 3809.

Prognostic Utility of Echocardiographic Atrial and Ventricular Strain Imaging in Patients With Cardiac Amyloidosis.

OBJECTIVES: The prognostic value of echocardiographic atrial and ventricular strain imaging in patients with biopsy-proven cardiac amyloidosis was assessed. BACKGROUND: Although left ventricular global longitudinal strain (GLS) is known to be predictive of outcome, the additive prognostic value of left (LA), right atrial (RA), and right ventricular (RV) strain is unclear. METHODS: One hundred thirty-six patients with cardiac amyloidosis and available follow-up data were studied by endomyocardial biopsy, noncardiac biopsy with supportive cardiac imaging, or autopsy confirmation. One hundred nine patients (80%) had light-chain, 23 (17%) had transthyretin, and 4 (3%) had amyloid A type cardiac amyloidosis. GLS, RV free wall strain, peak longitudinal LA strain, and peak longitudinal RA strain were measured from apical views. Clinical and routine echocardiographic data were compared. All-cause mortality was followed (median 5 years). RESULTS: Strain data were feasible for GLS in 127 (93%), LA strain in 119 (88%), RA strain in 117 (86%), and RV strain in 102 (75%). Strain values from all 4 chambers were significantly associated with survival. Hazard ratio (HR) and 95% confidence interval (CI) for low median strain values were as follows: GLS, HR: 2.3; 95% CI: 1.3 to 3.8 (p < 0.01); LA strain, HR: 7.5; 95% CI: 3.8 to 14.7 (p < 0.001); RA strain, HR: 3.5; 95% CI: 2.0 to 6.2 (p < 0.001); and RV free wall strain, HR: 2.8; 95% CI: 1.5 to 5.1 (p < 0.001). Peak longitudinal LA strain and RV strain remained independently associated with survival in multivariable analysis. Peak LA strain had the strongest association with survival (p < 0.001), and LA strain combined with GLS and RV free wall strain had the highest prognostic value (p < 0.001). CONCLUSIONS: Strain data from all 4 chambers had important prognostic associations with survival in patients with biopsy-confirmed cardiac amyloidosis. Peak longitudinal LA strain was particularly associated with prognosis. Atrial and ventricular strain have promise for clinical utility.

The Left and Right Ventricles Respond Differently to Variation of Pacing Delays in Cardiac Resynchronization Therapy: A Combined Experimental- Computational Approach.

Introduction: Timing of atrial, right (RV), and left ventricular (LV) stimulation in cardiac resynchronization therapy (CRT) is known to affect electrical activation and pump function of the LV. In this study, we used computer simulations, with input from animal experiments, to investigate the effect of varying pacing delays on both LV and RV electrical dyssynchrony and contractile function. Methods: A pacing protocol was performed in dogs with atrioventricular block (N = 6), using 100 different combinations of atrial (A)-LV and A-RV pacing delays. Regional LV and RV electrical activation times were measured using 112 electrodes and LV and RV pressures were measured with catheter-tip micromanometers. Contractile response to a pacing delay was defined as relative change of the maximum rate of LV and RV pressure rise (dP/dtmax) compared to RV pacing with an A-RV delay of 125 ms. The pacing protocol was simulated in the CircAdapt model of cardiovascular system dynamics, using the experimentally acquired electrical mapping data as input. Results: Ventricular electrical activation changed with changes in the amount of LV or RV pre-excitation. The resulting changes in dP/dtmax differed markedly between the LV and RV. Pacing the LV 10-50 ms before the RV led to the largest increases in LV dP/dtmax. In contrast, RV dP/dtmax was highest with RV pre-excitation and decreased up to 33% with LV pre-excitation. These opposite patterns of changes in RV and LV dP/dtmax were reproduced by the simulations. The simulations extended these observations by showing that changes in steady-state biventricular cardiac output differed from changes in both LV and RV dP/dtmax. The model allowed to explain the discrepant changes in dP/dtmax and cardiac output by coupling between atria and ventricles as well as between the ventricles. Conclusion: The LV and the RV respond in a opposite manner to variation in the amount of LV or RV pre-excitation. Computer simulations capture LV and RV behavior during pacing delay variation and may be used in the design of new CRT optimization studies.

Distinct lipid droplet characteristics and distribution unmask the apparent contradiction of the athlete's paradox.

OBJECTIVE: Intramyocellular lipid (IMCL) storage negatively associates with insulin resistance, albeit not in endurance-trained athletes. We investigated the putative contribution of lipid droplet (LD) morphology and subcellular localization to the so-called athlete's paradox. METHODS: We performed quantitative immunofluorescent confocal imaging of muscle biopsy sections from endurance Trained, Lean sedentary, Obese, and Type 2 diabetes (T2DM) participants (n = 8/group). T2DM patients and Trained individuals were matched for IMCL content. Furthermore we performed this analysis in biopsies of T2DM patients before and after a 12-week exercise program (n = 8). RESULTS: We found marked differences in lipid storage morphology between trained subjects and T2DM: the latter group mainly store lipid in larger LDs in the subsarcolemmal (SS) region of type II fibers, whereas Trained store lipid in a higher number of LDs in the intramyofibrillar (IMF) region of type I fibers. In addition, a twelve-week combined endurance and strength exercise program resulted in a LD phenotype shift in T2DM patients partly towards an 'athlete-like' phenotype, accompanied by improved insulin sensitivity. Proteins involved in LD turnover were also more abundant in Trained than in T2DM and partly changed in an 'athlete-like' fashion in T2DM patients upon exercise training. CONCLUSIONS: Our findings provide a physiological explanation for the athlete's paradox and reveal LD morphology and distribution as a major determinant of skeletal muscle insulin sensitivity.

Response to cardiac resynchronization therapy is determined by intrinsic electrical substrate rather than by its modification.

BACKGROUND: Electrocardiographic mapping (ECM) expresses electrical substrate through magnitude and direction of the activation delay vector (ADV). We investigated to what extent the response to cardiac resynchronization therapy (CRT) is determined by baseline ADV and by ADV modification through CRT and optimization of left ventricular (LV) pacing site. METHODS: ECM was performed in 79 heart failure patients (4 RBBB, 12 QRS < 120 ms, 23 non-specific conduction delay [NICD] and 40 left bundle branch block [LBBB]). 67 patients (QRS ≥ 120 ms) underwent CRT implantation and in 26 patients multiple LV pacing site optimization was performed. ADV was calculated from locations/depolarization times of 2000 virtual epicardial electrodes derived from ECM. Acute response was defined as ≥10% LVdP/dtmax increase, chronic response by composite clinical score at 6 months. RESULTS: During intrinsic conduction, ADV direction was similar in patients with QRS < 120 ms, NICD and LBBB, pointing towards the LV free wall, while ADV magnitude was larger in LBBB (117 ±â€¯25 ms) than in NICD (70 ±â€¯29 ms, P < 0.05) and QRS < 120 ms (52 ±â€¯14 ms, P < 0.05). Intrinsic ADV accurately predicted the acute (AUC = 0.93) and chronic (AUC = 0.90) response to CRT. ADV change by CRT only moderately predicted response (highest AUC = 0.76). LV pacing site optimization had limited effects: +3 ±â€¯4% LVdP/dtmax when compared to conventional basolateral LV pacing. CONCLUSION: The baseline electrical substrate, adequately measured by ADV amplitude, strongly determines acute and chronic CRT response, while the extent of its modification by conventional CRT or by varying LV pacing sites has limited effects.

Electrical Substrates Driving Response to Cardiac Resynchronization Therapy: A Combined Clinical-Computational Evaluation.

BACKGROUND: The predictive value of interventricular versus intraventricular dyssynchrony for response to cardiac resynchronization therapy (CRT) remains unclear. We investigated the relative importance of both ventricular electrical substrate components for left ventricular (LV) hemodynamic function. METHODS AND RESULTS: First, we used the cardiovascular computational model CircAdapt to characterize the isolated effect of intrinsic interventricular and intraventricular activation on CRT response (ΔLVdP/dtmax). Simulated ΔLVdP/dtmax (range: 1.3%-26.5%) increased considerably with increasing interventricular dyssynchrony. In contrast, the isolated effect of intraventricular dyssynchrony in either the LV or right ventricle was limited (ΔLVdP/dtmax range: 12.3%-18.3% and 14.1%-15.7%, respectively). Effects of activation during biventricular pacing on ΔLVdP/dtmax were small. Second, electrocardiographic imaging-derived activation characteristics of 51 CRT candidates were used to personalize ventricular activation in CircAdapt. The individualized models were subsequently used to assess the accuracy of ΔLVdP/dtmax prediction based on the electrical data. The model-predicted ΔLVdP/dtmax was close to the actual value in patients with left bundle branch block (measured-simulated: 2.7±9.0%) when only intrinsic interventricular dyssynchrony was personalized. Among patients without left bundle branch block, ΔLVdP/dtmax was systematically overpredicted by CircAdapt (measured-simulated: 9.2±7.1%). Adding intraventricular activation to the model did not improve the accuracy of the response prediction. CONCLUSIONS: Computer simulations revealed that intrinsic interventricular dyssynchrony is the dominant component of the electrical substrate driving the response to CRT. Intrinsic intraventricular dyssynchrony and any dyssynchrony during biventricular pacing play a minor role in this respect. This may facilitate patient-specific modeling for prediction of CRT response. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01270646.

Cardiac electrical dyssynchrony is accurately detected by noninvasive electrocardiographic imaging.

BACKGROUND: Poor identification of electrical dyssynchrony is postulated to be a major factor contributing to the low success rate for cardiac resynchronization therapy. OBJECTIVE: The purpose of this study was to evaluate the sensitivity of body surface mapping and electrocardiographic imaging (ECGi) to detect electrical dyssynchrony noninvasively. METHODS: Langendorff-perfused pig hearts (n = 11) were suspended in a human torso-shaped tank, with left bundle branch block (LBBB) induced through ablation. Recordings were taken simultaneously from a 108-electrode epicardial sock and 128 electrodes embedded in the tank surface during sinus rhythm and ventricular pacing. Computed tomography provided electrode and heart positions in the tank. Epicardial unipolar electrograms were reconstructed from torso potentials using ECGi. Dyssynchrony markers from torso potentials (eg, QRS duration) or ECGi (total activation time, interventricular delay [D-LR], and intraventricular markers) were correlated with those recorded from the sock. RESULTS: LBBB was induced (n = 8), and sock-derived activation maps demonstrated interventricular dyssynchrony (D-LR and total activation time) in all cases (P < .05) and intraventricular dyssynchrony for complete LBBB (P < .05) compared to normal sinus rhythm. Only D-LR returned to normal with biventricular pacing (P = .1). Torso markers increased with large degrees of dyssynchrony, and no reduction was seen during biventricular pacing (P > .05). Although ECGi-derived markers were significantly lower than recorded (P < .05), there was a significant strong linear relationship between ECGi and recorded values. ECGi correctly diagnosed electrical dyssynchrony and interventricular resynchronization in all cases. The latest site of activation was identified to 9.1 ± 0.6 mm by ECGi. CONCLUSION: ECGi reliably and accurately detects electrical dyssynchrony, resynchronization by biventricular pacing, and the site of latest activation, providing more information than do body surface potentials.

Dissociation of intramyocellular lipid storage and insulin resistance in trained athletes and type 2 diabetes patients; involvement of perilipin 5?

KEY POINTS: Intramyocellular lipid storage is negatively associated with insulin sensitivity. However, endurance trained athletes and type 2 diabetes mellitus (T2DM) patients store similar amounts of lipids in their muscle; the so-called athlete's paradox. Compared to T2DM, trained athletes possess higher levels of perilipin 5 (PLIN5), a lipid droplet (LD) coating protein. We examined whether coating LD with PLIN5 affects the pattern of muscle lipid (LD size and number) in relation to the athlete's paradox. Despite differences in PLIN5 protein content, we observed that coating the LD with PLIN5 could not explain the observed differences in LD size and number between athletes and T2DM. PLIN5-coated LDs were positively associated with oxidative capacity but not with insulin sensitivity. We conclude that coating of LDs with PLIN5 cannot causally explain the athlete's paradox. ABSTRACT: Intramyocellular lipid (IMCL) hampers insulin sensitivity, albeit not in endurance-trained athletes (Trained). Compared to type 2 diabetes mellitus (T2DM) patients, Trained subjects have high levels of perilipin 5 (PLIN5). In the present study, we tested whether the fraction of PLIN5-coated lipid droplets (LDs) is a determinant of skeletal muscle insulin sensitivity and contributes to the athlete's paradox. Muscle biopsies were taken from eight Trained, Lean sedentary, Obese and T2DM subjects. Trained, Obese and T2DM subjects were matched for total IMCL content. Confocal images were analysed for lipid area fraction, LD size and number and PLIN5+ and PLIN5- LDs were measured. A stepwise linear regression was performed to identify factors explaining observed variance in glucose infusion rate (GIR). Trained and T2DM subjects stored IMCL differently; Trained subjects had a higher number of LDs compared to T2DM subjects (0.037 ± 0.004 µm-2 vs. 0.023 ± 0.003 µm-2 , P = 0.024) that were non-significantly smaller (0.27 ± 0.01 µm2 vs. 0.32 ± 0.02 µm2 , P = 0.197, Trained vs. T2DM). Even though total PLIN5 protein content was almost double in Trained vs. T2DM subjects (1.65 ± 0.21 AU vs. 0.89 ± 0.09 AU, P = 0.004), PLIN5 coating did not affect LD number or size significantly. Of the observed variance in GIR, the largest fraction by far (70.2%) was explained by maximal oxygen uptake. Adding PLIN5 protein content or PLIN5+ LDs increased the explained variance in GIR (74.7% and 80.7% for PLIN5 protein content and PLIN5+ LDs, respectively). Thus, the putative relationship between PLIN5 and insulin sensitivity is at best indirect and is apparent only in conjunction with maximal oxygen uptake. Hence, PLIN5 abundance cannot be causally linked to the athlete's paradox.

Cardiovascular magnetic resonance features of mechanical dyssynchrony in patients with left bundle branch block.

Patients with left bundle branch block (LBBB) can exhibit mechanical dyssynchrony which may contribute to heart failure; such patients may benefit from cardiac resynchronization treatment (CRT). While cardiac magnetic resonance imaging (CMR) has become a common part of heart failure work-up, CMR features of mechanical dyssynchrony in patients with LBBB have not been well characterized. This study aims to investigate the potential of CMR to characterize mechanical features of LBBB. CMR examinations from 43 patients with LBBB on their electrocardiogram, but without significant focal structural abnormalities, and from 43 age- and gender-matched normal controls were retrospectively reviewed. The following mechanical features of LBBB were evaluated: septal flash (SF), apical rocking (AR), delayed aortic valve opening measured relative to both end-diastole (AVOED) and pulmonic valve opening (AVOPVO), delayed left-ventricular (LV) free-wall contraction, and curvatures of the septum and LV free-wall. Septal displacement curves were also generated, using feature-tracking techniques. The echocardiographic findings of LBBB were also reviewed in those subjects for whom they were available. LBBB was significantly associated with the presence of SF and AR; within the LBBB group, 79 % had SF and 65 % had AR. Delayed AVOED, AVOPVO, and delayed LV free-wall contraction were significantly associated with LBBB. AVOED and AVOPVO positively correlated with QRS duration and negatively correlated with ejection fraction. Hearts with electrocardiographic evidence of LBBB showed lower septal-to-LV free-wall curvature ratios at end-diastole compared to normal controls. CMR can be used to identify and evaluate mechanical dyssynchrony in patients with LBBB. None of the normal controls showed the mechanical features associated with LBBB. Moreover, not all patients with LBBB showed the same degree of mechanical dyssynchrony, which could have implications for CRT.

Septal flash and septal rebound stretch have different underlying mechanisms.

Abnormal left-right motion of the interventricular septum in early systole, known as septal flash (SF), is frequently observed in patients with left bundle branch block (LBBB). Transseptal pressure gradient and early active septal contraction have been proposed as explanations for SF. Similarities in timing (early systole) and location (septum) suggest that SF may be related to septal systolic rebound stretch (SRSsept). We aimed to clarify the mechanisms generating SF and SRSsept. The CircAdapt computer model was used to isolate the effects of timing of activation of the left ventricular free wall (LVFW), right ventricular free wall (RVFW), and septum on SF and SRSsept. LVFW and septal activation times were varied by ±80 ms relative to RVFW activation time. M-mode-derived wall motions and septal strains were computed and used to quantify SF and SRSsept, respectively. SF depended on early activation of the RVFW relative to the LVFW. SF and SRSsept occurred in LBBB-like simulations and against a rising transseptal pressure gradient. When the septum was activated before both LVFW and RVFW, no SF occurred despite the presence of SRSsept. Computer simulations therefore indicate that SF and SRSsept have different underlying mechanisms, even though both can occur in LBBB. The mechanism of leftward motion during SF is early RVFW contraction pulling on and straightening the septum when unopposed by the LVFW. SRSsept is caused by late LVFW contraction following early contraction of the septum. Changes in transseptal pressure gradient are not the main cause of SF in LBBB.

Differentiating Electromechanical From Non-Electrical Substrates of Mechanical Discoordination to Identify Responders to Cardiac Resynchronization Therapy.

BACKGROUND: Left ventricular (LV) mechanical discoordination, often referred to as dyssynchrony, is often observed in patients with heart failure regardless of QRS duration. We hypothesized that different myocardial substrates for LV mechanical discoordination exist from (1) electromechanical activation delay, (2) regional differences in contractility, or (3) regional scar and that we could differentiate electromechanical substrates responsive to cardiac resynchronization therapy (CRT) from unresponsive non-electrical substrates. METHODS AND RESULTS: First, we used computer simulations to characterize mechanical discoordination patterns arising from electromechanical and non-electrical substrates and accordingly devise the novel systolic stretch index (SSI), as the sum of posterolateral systolic prestretch and septal systolic rebound stretch. Second, 191 patients with heart failure (QRS duration ≥120 ms; LV ejection fraction ≤35%) had baseline SSI quantified by automated echocardiographic radial strain analysis. Patients with SSI≥9.7% had significantly less heart failure hospitalizations or deaths 2 years after CRT (hazard ratio, 0.32; 95% confidence interval, 0.19-0.53; P<0.001) and less deaths, transplants, or LV assist devices (hazard ratio, 0.28; 95% confidence interval, 0.15-0.55; P<0.001). Furthermore, in a subgroup of 113 patients with intermediate electrocardiographic criteria (QRS duration of 120-149 ms or non-left bundle branch block), SSI≥9.7% was independently associated with significantly less heart failure hospitalizations or deaths (hazard ratio, 0.41; 95% confidence interval, 0.23-0.79; P=0.004) and less deaths, transplants, or LV assist devices (hazard ratio, 0.27; 95% confidence interval, 0.12-0.60; P=0.001). CONCLUSIONS: Computer simulations differentiated patterns of LV mechanical discoordination caused by electromechanical substrates responsive to CRT from those related to regional hypocontractility or scar unresponsive to CRT. The novel SSI identified patients who benefited more favorably from CRT, including those with intermediate electrocardiographic criteria, where CRT response is less certain by ECG alone.

Influence of left ventricular lead position relative to scar location on response to cardiac resynchronization therapy: a model study.

AIMS: It is unclear how the position of the left ventricular (LV) lead relative to a scar affects the haemodynamic response in patients with dyssynchronous heart failure receiving cardiac resynchronization therapy. We investigated this complex interaction using a computational model. METHODS AND RESULTS: The CircAdapt computational cardiovascular system model was used to simulate heart failure with left bundle branch block (LBBB). Myocardial scar was induced in four different regions of the LV free wall (LVFW). We then simulated biventricular pacing (BVP) in each heart, in which LV lead position was varied. The LV lead position leading to maximal acute change in LV stroke volume (SV) was defined as optimal lead position. In LBBB without scar, SV increase was maximal when pacing the LVFW region most distant from the septum. With a scar adjacent to the septum, maximal response was achieved when pacing remote from both the septum and the scar. When the scar was located further from the septum, the BVP-induced increase of SV was small. For all hearts, pacing from the optimal LV lead position resulted in the most homogeneous distribution of local ventricular myofibre work and the largest increase in summed left and right ventricular pump work. CONCLUSIONS: These computer simulations suggest that, in hearts with LBBB and scar, the optimal LV lead position is a compromise between a position distant from the scar and from the septum. In infarcted hearts, the best haemodynamic effect is achieved when electromechanical resynchronization of the remaining viable myocardium is most effective.