Sanjay Prasad

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.)

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.

Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning.

Stress cardiomyopathy, also referred to as Takotsubo cardiomyopathy, is an increasingly recognized clinical syndrome characterized by acute reversible apical ventricular dysfunction. We hypothesize that stress cardiomyopathy is a form of myocardial stunning, but with different cellular mechanisms to those seen during transient episodes of ischemia secondary to coronary stenoses. In this syndrome, we believe that high levels of circulating epinephrine trigger a switch in intracellular signal trafficking in ventricular cardiomyocytes, from Gs protein to Gi protein signaling via the β2-adrenoceptor. Although this switch to β2-adrenoceptor–Gi protein signaling protects against the proapoptotic effects of intense activation of β1-adrenoceptors, it is also negatively inotropic. This effect is greatest at the apical myocardium, in which the β-adrenoceptor density is greatest. Our hypothesis has implications for the use of drugs or devices in the treatment of patients with stress cardiomyopathy.

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.

Association of Fibrosis With Mortality and Sudden Cardiac Death in Patients With Nonischemic Dilated Cardiomyopathy

IMPORTANCE Risk stratification of patients with nonischemic dilated cardiomyopathy is primarily based on left ventricular ejection fraction (LVEF). Superior prognostic factors may improve patient selection for implantable cardioverter-defibrillators (ICDs) and other management decisions. OBJECTIVE To determine whether myocardial fibrosis (detected by late gadolinium enhancement cardiovascular magnetic resonance [LGE-CMR] imaging) is an independent and incremental predictor of mortality and sudden cardiac death (SCD) in dilated cardiomyopathy. DESIGN, SETTING, AND PATIENTS Prospective, longitudinal study of 472 patients with dilated cardiomyopathy referred to a UK center for CMR imaging between November 2000 and December 2008 after presence and extent of midwall replacement fibrosis were determined. Patients were followed up through December 2011. MAIN OUTCOME MEASURES Primary end point was all-cause mortality. Secondary end points included cardiovascular mortality or cardiac transplantation; an arrhythmic composite of SCD or aborted SCD (appropriate ICD shock, nonfatal ventricular fibrillation, or sustained ventricular tachycardia); and a composite of HF death, HF hospitalization, or cardiac transplantation. RESULTS Among the 142 patients with midwall fibrosis, there were 38 deaths (26.8%) vs 35 deaths (10.6%) among the 330 patients without fibrosis (hazard ratio [HR], 2.96 [95% CI, 1.87-4.69]; absolute risk difference, 16.2% [95% CI, 8.2%-24.2%]; P < .001) during a median follow-up of 5.3 years (2557 patient-years of follow-up). The arrhythmic composite was reached by 42 patients with fibrosis (29.6%) and 23 patients without fibrosis (7.0%) (HR, 5.24 [95% CI, 3.15-8.72]; absolute risk difference, 22.6% [95% CI, 14.6%-30.6%]; P < .001). After adjustment for LVEF and other conventional prognostic factors, both the presence of fibrosis (HR, 2.43 [95% CI, 1.50-3.92]; P < .001) and the extent (HR, 1.11 [95% CI, 1.06-1.16]; P < .001) were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation (by fibrosis presence: HR, 3.22 [95% CI, 1.95-5.31], P < .001; and by fibrosis extent: HR, 1.15 [95% CI, 1.10-1.20], P < .001), SCD or aborted SCD (by fibrosis presence: HR, 4.61 [95% CI, 2.75-7.74], P < .001; and by fibrosis extent: HR, 1.10 [95% CI, 1.05-1.16], P < .001), and the HF composite (by fibrosis presence: HR, 1.62 [95% CI, 1.00-2.61], P = .049; and by fibrosis extent: HR, 1.08 [95% CI, 1.04-1.13], P < .001). Addition of fibrosis to LVEF significantly improved risk reclassification for all-cause mortality and the SCD composite (net reclassification improvement: 0.26 [95% CI, 0.11-0.41]; P = .001 and 0.29 [95% CI, 0.11-0.48]; P = .002, respectively). CONCLUSIONS AND RELEVANCE Assessment of midwall fibrosis with LGE-CMR imaging provided independent prognostic information beyond LVEF in patients with nonischemic dilated cardiomyopathy. The role of LGE-CMR in the risk stratification of dilated cardiomyopathy requires further investigation.

Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis.

OBJECTIVES The goal of this study was to assess the prognostic significance of midwall and infarct patterns of late gadolinium enhancement (LGE) in aortic stenosis. BACKGROUND Myocardial fibrosis occurs in aortic stenosis as part of the hypertrophic response. It can be detected by LGE, which is associated with an adverse prognosis in a range of other cardiac conditions. METHODS Between January 2003 and October 2008, consecutive patients with moderate or severe aortic stenosis undergoing cardiovascular magnetic resonance with administration of gadolinium contrast were enrolled into a registry. Patients were categorized into absent, midwall, or infarct patterns of LGE by blinded independent observers. Patient follow-up was completed using patient questionnaires, source record data, and the National Strategic Tracing Service. RESULTS A total of 143 patients (age 68 ± 14 years; 97 male) were followed up for 2.0 ± 1.4 years. Seventy-two underwent aortic valve replacement, and 27 died (24 cardiac, 3 sudden cardiac deaths). Compared with those with no LGE (n = 49), univariate analysis revealed that patients with midwall fibrosis (n = 54) had an 8-fold increase in all-cause mortality despite similar aortic stenosis severity and coronary artery disease burden. Patients with an infarct pattern (n = 40) had a 6-fold increase. Midwall fibrosis (hazard ratio: 5.35; 95% confidence interval: 1.16 to 24.56; p = 0.03) and ejection fraction (hazard ratio: 0.96; 95% confidence interval: 0.94 to 0.99; p = 0.01) were independent predictors of all-cause mortality by multivariate analysis. CONCLUSIONS Midwall fibrosis was an independent predictor of mortality in patients with moderate and severe aortic stenosis. It has incremental prognostic value to ejection fraction and may provide a useful method of risk stratification.

169 Mid-wall fibrosis is an independent predictor of mortality in patients with aortic stenosis

Introduction Predicting adverse clinical outcomes in aortic stenosis is challenging. Late gadolinium enhancement (LGE) has been associated with an adverse prognosis in a range of other cardiac conditions. Using late gadolinium enhancement, we sought to assess the prognostic significance of mid-wall and infarct patterns of myocardial fibrosis in aortic stenosis. Methods Between January 2003 and October 2008, consecutive patients with moderate or severe aortic stenosis (aortic valve area <1.5 cm2) underwent cardiovascular magnetic resonance with assessment of myocardial fibrosis by late gadolinium enhancement. Patients were categorised into absent, mid-wall or infarct patterns of late gadolinium enhancement by blinded independent observers. Patient follow-up was completed using the National Strategic Tracing Scheme. Results 143 patients (aged 68±14 years; 97 male) were followed up for 2.0±1.4 years. 81 patients had coronary artery disease, 72 underwent aortic valve replacement and 27 died. Compared to those with no late gadolinium enhancement (n=49), univariate analysis revealed that patients with mid-wall fibrosis (n=54) had an eightfold increase in all-cause mortality despite similar aortic stenosis severity and coronary artery disease burden. Patients with an infarct pattern (n=40) had a six-fold increase. Mid-wall fibrosis (HR, 5.35 (95% CI, 1.16 to 24.56); p=0.03) and ejection fraction (HR 0.96 (95% CI, 0.94 to 0.99); p=0.01) were independent predictors of all cause mortality by multivariate analysis. Conclusion: Mid-wall fibrosis is an independent predictor of mortality in patients with moderate and severe aortic stenosis. It has incremental prognostic value to ejection fraction and may provide a useful method of risk stratification in patients with advanced disease (Abstract 169 figure 1).Abstract 169 Figure 1 Kaplan-Meier curves of cardiac mortality (left) and all cause mortality (right) according to pattern of LGE (A= No LGE, B= Infarct LGE, C= Mid-wall LGE).Abstract 169 Table 1 No LGE Mid-wall LGE Infarct LGE p Value Number of patients 49 54 40 – Mean age yrs 64±16 70±11 70±13 0.031 Documented CAD % 37 42 98 <0.001 Ejection fraction % 69±13 58±21 44±18 <0.001 Aortic valve area 1.05±0.37 1.00±0.31 0.91±0.26 0.111 Indexed LV mass g/m2 92.6* (86.0, 99.6) 113.7* (104.5, 123.8) 97.8* (90.9, 105.2) 0.005 Mortality rate (deaths / 1000 pt years) 15.7 142.7 173.7 * Geometric mean (95%)

Cardiovascular Magnetic Resonance and prognosis in cardiac amyloidosis

BackgroundCardiac involvement is common in amyloidosis and associated with a variably adverse outcome. We have previously shown that cardiovascular magnetic resonance (CMR) can assess deposition of amyloid protein in the myocardial interstitium. In this study we assessed the prognostic value of late gadolinium enhancement (LGE) and gadolinium kinetics in cardiac amyloidosis in a prospective longitudinal study.Materials and methodsThe pre-defined study end point was all-cause mortality. We prospectively followed a cohort of 29 patients with proven cardiac amyloidosis. All patients underwent biopsy, 2D-echocardiography and Doppler studies, 123I-SAP scintigraphy, serum NT pro BNP assay, and CMR with a T1 mapping method and late gadolinium enhancement (LGE).ResultsPatients with were followed for a median of 623 days (IQ range 221, 1436), during which 17 (58%) patients died. The presence of myocardial LGE by itself was not a significant predictor of mortality. However, death was predicted by gadolinium kinetics, with the 2 minute post-gadolinium intramyocardial T1 difference between subepicardium and subendocardium predicting mortality with 85% accuracy at a threshold value of 23 ms (the lower the difference the worse the prognosis). Intramyocardial T1 gradient was a better predictor of survival than FLC response to chemotherapy (Kaplan Meier analysis P = 0.049) or diastolic function (Kaplan-Meier analysis P = 0.205).ConclusionIn cardiac amyloidosis, CMR provides unique information relating to risk of mortality based on gadolinium kinetics which reflects the severity of the cardiac amyloid burden.

Multimodality Imaging in Transcatheter Aortic Valve Implantation and Post-Procedural Aortic Regurgitation : Comparison Among Cardiovascular Magnetic Resonance, Cardiac Computed Tomography, and Echocardiography

OBJECTIVES The purpose of this study was to determine imaging predictors of aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) and the agreement and reproducibility of cardiovascular magnetic resonance (CMR), cardiac computed tomography (CCT), and transthoracic echocardiography (TTE) in aortic root assessment. BACKGROUND The optimal imaging strategy for planning TAVI is unclear with a paucity of comparative multimodality imaging data. The association between aortic root morphology and outcomes after TAVI also remains incompletely understood. METHODS A total of 202 consecutive patients assessed by CMR, CCT, and TTE for TAVI were studied. Agreement and variability among and within imaging modalities was assessed by Bland-Altman analysis. Postoperative AR was assessed by TTE. RESULTS Of the 202 patients undergoing TAVI assessment with both CMR and TTE, 133 also underwent CCT. Close agreement was observed between CMR and CCT in dimensions of the aortic annulus (bias, -0.4 mm; 95% limits of agreement: -5.7 to 5.0 mm), and similarly for sinus of Valsalva, sinotubular junction, and ascending aortic measures. Agreement between TTE-derived measures and either CMR or CCT was less precise. Intraobserver and interobserver variability were lowest with CMR. The presence and severity of AR after TAVI were associated with larger aortic valve annulus measurements by both CMR (p = 0.03) and CCT (p = 0.04) but not TTE-derived measures (p = 0.10). Neither CCT nor CMR measures of annulus eccentricity, however, predicted AR after TAVI (p = 0.33 and p = 0.78, respectively). CONCLUSIONS In patients undergoing imaging assessment for TAVI, the presence and severity of AR after TAVI were associated with larger aortic annulus measurements by both CMR and CCT, but not TTE. Both CMR and CCT provide highly reproducible information in the assessment of patients undergoing TAVI.