Gerry Carr-White

T1-Mapping and Outcome in Nonischemic Cardiomyopathy: All-Cause Mortality and Heart Failure

OBJECTIVES The study sought to examine prognostic relevance of T1 mapping parameters (based on a T1 mapping method) in nonischemic dilated cardiomyopathy (NIDCM) and compare them with conventional markers of adverse outcome. BACKGROUND NIDCM is a recognized cause of poor clinical outcome. NIDCM is characterized by intrinsic myocardial remodeling due to complex pathophysiological processes affecting myocardium diffusely. Lack of accurate and noninvasive characterization of diffuse myocardial disease limits recognition of early cardiomyopathy and effective clinical management in NIDCM. Cardiac magnetic resonance (CMR) supports detection of diffuse myocardial disease by T1 mapping. METHODS This is a prospective observational multicenter longitudinal study in 637 consecutive patients with dilated NIDCM (mean age 50 years [interquartile range: 37 to 76 years]; 395 males [62%]) undergoing CMR with T1 mapping and late gadolinium enhancement (LGE) at 1.5-T and 3.0-T. The primary endpoint was all-cause mortality. A composite of heart failure (HF) mortality and hospitalization was a secondary endpoint. RESULTS During a median follow-up period of 22 months (interquartile range: 19 to 25 months), we observed a total of 28 deaths (22 cardiac) and 68 composite HF events. T1 mapping indices (native T1 and extracellular volume fraction), as well as the presence and extent of LGE, were predictive of all-cause mortality and HF endpoint (p < 0.001 for all). In multivariable analyses, native T1 was the sole independent predictor of all-cause and HF composite endpoints (hazard ratio: 1.1; 95% confidence interval: 1.06 to 1.15; hazard ratio: 1.1; 95% confidence interval: 1.05 to 1.1; p < 0.001 for both), followed by the models including the extent of LGE and right ventricular ejection fraction, respectively. CONCLUSIONS Noninvasive measures of diffuse myocardial disease by T1 mapping are significantly predictive of all-cause mortality and HF events in NIDCM. We provide a basis for a novel algorithm of risk stratification in NIDCM using a complementary assessment of diffuse and regional disease by T1 mapping and LGE, respectively.

Invasive Acute Hemodynamic Response to Guide Left Ventricular Lead Implantation Predicts Chronic Remodeling in Patients Undergoing Cardiac Resynchronization Therapy

OBJECTIVES We evaluated the relationship between acute hemodynamic response (AHR) and reverse remodeling (RR) in cardiac resynchronization therapy (CRT). BACKGROUND CRT reduces mortality and morbidity in heart failure patients; however, up to 30% of patients do not derive symptomatic benefit. Higher proportions do not remodel. Multicenter trials have shown echocardiographic techniques are poor at improving response rates. We hypothesized the degree of AHR at implant can predict which patients remodel. METHODS Thirty-three patients undergoing CRT (21 dilated and 12 ischemic cardiomyopathy) were studied. Left ventricular (LV) volumes were assessed before and after CRT. The AHR (maximum rate of left ventricular pressure [LV-dP/dt(max)]) was assessed at implant with a pressure wire in the LV cavity. Largest percentage rise in LV-dP/dt(max) from baseline (atrial antibradycardia pacing or right ventricular pacing with atrial fibrillation) to dual-chamber pacing (DDD)-LV was used to determine optimal coronary sinus LV lead position. Reverse remodeling was defined as reduction in LV end systolic volume ≥15% at 6 months. RESULTS The LV-dP/dt(max) increased significantly from baseline (801 ± 194 mm Hg/s to 924 ± 203 mm Hg/s, p < 0.001) with DDD-LV pacing for the optimal LV lead position. The LV end systolic volume decreased from 186 ± 68 ml to 157 ± 68 ml (p < 0.001). Eighteen (56%) patients exhibited RR. There was a significant relationship between percentage rise in LV-dP/dt(max) and RR for DDD-LV pacing (p < 0.001). A similar relationship for AHR and RR in dilated cardiomyopathy and ischemic cardiomyopathy (p = 0.01 and p = 0.006) was seen. CONCLUSIONS Acute hemodynamic response to LV pacing is useful for predicting which patients are likely to remodel in response to CRT both for dilated cardiomyopathy and ischemic cardiomyopathy. Using AHR has the potential to guide LV lead positioning and improve response rates.

Relationship between endocardial activation sequences defined by high-density mapping to early septal contraction (septal flash) in patients with left bundle branch block undergoing cardiac resynchronization therapy

AIMS Early inward motion and thickening/thinning of the ventricular septum associated with left bundle branch block is known as the septal flash (SF). Correction of SF corresponds to response to cardiac resynchronization therapy (CRT). We hypothesized that SF was associated with a specific left ventricular (LV) activation pattern predicting a favourable response to CRT. We sought to characterize the spatio-temporal relationship between electrical and mechanical events by directly comparing non-contact mapping (NCM), acute haemodynamics, and echocardiography. METHODS AND RESULTS Thirteen patients (63 ± 10 years, 10 men) with severe heart failure (ejection fraction 22.8 ± 5.8%) awaiting CRT underwent echocardiography and NCM pre-implant. Presence and extent of SF defined visually and with M-mode was fused with NCM bulls eye plots of endocardial activation patterns. LV-dP/dt(max) was measured during different pacing modes. Five patients had a large SF, four small SF, and four no SF. Large SF patients had areas of conduction block in non-infarcted regions, whereas those with small or no SF did not. Patients with large SF had greater acute response to LV and biventricular (BIV) pacing vs. those with small/no SF (% increase dP/dt 28 ± 14 vs. 11 ± 19% for LV pacing and 42 ± 28 vs. 22 ± 21% for BIV pacing) (P < 0.05). This translated into a more favourable chronic response to CRT. The lines of conduction block disappeared with LV/BIV pacing while remaining with right ventricle pacing. CONCLUSION A strong association exists between electrical activation and mechanical deformation of the septum. Correction of both mechanical synchrony and the functional conduction block by CRT may explain the favourable response in patients with SF.

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.

Cardiac MRI to investigate myocardial scar and coronary venous anatomy using a slow infusion of dimeglumine gadobenate in patients undergoing assessment for cardiac resynchronization therapy.

To evaluate a cardiac MR (CMR) examination with slow infusion of a high‐relaxivity contrast agent to visualize coronary venous anatomy (CVA) and myocardial scar in heart failure patients awaiting cardiac resynchronization therapy (CRT).

Aortic Stiffness and Interstitial Myocardial Fibrosis by Native T1 Are Independently Associated With Left Ventricular Remodeling in Patients With Dilated Cardiomyopathy

Increased aortic stiffness is related to increased ventricular stiffness and remodeling. Myocardial fibrosis is the pathophysiological hallmark of failing heart. We investigated the relationship between noninvasive imaging markers of myocardial fibrosis, native T1, and late gadolinium enhancement, respectively, and aortic stiffness in ventricular remodeling. Consecutive patients with known dilated cardiomyopathy (n=173) underwent assessment of cardiac volumes and function, T1 mapping, scar imaging, and pulse wave velocity, a measure of aortic stiffness. Asymptomatic healthy volunteers served as controls (n=47). Controls and patients showed an increase in pulse wave velocity with age, which was accelerated in the presence of cardiovascular disease. On the contrary, native T1 increased with age in patients, but not in controls. Pulse wave velocity was associated with native T1 in the presence of disease, but not in health. Native T1 showed a strong relationship with markers of structural and functional left ventricular remodeling and diastolic impairment. Ischemic and nonischemic pathophysiology of ventricular remodeling showed a similar slope of relationship between pulse wave velocity and native T1. However, in nonischemic patients, increase in pulse wave velocity was associated with greater increase in native T1. Aortic stiffness is related to age, and this process is accelerated in the presence of disease. On the contrary, increase in interstitial myocardial fibrosis is associated with age in the presence of disease. Patients with ischemic and nonischemic dilated cardiomyopathy have a similar relationship between native T1 and pulse wave velocity, which is stronger in the latter group.

Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

AIMS The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible. METHODS AND RESULTS To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands. CONCLUSION Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution.

Native T1 and T2 mapping by CMR in lupus myocarditis: Disease recognition and response to treatment

BACKGROUND Lupus myocarditis is likely more common than recognized clinically due to non-specific symptoms and lack of reliable non-invasive diagnostic tests. We investigated the role of native T1 and T2 in recognition of active myocardial inflammatory involvement in patients with systemic lupus erythematous (SLE). METHODS 76 patients with clinically suspected lupus myocarditis (14 males, age: 44±16years) underwent quantitative tissue characterization with native T1 and T2 mapping. Normotensive healthy subjects taking no medication served as controls (n=46). Follow-up CMR studies were performed in a total of 35 subjects of which 14 patients received intensified anti-inflammatory treatment, as guided by SLE disease activity. RESULTS Compared to controls SLE patients had higher inflammatory markers, LV mass, native T1 and T2 values, and reduced longitudinal strain (p<0.01). In patients with a positive troponin test (n=36; 46%), native T1 and T2 were significantly higher (p<0.01) with otherwise similar proportions of diffuse perimyocardial LGE (33%) and pericardial effusion (32%). Sixty-nine patients (83%) had an abnormal native T1, whereas 51 (71%) met diagnostic criteria for acute myocarditis. Follow-up CMRs revealed significantly greater reduction in native T1 and T2 values in patients with intensified anti-inflammatory treatment (p<0.001) with the greatest change observed within the first follow-up period and plateauing thereafter. Native T1 and T2 were significant predictors of treatment response. CONCLUSIONS Native T1 and T2 mapping support recognition of lupus myocarditis and reflect the response to anti-inflammatory treatment. Native T1 and T2 mapping may support an effective, noninvasive, radiation- and gadolinium contrast-free screening method for lupus myocarditis.

Three-dimensional atrial wall thickness maps to inform catheter ablation procedures for atrial fibrillation

AIMS Transmural lesion formation is critical to success in atrial fibrillation ablation and is dependent on left atrial wall thickness (LAWT). Pre- and peri-procedural planning may benefit from LAWT measurements. METHODS AND RESULTS To calculate the LAWT, the Laplace equation was solved over a finite element mesh of the left atrium derived from the segmented computed tomographic angiography (CTA) dataset. Local LAWT was then calculated from the length of field lines derived from the Laplace solution that spanned the wall from the endocardium or epicardium. The method was validated on an atrium phantom and retrospectively applied to 10 patients who underwent routine coronary CTA for standard clinical indications at our institute. The Laplace wall thickness algorithm was validated on the left atrium phantom. Wall thickness measurements had errors of <0.2 mm for thicknesses of 0.5-5.0 mm that are attributed to image resolution and segmentation artefacts. Left atrial wall thickness measurements were performed on 10 patients. Successful comprehensive LAWT maps were generated in all patients from the coronary CTA images. Mean LAWT measurements ranged from 0.6 to 1.0 mm and showed significant inter and intra patient variability. CONCLUSIONS Left atrial wall thickness can be measured robustly and efficiently across the whole left atrium using a solution of the Laplace equation over a finite element mesh of the left atrium. Further studies are indicated to determine whether the integration of LAWT maps into pre-existing 3D anatomical mapping systems may provide important anatomical information for guiding radiofrequency ablation.

Prevalence of myocardial crypts in a large retrospective cohort study by cardiovascular magnetic resonance

BackgroundMyocardial crypts are discrete clefts or fissures in otherwise compacted myocardium of the left ventricle (LV). Recent reports suggest a higher prevalence of crypts in patients with hypertrophic cardiomyopathy (HCM) and also within small samples of genotype positive but phenotype negative relatives. The presence of a crypt has been suggested to be a predictor of gene carrier status. However, the prevalence and clinical significance of crypts in the general population is unclear. We aimed to determine the prevalence of myocardial crypts in a large cohort of subjects using clinical cardiovascular magnetic resonance (CMR).MethodsConsecutive subjects referred for clinical CMR during a 12-month period (n = 1020, age 52.6 ± 17, males: 61%) were included. Crypts were defined as >50% invagination into normal myocardium and their overall prevalence, location and shape was investigated and compared between different patient groups.ResultsThe overall prevalence of crypts was 64/1020 (6.3%). In a predefined ‘normal’ control group the prevalence was lower (11/306, 3.6%, p = 0.031), but were equally prevalent in ischemic heart disease (12/236, 5.1%, p = n/s) and the combined non-ischemic cardiomyopathy (NICM) groups (24/373; 6.4%, p = n/s). Within the NICM group, crypts were significantly more common in HCM (9/76, 11.7%, p = 0.04) and hypertensive CM subjects (3/11, 27%, p = 0.03). In patients referred for CMR for family screening of inherited forms of CM, crypts were significantly more prevalent (10/41, 23%, p < 0.001), including a smaller group with a first degree relative with HCM (3/9, 33%, p = 0.01).ConclusionMyocardial crypts are relatively common in the normal population, and increasingly common in HCM and hypertensive cardiomyopathy. Crypts are also more frequently seen in normal phenotype subjects referred because of a family history of an inherited cardiomyopathy and HCM specifically. It is uncertain what the significance of crypts are in this group, and because of variability in the imaging protocols used and their relative frequency within the normal population, should not be used to clinically stratify these patients. Prospective studies are required to confirm the clinical significance of myocardial crypts, as their significance remains unclear.