Dudley J. Pennell

Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy

Fast breath-hold cardiovascular magnetic resonance (CMR) shows excellent results for interstudy reproducibility of left ventricular (LV) volumes, ejection fraction, and mass, which are thought to be superior to results of 2-dimensional echocardiography. However, there is no direct comparison of the interstudy reproducibility of both methods in the same subjects. A total of 60 subjects (normal volunteers [n = 20], or patients with heart failure [n = 20] or LV hypertrophy [n = 20]) underwent 2 CMRs and 2 echocardiographic studies for assessment of LV volumes, function, and mass. The interstudy reproducibility coefficient of variability was superior for CMR in all groups for all parameters. Statistical significance was reached for end-systolic volume (4.4% to 9.2% vs 13.7% to 20.3%, p <0.001), ejection fraction (2.4% to 7.3% vs 8.6% to 19.4%, p <0.001), and mass (2.8% to 4.8% vs 11.6% to 15.7% p <0.001), with a trend for end-diastolic volume (2.9% to 4.9% vs 5.5% to 10.5%, p = 0.17). The superior interstudy reproducibility resulted in considerably lower calculated sample sizes (reductions of 55% to 93%) required by CMR compared with echocardiography to show clinically relevant changes in LV dimensions and function. Thus, CMR has excellent interstudy reproducibility in normal, dilated, and hypertrophic hearts, and is superior to 2-dimensional echocardiography.

Differentiation of Heart Failure Related to Dilated Cardiomyopathy and Coronary Artery Disease Using Gadolinium-Enhanced Cardiovascular Magnetic Resonance

Background Heart failure treatment depends partly on the underlying cause of the disease. We evaluated cardiovascular magnetic resonance (CMR) for the problem of differentiating dilated cardiomyopathy (DCM) from left ventricular (LV) dysfunction caused by coronary artery disease (CAD). Methods and Results Late gadolinium enhancement with CMR was performed in 90 patients with heart failure and LV systolic dysfunction (63 patients with DCM and unobstructed coronary arteries and 27 with significant CAD at angiography). We also studied 15 control subjects with no coronary risk factors and/or unobstructed coronary arteries. None (0%) of the control subjects had myocardial gadolinium enhancement; however, all patients (100%) with LV dysfunction and CAD had enhancement, which was subendocardial or transmural. In patients with DCM, there were 3 findings: no enhancement (59%); myocardial enhancement indistinguishable from the patients with CAD (13%); and patchy or longitudinal striae of midwall enhancement clearly different from the distribution in patients with CAD (28%). Conclusions Gadolinium CMR is a powerful technique to distinguish DCM from LV dysfunction related to CAD and yields new insights in DCM. These data suggest that using the coronary angiogram as the arbiter for the presence of LV dysfunction caused by CAD could have lead to an incorrect assignment of DCM cause in 13% of patients, possibly because of coronary recanalization after infarction. The midwall myocardial enhancement in patients with DCM is similar to the fibrosis found at autopsy; it has not previously been visualized in vivo and warrants further investigation. CMR may become a useful alternative to routine coronary angiography in the diagnostic workup of DCM. (Circulation. 2003;108:54‐59.)

Toward clinical risk assessment inhypertrophic cardiomyopathy withgadolinium cardiovascular magnetic resonance

OBJECTIVES We sought to assess whether hyperenhancement by gadolinium cardiovascular magnetic resonance (CMR) occurs in hypertrophic cardiomyopathy (HCM) and correlates with the risk of heart failure and sudden death. BACKGROUND The myocardial interstitium is abnormal in HCM at post-mortem. Focally increased interstitial myocardial space appears as hyperenhancement with gadolinium CMR. METHODS In a blinded, prospective study, HCM patients were selected for the presence (n = 23) or absence (n = 30) of an increased clinical risk of sudden death and/or progressive adverse left ventricular (LV) remodeling. Gadolinium-enhanced CMR was performed. RESULTS Myocardial hyperenhancement was found in 42 patients (79%), affecting 10.9% (range 0% to 48%) of the LV mass. There was a greater extent of hyperenhancement in patients with progressive disease (28.5% vs. 8.7%, p < 0.001) and in patients with two or more risk factors for sudden death (15.7% vs. 8.6%, p = 0.02). Improved discrimination was seen in patients >40 years old (29.6% vs. 6.7%, p < 0.001) for progressive disease and for patients <40 years old for risk factors for sudden death (15.7% vs. 2.1%, p = 0.002). Patients with diffuse rather than confluent enhancement had two or more risk factors for sudden death (87% vs. 33%, p = 0.01). CONCLUSIONS Gadolinium CMR reveals myocardial hyperenhancement in HCM. The extent of hyperenhancement is associated with progressive ventricular dilation and markers of sudden death.

Cardiovascular Magnetic Resonance in Cardiac Amyloidosis

Background—Cardiac amyloidosis can be diagnostically challenging. Cardiovascular magnetic resonance (CMR) can assess abnormal myocardial interstitium. Methods and Results—Late gadolinium enhancement CMR was performed in 30 patients with cardiac amyloidosis. In 22 of these, myocardial gadolinium kinetics with T1 mapping was compared with that in 16 hypertensive controls. One patient had CMR and autopsy only. Subendocardial T1 in amyloid patients was shorter than in controls (at 4 minutes: 427±73 versus 579±75 ms; P<0.01), was shorter than subepicardium T1 for the first 8 minutes (P≤0.01), and was correlated with markers of increased myocardial amyloid load, as follows: left ventricular (LV) mass (r=−0.51, P=0.013); wall thickness (r=−0.54 to −0.63, P<0.04); interatrial septal thickness (r=−0.52, P=0.001); and diastolic function (r=−0.42, P=0.025). Global subendocardial late gadolinium enhancement was found in 20 amyloid patients (69%); these patients had greater LV mass (126±30 versus 93±25 g/m2; P=0.009) than unenhanced patients. Histological quantification showed substantial interstitial expansion with amyloid (30.5%) but only minor fibrosis (1.3%). Amyloid was dominantly subendocardial (42%) compared with midwall (29%) and subepicardium (18%). There was 97% concordance in diagnosis of cardiac amyloid by combining the presence of late gadolinium enhancement and an optimized T1 threshold (191 ms at 4 minutes) between myocardium and blood. Conclusions—In cardiac amyloidosis, CMR shows a characteristic pattern of global subendocardial late enhancement coupled with abnormal myocardial and blood-pool gadolinium kinetics. The findings agree with the transmural histological distribution of amyloid protein and the cardiac amyloid load and may prove to have value in diagnosis and treatment follow-up.

Reduction in Sample Size for Studies of Remodeling in Heart Failure by the Use of Cardiovascular Magnetic Resonance

Fast breathhold cardiovascular magnetic resonance (CMR) has become a reference standard for the measurement of cardiac volumes, function, and mass. The implications of this for sample sizes for remodeling studies in heart failure (HF) have not been elucidated. We determined the reproducibility of CMR in HF and calculated the sample size requirements and compared them with published values for echocardiography. Breathhold gradient echo cines of the left ventricle were acquired in 20 patients with HF and 20 normal subjects. Sample size values were calculated from the interstudy standard deviation of the difference. The percentage variability of the measured parameters in our HF group of intraobserver (2.0-7.4%), interobserver (3.3-7.7%), and interstudy (2.5-4.8%) measurements was slightly larger than for our normal group (1.6-6.6%, 1.6-7.3%, and 2.0-7.3%, respectively) but remained comparable with previous studies in normal subjects. The calculated sample sizes in patients with HF for CMR to detect a 10-ml change in end-diastolic volume (n = 12) and end-systolic volume (n = 10), a 3% change in ejection fraction (n = 15), and a 10-g change in mass was (n = 9) were substantially smaller than recently published values for two-dimensional echocardiography (reduction of 81-97%). Breathhold CMR is a fast comprehensive technique for the assessment of cardiac volumes, function, and mass in HF that is accurate but also highly reproducible. This allows a considerable reduction in the patient numbers required to prove a hypothesis in research studies, which suggests a potential for important research cost savings.

Truncations of Titin Causing Dilated Cardiomyopathy

BACKGROUND Dilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size. METHODS We analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics. RESULTS We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P=3×10(-16)) or controls (7 of 249 [3%], P=9×10(-14)). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P≤0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P=4×10(-5)). CONCLUSIONS TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.).

Prognostic Significance of Myocardial Fibrosis in Hypertrophic Cardiomyopathy

OBJECTIVES We investigated the significance of fibrosis detected by late gadolinium enhancement cardiovascular magnetic resonance for the prediction of major clinical events in hypertrophic cardiomyopathy (HCM). BACKGROUND The role of myocardial fibrosis in the prediction of sudden death and heart failure in HCM is unclear with a lack of prospective data. METHODS We assessed the presence and amount of myocardial fibrosis in HCM patients and prospectively followed them for the development of morbidity and mortality in patients over 3.1 +/- 1.7 years. RESULTS Of 217 consecutive HCM patients, 136 (63%) showed fibrosis. Thirty-four of the 136 patients (25%) in the fibrosis group but only 6 of 81 (7.4%) patients without fibrosis reached the combined primary end point of cardiovascular death, unplanned cardiovascular admission, sustained ventricular tachycardia or ventricular fibrillation, or appropriate implantable cardioverter-defibrillator discharge (hazard ratio [HR]: 3.4, p = 0.006). In the fibrosis group, overall risk increased with the extent of fibrosis (HR: 1.18/5% increase, p = 0.008). The risk of unplanned heart failure admissions, deterioration to New York Heart Association functional class III or IV, or heart failure-related death was greater in the fibrosis group (HR: 2.5, p = 0.021), and this risk increased as the extent of fibrosis increased (HR: 1.16/5% increase, p = 0.017). All relationships remained significant after multivariate analysis. The extent of fibrosis and nonsustained ventricular tachycardia were univariate predictors for arrhythmic end points (sustained ventricular tachycardia or ventricular fibrillation, appropriate implantable cardioverter-defibrillator discharge, sudden cardiac death) (HR: 1.30, p = 0.014). Nonsustained ventricular tachycardia remained an independent predictor of arrhythmic end points after multivariate analysis, but the extent of fibrosis did not. CONCLUSIONS In patients with HCM, myocardial fibrosis as measured by late gadolinium enhancement cardiovascular magnetic resonance is an independent predictor of adverse outcome. (The Prognostic Significance of Fibrosis Detection in Cardiomyopathy; NCT00930735).

Normalized Left Ventricular Systolic and Diastolic Function by Steady State Free Precession Cardiovascular Magnetic Resonance

We used state of the art CMR to define ranges for normal left ventricular volumes and systolic/diastolic function normalized to the influence of gender, body surface area and age. New CMR normalized ranges were modeled and displayed in graphical form for clinical use, with normalization for body surface area, gender, and age. The determination of normality, or the severity of abnormality, depends on the use of the appropriate reference ranges normalized to all 3 variables. These novel data have particular importance for clinical practice and clinical trials using CMR.

Right ventricular function in adults with repaired tetralogy of Fallot assessed with cardiovascular magnetic resonance imaging: detrimental role of right ventricular outflow aneurysms or akinesia and adverse right-to-left ventricular interaction.

OBJECTIVES We examined the relationship among biventricular hemodynamics, pulmonary regurgitant fraction (PRF), right ventricular outflow tract (RVOT) aneurysm or akinesia, and baseline and surgical characteristics in adults with repaired tetralogy of Fallot (rTOF). BACKGROUND The precise relationship of pulmonary regurgitation with biventricular hemodynamics has been hampered by limitations of right ventricular (RV) imaging. METHODS We assessed 85 consecutive adults with rTOF and 26 matched healthy controls using cardiovascular magnetic resonance imaging. RESULTS Patients had higher right ventricular end-diastolic volume index (RVEDVi) (p < 0.001), right ventricular end-systolic volume index (RVESVi) (p < 0.001), right ventricular mass index (RVMi) (p < 0.001), and lower right ventricular ejection fraction (RVEF) (p < 0.001) and left ventricular ejection fraction (LVEF) (p = 0.002) compared to controls. The PRF (range 0% to 55%) independently predicted RVEDVi (p < 0.01) and the latter predicted RVESVi (p < 0.01) and RVMi (p < 0.01). The RVOT aneurysm/akinesia was present in 48/85 (56.9%) of patients and predicted RV volumes (RVEDVi, p = 0.01, and RVESVi, p = 0.03). There was a negative effect of RVOT aneurysm/akinesia and RVMi on RVEF (p < 0.01 and p = 0.02, respectively). There was only a tendency among patients with transannular or RVOT patching toward RVOT aneurysm/akinesia (p = 0.09). The LVEF correlated with RVEF (r = 0.67, p < 0.001). CONCLUSIONS Pulmonary regurgitation and RVOT aneurysm/akinesia were independently associated with RV dilation and the latter with RV hypertrophy late after rTOF. The RVOT aneurysm/akinesia was common but related only in part to RVOT or transannular patching. Both RV hypertrophy and RVOT aneurysm/akinesia were associated with lower RVEF. Left ventricular systolic dysfunction correlated with RV dysfunction, suggesting an unfavorable ventricular-ventricular interaction. Measures to maintain or restore pulmonary valve function and avoid RVOT aneurysm/akinesia are mandatory for preserving biventricular function late after rTOF.

Ventricular Fibrosis Suggested by Cardiovascular Magnetic Resonance in Adults With Repaired Tetralogy of Fallot and Its Relationship to Adverse Markers of Clinical Outcome

Background— Late morbidity and mortality remain problematic after repair of tetralogy of Fallot (TOF). We hypothesized that fibrosis detected by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) would be present in adults with repaired TOF and would be related to adverse markers of outcome. Method and Results— LGE was scored in the right and left ventricles (RV and LV) of 92 adult patients who had undergone TOF repair. RV LGE was seen in all patients at surgical sites located in the outflow tract (99%) or the site of ventricular septal defect patching (98%) and in the inferior RV insertion point (79%) and trabeculated myocardium (24%). LV LGE (53%) was located at the apex consistent with apical vent insertion (49%), in the inferior or lateral wall consistent with infarction (5%), or in other areas (8%). Patients with supramedian RV LGE score were older (38 versus 27 years, P<0.001) and more symptomatic (38% versus 8% in New York Heart Association class II or greater, P=0.001), had increased levels of atrial natriuretic peptide (7.3 versus 4.9 pmol/L, P=0.041), and had a trend to higher brain natriuretic peptide (12.3 versus 7.2 pmol/L, P=0.086), exercise intolerance (maximum &OV0312;o2 24 versus 28 mL · min−1 · kg−1, P=0.021), RV dysfunction (RV end-systolic volume 61 versus 55 mL/m2, P=0.018; RV ejection fraction 50% versus 56%, P=0.007), and clinical arrhythmia (26% versus 10%, P=0.039). Non–apical vent LV LGE also correlated with markers of adverse outcome. In a multivariate model, RV LGE remained a predictor of arrhythmia. Conclusions— RV and LV LGE were common after TOF repair and were related to adverse clinical markers, including ventricular dysfunction, exercise intolerance, and neurohormonal activation. Furthermore, RV LGE was significantly associated with clinical arrhythmia.