Brandon K Fornwalt

Agreement Is Poor Among Current Criteria Used to Define Response to Cardiac Resynchronization Therapy

Background— Numerous criteria believed to define a positive response to cardiac resynchronization therapy have been used in the literature. No study has investigated agreement among these response criteria. We hypothesized that the agreement among the various response criteria would be poor. Methods and Results— A literature search was conducted with the keywords “cardiac resynchronization” and “response.” The 50 publications with the most citations were reviewed. After the exclusion of editorials and reviews, 17 different primary response criteria were identified from 26 relevant articles. The agreement among 15 of these 17 response criteria was assessed in 426 patients from the Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study with Cohens &kgr;-coefficient (2 response criteria were not calculable from PROSPECT data). The overall response rate ranged from 32% to 91% for the 15 response criteria. Ninety-nine percent of patients showed a positive response according to at least 1 of the 15 criteria, whereas 94% were classified as a nonresponder by at least 1 criterion. &kgr;-Values were calculated for all 105 possible comparisons among the 15 response criteria and classified into standard ranges: Poor agreement (&kgr;≤0.4), moderate agreement (0.4<&kgr;<0.75), and strong agreement (&kgr;≥0.75). Seventy-five percent of the comparisons showed poor agreement, 21% showed moderate agreement, and only 4% showed strong agreement. Conclusions— The 26 most-cited publications on predicting response to cardiac resynchronization therapy define response using 17 different criteria. Agreement between different methods to define response to cardiac resynchronization therapy is poor 75% of the time and strong only 4% of the time, which severely limits the ability to generalize results over multiple studies.

Patients with repaired tetralogy of Fallot suffer from intra- and inter-ventricular cardiac dyssynchrony: a cardiac magnetic resonance study

AIMS Patients with repaired tetralogy of Fallot (rTOF) frequently have right bundle branch block. To better understand the contribution of cardiac dyssynchrony to dysfunction, we developed a method to quantify left (LV), right (RV), and inter-ventricular dyssynchrony using standard cine cardiac magnetic resonance (CMR). METHODS AND RESULTS Thirty patients with rTOF and 17 healthy controls underwent cine CMR. Patients were imaged twice to assess inter-test reproducibility. Circumferential strain curves were generated with a custom feature-tracking algorithm for 12 LV and 12 RV segments in each of 4-7 short-axis slices encompassing the ventricles. Temporal offsets (TOs, in ms) of the strain curves relative to a patient-specific reference curve were calculated. The intra-ventricular dyssynchrony index (DI) for each ventricle was computed as the standard deviation of the TOs. The inter-ventricular DI was calculated as the difference in median RV and median LV TOs. Compared with controls, patients had a greater LV DI (21 ± 8 vs. 11 ± 5 ms, P < 0.001) and RV DI (60 ± 19 vs. 47 ± 17 ms, P = 0.02). RV contraction was globally delayed in patients, resulting in a greater inter-ventricular DI with the RV contracting 45 ± 25 ms later than the LV vs. 12 ± 29 ms earlier in controls (P < 0.001). Inter-test reproducibility was moderate with all coefficients of variation ≤22%. Both LV and RV DIs were correlated with measures of LV, but not RV, function. CONCLUSION Patients with rTOF have intra- and inter-ventricular dyssynchrony, which can be quantified from standard cine CMR. This new approach can potentially help determine the contribution of dyssynchrony to ventricular dysfunction in future studies.

Reproducibility of cine displacement encoding with stimulated echoes (DENSE) cardiovascular magnetic resonance for measuring left ventricular strains, torsion, and synchrony in mice

BackgroundAdvanced measures of cardiac function are increasingly important to clinical assessment due to their superior diagnostic and predictive capabilities. Cine DENSE cardiovascular magnetic resonance (CMR) is ideal for quantifying advanced measures of cardiac function based on its high spatial resolution and streamlined post-processing. While many studies have utilized cine DENSE in both humans and small-animal models, the inter-test and inter-observer reproducibility for quantification of advanced cardiac function in mice has not been evaluated. This represents a critical knowledge gap for both understanding the capabilities of this technique and for the design of future experiments. We hypothesized that cine DENSE CMR would show excellent inter-test and inter-observer reproducibility for advanced measures of left ventricular (LV) function in mice.MethodsFive normal mice (C57BL/6) and four mice with depressed cardiac function (diet-induced obesity) were imaged twice, two days apart, on a 7T ClinScan MR system. Images were acquired with 15–20 frames per cardiac cycle in three short-axis (basal, mid, apical) and two long-axis orientations (4-chamber and 2-chamber). LV strain, twist, torsion, and measures of synchrony were quantified. Images from both days were analyzed by one observer to quantify inter-test reproducibility, while inter-observer reproducibility was assessed by a second observer’s analysis of day-1 images. The coefficient of variation (CoV) was used to quantify reproducibility.ResultsLV strains and torsion were highly reproducible on both inter-observer and inter-test bases with CoVs ≤ 15%, and inter-observer reproducibility was generally better than inter-test reproducibility. However, end-systolic twist angles showed much higher variance, likely due to the sensitivity of slice location within the sharp longitudinal gradient in twist angle. Measures of synchrony including the circumferential (CURE) and radial (RURE) uniformity of strain indices, showed excellent reproducibility with CoVs of 1% and 3%, respectively. Finally, peak measures (e.g., strains) were generally more reproducible than the corresponding rates of change (e.g., strain rate).ConclusionsCine DENSE CMR is a highly reproducible technique for quantification of advanced measures of left ventricular cardiac function in mice including strains, torsion and measures of synchrony. However, myocardial twist angles are not reproducible and future studies should instead report torsion.

Smooth Muscle Cell Deletion of Low-Density Lipoprotein Receptor–Related Protein 1 Augments Angiotensin II–Induced Superior Mesenteric Arterial and Ascending Aortic Aneurysms

Objective—Low-density lipoprotein receptor–related protein 1 (LRP1), a multifunctional protein involved in endocytosis and cell signaling pathways, leads to several vascular pathologies when deleted in vascular smooth muscle cells (SMCs). The purpose of this study was to determine whether LRP1 deletion in SMCs influenced angiotensin II–induced arterial pathologies. Approach and Results—LRP1 protein abundance was equivalent in selected arterial regions, but SMC-specific LRP1 depletion had no effect on abdominal and ascending aortic diameters in young mice. To determine the effects of LRP1 deficiency on angiotensin II vascular responses, SMC-specific LRP1 (smLRP1+/+) and smLRP1-deficient (smLRP1−/−) mice were infused with saline, angiotensin II, or norepinephrine. Several smLRP−/− mice died of superior mesenteric arterial (SMA) rupture during angiotensin II infusion. In surviving mice, angiotensin II profoundly augmented SMA dilation in smLRP1−/− mice. SMA dilation was blood pressure dependent as demonstrated by a similar response during norepinephrine infusion. SMA dilation was also associated with profound macrophage accumulation, but minimal elastin fragmentation. Angiotensin II infusion led to no significant differences in abdominal aorta diameters between smLRP1+/+ and smLRP1−/− mice. In contrast, ascending aortic dilation was exacerbated markedly in angiotensin II–infused smLRP1−/− mice, but norepinephrine had no significant effect on either aortic region. Ascending aortas of smLRP1−/− mice infused with angiotensin II had minimal macrophage accumulation but significantly increased elastin fragmentation and mRNA abundance of several LRP1 ligands including MMP-2 (matrix metalloproteinase-2) and uPA (urokinase plasminogen activator). Conclusions—smLRP1 deficiency had no effect on angiotensin II–induced abdominal aortic aneurysm formation. Conversely, angiotensin II infusion in smLRP1−/− mice exacerbated SMA and ascending aorta dilation. Dilation in these 2 regions had differential association with blood pressure and divergent pathological characteristics.

It's Time for a Paradigm Shift in the Quantitative Evaluation of Left Ventricular Dyssynchrony

The acute adverse effects of left ventricular (LV) dyssynchrony on cardiac performance were first described in 1925 by Carl Wiggers1. In recent years, the accurate diagnosis of LV dyssynchrony has become the focus of a myriad of publications, driven by the advent of cardiac resynchronization therapy (CRT) to treat heart failure due to severe LV dysfunction in the setting of marked prolongation of the QRS interval2–4. In the initial large clinical trials of CRT, QRS duration was used as a measure of dyssynchrony to select patients for treatment2, 3. However, sensitivity5 and specificity6 of QRS duration to predict response to CRT were less than optimal. Subsequently, numerous “time-to-peak” parameters based directly on the motion of the LV walls were developed to diagnose LV mechanical dyssynchrony with echocardiography in an attempt to improve CRT selection criteria7. Echocardiographic mechanical dyssynchrony parameters initially showed promise in predicting response to CRT in single-center studies8–12. However, the multicenter Predictors of Response to CRT (PROSPECT) study recently reported that no echocardiographic dyssynchrony parameter could be recommended to improve patient selection for CRT beyond current guidelines13. In addition, the Resynchronization Therapy in Narrow QRS (RETHINQ) trial recently reported that patients with narrow QRS and evidence of mechanical dyssynchrony do not benefit from CRT14. So where do we go from here? Should selection of patients for CRT based on mechanical dyssynchrony be abandoned in the wake of the negative results from PROSPECT and RETHINQ? We believe that techniques to quantify LV mechanical dyssynchrony need to be refined, not forgotten, and will still play a role in improving CRT selection criteria in the future. This refinement of dyssynchrony quantification requires a paradigm shift. First, time-to-peak methods for quantifying dyssynchrony utilize only a single time point on the velocity or strain curves and should be replaced with more quantitatively sophisticated methods. Utilizing more data reduces variability and increases accuracy. Second, “response to CRT” should no longer be considered synonymous with “presence of left ventricular dyssynchrony”. There is no method based on LV dyssynchrony measures that by itself will predict response to CRT with high accuracy.

Variability in Tissue Doppler Echocardiographic Measures of Dyssynchrony Is Reduced With Use of a Larger Region of Interest

BACKGROUND Doppler tissue imaging (DTI)-based dyssynchrony parameters failed to predict response to cardiac resynchronization therapy (CRT) in the multicenter Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) trial. Large variability during the interpretation of DTI data was one of several factors thought to contribute to this failure. In this study, the authors hypothesized that using larger regions of interest (ROIs) to generate velocity curves from Doppler tissue images would significantly reduce the variability of DTI dyssynchrony parameters. METHODS The variability of 3 ROI sizes (6 x 6, 18 x 6, and 30 x 6 mm) was compared in 30 patients undergoing CRT. Variability due to manual ROI placement was determined for each ROI size by placing 3 ROIs in each myocardial segment, 6mm apart from one another. Thus, 3 velocity curves were generated for each segment and each ROI size. Four published dyssynchrony parameters were calculated from all permutations of the 3 ROI positions per segment. A mean modified coefficient of variation was calculated for each parameter and ROI size. RESULTS The 6 x 6 mm ROI had a mean coefficient of variation of 27%. The 18 x 6 and 30 x 6 mm ROIs had significantly lower coefficients of variation (17% and 14%, respectively) than the 6 x 6 mm ROI (P < .01 for both). The 30 x 6 mm ROI also reduced the diagnostic inconsistency of dyssynchrony parameters by 44% (P = .024) compared with the 6 x 6 mm ROI. CONCLUSION Using a 30 x 6 mm ROI instead of a 6 x 6 mm ROI to quantify tissue Doppler dyssynchrony reduces variability by 47% and diagnostic inconsistency by 44%. The authors recommend using a 30 x 6 mm ROI in future trials to minimize variability.

Telemetric Blood Pressure Assessment in Angiotensin II-Infused ApoE-/- Mice: 28 Day Natural History and Comparison to Tail-Cuff Measurements

Abdominal aortic aneurysm (AAA) is a disease of the aortic wall, which can progress to catastrophic rupture. Assessment of mechanical characteristics of AAA, such as aortic distensibility, may provide important insights to help identify at-risk patients and understand disease progression. While the majority of studies on this topic have focused on retrospective patient data, recent studies have used mouse models of AAA to prospectively evaluate the evolution of aortic mechanics. Quantification of aortic distensibility requires accurate measurement of arterial blood pressure, particularly pulse pressure, which is challenging to perform accurately in murine models. We hypothesized that volume/pressure tail-cuff measurements of arterial pulse pressure in anesthetized mice would have sufficient accuracy to enable calculations of aortic distensibility with minimal error. Telemetry devices and osmotic mini-pumps filled with saline or angiotensin-II were surgically implanted in male apolipoprotein-E deficient (ApoE-/-) mice. Blood pressure in the aortic arch was measured continuously via telemetry. In addition, simultaneous blood pressure measurements with a volume/pressure tail-cuff system were performed under anesthesia at specific intervals to assess agreement between techniques. Compared to controls, mice infused with angiotensin-II had an overall statistically significant increase in systolic pressure, with no overall difference in pulse pressure; however, pulse pressure did increase significantly with time. Systolic measurements agreed well between telemetry and tail-cuff (coefficient of variation = 10%), but agreement of pulse pressure was weak (20%). In fact, group-averaged pulse pressure from telemetry was a better predictor of a subject’s pulse pressure on a given day than a simultaneous tail-cuff measurement. Furthermore, these approximations introduced acceptable errors (15.1 ± 12.8%) into the calculation of aortic distensibility. Contrary to our hypothesis, we conclude that tail-cuff measures of arterial pulse pressure have limited accuracy. Future studies of aneurysm mechanics using the ApoE-/-/angiotensin-II model would be better in assuming pulse pressure profiles consistent with our telemetry findings instead of attempting to measure pulse pressure in individual mice.

Quantification of left ventricular volumes, mass, and ejection fraction using cine displacement encoding with stimulated echoes (DENSE) MRI

To test the hypothesis that magnitude images from cine displacement encoding with stimulated echoes (DENSE) magnetic resonance imaging (MRI) can accurately quantify left ventricular (LV) volumes, mass, and ejection fraction (EF).

Method to create regional mechanical dyssynchrony maps from short-axis cine steady-state free-precession images

To develop a robust method to assess regional mechanical dyssynchrony from cine short‐axis MR images. Cardiac resynchronization therapy (CRT) is an effective treatment for patients with heart failure and evidence of left‐ventricular (LV) dyssynchrony. Patient response to CRT is greatest when the LV pacing lead is placed in the most dyssynchronous segment. Existing techniques for assessing regional dyssynchrony require difficult acquisition and/or postprocessing. Our goal was to develop a widely applicable and robust method to assess regional mechanical dyssynchrony.

QRS duration predicts death and hospitalization among patients with atrial fibrillation irrespective of heart failure: evidence from the AFFIRM study

AIMS The association of QRS duration (QRSd) with morbidity and mortality is understudied in patients with atrial fibrillation (AF). We sought to assess any association of prolonged QRS with increased risk of death or hospitalization among patients with AF. METHODS AND RESULTS QRS duration was retrieved from the baseline electrocardiograms of patients enroled in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study and divided into three categories: <90, 90-119, ≥120 ms. Cox models were applied relating the hazards of mortality and hospitalizations to QRSd. Among 3804 patients with AF, 593 died and 2305 were hospitalized. Compared with those with QRS < 90 ms, patients with QRS ≥ 120 ms, had an increased mortality [hazard ratio (HR) 1.61, 95% confidence interval (CI): 1.29-2.03, P < 0.001] and hospitalizations (HR 1.14, 95% CI: 1.07-1.34, P = 0.043) over an average follow-up of 3.5 years. Importantly, for patients with QRS 90-119 ms, mortality and hospitalization were also increased (HR 1.31, P = 0.005 and 1.11, P = 0.026, respectively). In subgroup analysis based on heart failure (HF) status (previously documented or ejection fraction <40%), mortality was increased for QRS ≥ 120 ms patients with (HR 1.87, P < 0.001) and without HF (HR 1.63, P = 0.02). In the QRS 90-119 ms group, mortality was increased (HR 1.38, P = 0.03) for those with HF, but not significantly among those without HF (HR 1.23, P = 0.14). CONCLUSION Among patients with AF, QRSd ≥ 120 ms was associated with a substantially increased risk for mortality (all-cause, cardiovascular, and arrhythmic) and hospitalization. Interestingly, an increased mortality was also observed among those with QRS 90-119 ms and concomitant HF.