Focal But Not Diffuse Myocardial Fibrosis Burden Quantification Using Cardiac Magnetic Resonance Imaging Predicts Left Ventricular Reverse Modeling Following Cardiac Resynchronization Therapy.

INTRODUCTION: Many heart failure patients with dyssynchrony do not reverse remodel (RR) in response to cardiac resynchronization therapy (CRT). The presence of focal and diffuse interstitial myocardial fibrosis may explain this high nonresponse rate. T1 mapping is a new cardiac magnetic resonance imaging (CMR) technique that overcomes the limitations of conventional contrast CMR and provides reliable quantitative assessment of diffuse myocardial fibrosis. The study tested the hypothesis that focal and diffuse fibrosis quantification would correlate with a lack of left ventricular (LV) RR to CRT. METHODS AND RESULTS: In a prospective study of 48 consecutive patients (27 ischemic cardiomyopathy, 21 dilated cardiomyopathy) LV scar burdens were quantified (scar core and gray zone using late gadolinium enhancement LGE CMR; interstitial fibrosis using T1 mapping) before CRT implant. LV RR was defined by a ≥ 15% reduction in LV end-systolic volume 6 months postimplant. Twenty-seven (56%) patients were responders with RR. Association between scar quantification and LV RR was assessed using the Poisson regression model. Univariate analysis showed that QRS duration/morphology, scar core, and gray zone volumes expressed as % of LV mass and extracellular volume index (ECV) (a measure of interstitial fibrosis from T1 mapping) to be significant predictors of LV RR. Multivariable-adjusted analyses demonstrated scar core quantification (≥ 13.7% LV mass) to be the only independent predictor of LV RR (prevalence ratio 0.40, P = 0.038). CONCLUSIONS: Focal scar burden detected by LGE CMR is associated with a poor response to CRT. Diffuse interstitial fibrosis assessment by T1 mapping, however, is not independently predictive of CRT response.

Effect of autonomic blocking agents on the respiratory-related oscillations of ventricular action potential duration in humans.

Ventricular action potential duration (APD) is an important component of many physiological functions including arrhythmogenesis. APD oscillations have recently been reported in humans at the respiratory frequency. This study investigates the contribution of the autonomic nervous system to these oscillations. In 10 patients undergoing treatment for supraventricular arrhythmias, activation recovery intervals (ARI; a conventional surrogate for APD) were measured from multiple left and right ventricular (RV) endocardial sites, together with femoral artery pressure. Respiration was voluntarily regulated and heart rate clamped by RV pacing. Sympathetic and parasympathetic blockade was achieved using intravenous metoprolol and atropine, respectively. Metroprolol reduced the rate of pressure development (maximal change in pressure over time): 1,271 (± 646) vs. 930 (± 433) mmHg/s; P < 0.01. Systolic blood pressure (SBP) showed a trend to decrease after metoprolol, 133 (± 21) vs. 128 (± 25) mmHg; P = 0.06, and atropine infusion, 122 (± 26) mmHg; P < 0.05. ARI and SBP exhibited significant cyclical variations (P < 0.05) with respiration in all subjects with peak-to-peak amplitudes ranging between 0.7 and 17.0 mmHg and 1 and 16 ms, respectively. Infusion of metoprolol reduced the mean peak-to-peak amplitude [ARI, 6.2 (± 1.4) vs. 4.4 (± 1.0) ms, P = 0.008; SBP, 8.4 (± 1.6) vs. 6.2 (± 2.0) mmHg, P = 0.002]. The addition of atropine had no significant effect. ARI, SBP, and respiration showed significant coupling (P < 0.05) at the breathing frequency in all subjects. Directed coherence from respiration to ARI was high and reduced after metoprolol infusion [0.70 (± 0.17) vs. 0.50 (± 0.23); P < 0.05]. These results suggest a role of respiration in modulating the electrophysiology of ventricular myocardium in humans, which is partly, but not totally, mediated by ß-adrenergic mechanisms.

Cardiac arrest secondary to type 2 Kounis syndrome resulting from urticaria and angioedema.

A 43-year-old man with no cardiac history presented with chest pain followed by cardiac arrest. He was successfully defibrillated and underwent primary percutaneous coronary angioplasty to a culprit coronary artery lesion. He later re-presented with a diffuse urticarial rash and lip swelling, reporting that these symptoms had been present for 4 weeks before his cardiac arrest and voicing concern that a further cardiac arrest may be imminent. A diagnosis of post-viral or idiopathic autoimmune urticaria and angioedema was made. Given the absence of cardiac symptoms before the development of the rash, it was hypothesised that coronary artery spasm precipitated by histamine release due to his dermatological condition contributed to his myocardial infarction and cardiac arrest. The final diagnosis was therefore cardiac arrest secondary to type II Kounis syndrome, resulting from idiopathic autoimmune or post-viral urticaria and angioedema.

Pulse Arrival Time and Pulse Interval as Accurate Markers to Detect Mechanical Alternans.

Mechanical alternans (MA) is a powerful predictor of adverse prognosis in patients with heart failure and cardiomyopathy, but its use remains limited due to the need of invasive continuous arterial pressure recordings. This study aims to assess novel cardiovascular correlates of MA in the intact human heart to facilitate affordable and non-invasive detection of MA and advance our understanding of the underlying pathophysiology. Arterial pressure, respiration, and ECG were recorded in 12 subjects with healthy ventricles during voluntarily controlled breathing at different respiratory rate, before and after administration of beta-blockers. MA was induced by ventricular pacing. A total of 67 recordings lasting approximately 90 s each were analyzed. Mechanical alternans (MA) was measured in the systolic blood pressure. We studied cardiovascular correlates of MA, including maximum pressure rise during systole (dPdtmax), pulse arrival time (PAT), pulse wave interval (PI), RR interval (RRI), ECG QRS complexes and T-waves. MA was detected in 30% of the analyzed recordings. Beta-blockade significantly reduced MA prevalence (from 50 to 11%, p < 0.05). Binary classification showed that MA was detected by alternans in dPdtmax (100% sens, 96% spec), PAT (100% sens, 81% spec) and PI (80% sens, 81% spec). Alternans in PAT and in PI also showed high degree of temporal synchronization with MA (80 ± 33 and 73 ± 40%, respectively). These data suggest that cardiac contractility is a primary factor in the establishment of MA. Our findings show that MA was highly correlated with invasive measurements of PAT and PI. Since PAT and PI can be estimated using non-invasive technologies, these markers could potentially enable affordable MA detection for risk-prediction.

Investigating a Novel Activation-Repolarisation Time Metric to Predict Localised Vulnerability to Reentry Using Computational Modelling.

Exit sites associated with scar-related reentrant arrhythmias represent important targets for catheter ablation therapy. However, their accurate location in a safe and robust manner remains a significant clinical challenge. We recently proposed a novel quantitative metric (termed the Reentry Vulnerability Index, RVI) to determine the difference between activation and repolarisation intervals measured from pairs of spatial locations during premature stimulation to accurately locate the critical site of reentry formation. In the clinic, the method showed potential to identify regions of low RVI corresponding to areas vulnerable to reentry, subsequently identified as ventricular tachycardia (VT) circuit exit sites. Here, we perform an in silico investigation of the RVI metric in order to aid the acquisition and interpretation of RVI maps and optimise its future usage within the clinic. Within idealised 2D sheet models we show that the RVI produces lower values under correspondingly more arrhythmogenic conditions, with even low resolution (8 mm electrode separation) recordings still able to locate vulnerable regions. When applied to models of infarct scars, the surface RVI maps successfully identified exit sites of the reentrant circuit, even in scenarios where the scar was wholly intramural. Within highly complex infarct scar anatomies with multiple reentrant pathways, the identified exit sites were dependent upon the specific pacing location used to compute the endocardial RVI maps. However, simulated ablation of these sites successfully prevented the reentry re-initiation. We conclude that endocardial surface RVI maps are able to successfully locate regions vulnerable to reentry corresponding to critical exit sites during sustained scar-related VT. The method is robust against highly complex and intramural scar anatomies and low resolution clinical data acquisition. Optimal location of all relevant sites requires RVI maps to be computed from multiple pacing locations.

T1 Mapping in Discrimination of Hypertrophic Phenotypes: Hypertensive Heart Disease and Hypertrophic Cardiomyopathy: Findings From the International T1 Multicenter Cardiovascular Magnetic Resonance Study.

BACKGROUND: The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice, in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere-gene mutations in subexpressed family members (G+P- subjects). This study aimed to investigate whether detecting diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as to detect genetically driven interstitial changes in the G+P- subjects. METHODS AND RESULTS: Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P- subjects (n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1 and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension (P<0.0001), including in subgroup comparisons of HCM subjects without evidence of late gadolinium enhancement, as well as of hypertensive patients LV wall thickness of >15 mm (P<0.0001). Compared with controls, native T1 was significantly higher in G+P- subjects (P<0.0001) and 65% of G+P- subjects had a native T1 value >2 SD above the mean of the normal range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P- subjects from controls. CONCLUSIONS: Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early changes in G+P- subjects.

Myocardial tissue characterization by cardiac magnetic resonance imaging using T1 mapping predicts ventricular arrhythmia in ischemic and non-ischemic cardiomyopathy patients with implantable cardioverter-defibrillators.

BACKGROUND: Diffuse myocardial fibrosis may provide a substrate for the initiation and maintenance of ventricular arrhythmia. T1 mapping overcomes the limitations of the conventional delayed contrast-enhanced cardiac magnetic resonance (CE-CMR) imaging technique by allowing quantification of diffuse fibrosis. OBJECTIVE: The purpose of this study was to assess whether myocardial tissue characterization using T1 mapping would predict ventricular arrhythmia in ischemic and non-ischemic cardiomyopathies. METHODS: This was a prospective longitudinal study of consecutive patients receiving implantable cardioverter-defibrillators in a tertiary cardiac center. Participants underwent CMR myocardial tissue characterization using T1 mapping and conventional CE-CMR scar assessment before device implantation. The primary end point was an appropriate implantable cardioverter-defibrillator therapy or documented sustained ventricular arrhythmia. RESULTS: One hundred thirty patients (71 ischemic and 59 non-ischemic) were included with a mean follow-up period of 430 ± 185 days (median 425 days; interquartile range 293 days). At follow-up, 23 patients (18%) experienced the primary end point. In multivariable-adjusted analyses, the following factors showed a significant association with the primary end point: secondary prevention (hazard ratio [HR] 1.70; 95% confidence interval [95% CI] 1.01-1.91), noncontrast T1(_native) for every 10-ms increment in value (HR 1.10; CI 1.04-1.16; 90-ms difference between the end point-positive and end point-negative groups), and Grayzone(_2sd-3sd) for every 1% left ventricular increment in value (HR 1.36; CI 1.15-1.61; 4% difference between the end point-positive and end point-negative groups). Other CE-CMR indices including Scar(_2sd), Scar(_FWHM), and Grayzone(_2sd-FWHM) were also significantly, even though less strongly, associated with the primary end point as compared with Grayzone(_2sd-3sd). CONCLUSION: Quantitative myocardial tissue assessment using T1 mapping is an independent predictor of ventricular arrhythmia in both ischemic and non-ischemic cardiomyopathies.

Oscillatory behavior of ventricular action potential duration in heart failure patients at respiratory rate and low frequency.

Oscillations of arterial pressure occur spontaneously at a frequency of approximately 0.1 Hz coupled with synchronous oscillations of sympathetic nerve activity ("Mayer waves"). This study investigated the extent to which corresponding oscillations may occur in ventricular action potential duration (APD). Fourteen ambulatory (outpatient) heart failure patients with biventricular pacing devices were studied while seated upright watching movie clips to maintain arousal. Activation recovery intervals (ARI) as a measure of ventricular APD were obtained from unipolar electrograms recorded from the LV epicardial pacing lead during steady state RV pacing from the device. Arterial blood pressure was measured non-invasively (Finapress) and respiration monitored. Oscillations were quantified using time frequency and coherence analysis. Oscillatory behavior of ARI at the respiratory frequency was observed in all subjects. The magnitude of the ARI variation ranged from 2.2 to 6.9 ms (mean 5.0 ms). Coherence analysis showed a correlation with respiratory oscillation for an average of 43% of the recording time at a significance level of p < 0.05. Oscillations in systolic blood pressure in the Mayer wave frequency range were observed in all subjects for whom blood pressure was recorded (n = 13). ARI oscillation in the Mayer wave frequency range was observed in 6/13 subjects (46%) over a range of 2.9 to 9.2 ms. Coherence with Mayer waves at the p < 0.05 significance level was present for an average of 29% of the recording time. In ambulatory patients with heart failure during enhanced mental arousal, left ventricular epicardial APD (ARI) oscillated at the respiratory frequency (approximately 0.25 Hz). In 6 patients (46%) APD oscillated at the slower Mayer wave frequency (approximately 0.1 Hz). These findings may be important in understanding sympathetic activity-related arrhythmogenesis.

Left ventricular epicardial electrograms show divergent changes in action potential duration in responders and nonresponders to cardiac resynchronization therapy.

BACKGROUND: A consistent feature of electrophysiological remodeling in heart failure is ventricular action potential duration (APD) prolongation. However, the effect of reverse remodeling on APD during cardiac resynchronization therapy (CRT) has not been determined in these patients. We hypothesized (1) that CRT may alter APD and (2) that the effect of CRT on APD may be different in patients who exhibit a good hemodynamic response to CRT compared with those with a poor response. METHODS AND RESULTS: Left ventricular (LV) activation recovery intervals, as a surrogate for APD, were measured from the LV epicardium in 13 patients at day 0, 6 weeks, and 6 months after CRT implant. Responders to CRT were defined as those demonstrating a ≥15% reduction in LV end-systolic volume at 6 months. The responder group had a significant reduction in LV activation recovery interval (mean, -13±12 ms; median, -16 ms; interquartile range, -2 to -19 ms) during right ventricular pacing at 6 months (P<0.05). Conversely, the nonresponders showed a significant increase in activation recovery interval (mean, +22 ms±16; median, 17 ms; interquartile range, 8 to 35 ms; P<0.05). One patient in each group was on amiodarone. CONCLUSIONS: In patients with heart failure, LV epicardial APD (activation recovery interval) altered during CRT. The effect on APD was opposite in patients showing a good hemodynamic response compared with nonresponders. The findings may provide an explanation for the persistent high incidence of arrhythmias in some patients with CRT and the additional mortality benefit observed in responders of CRT.