Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial.

BACKGROUND: Omega-3 fatty acids from fish oil have been associated with beneficial cardiovascular effects, but their role in modifying cardiac structures and tissue characteristics in patients who have had an acute myocardial infarction while receiving current guideline-based therapy remains unknown. METHODS: In a multicenter, double-blind, placebo-controlled trial, participants presenting with an acute myocardial infarction were randomly assigned 1:1 to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and after study therapy. The primary study endpoint was change in left ventricular systolic volume index. Secondary endpoints included change in noninfarct myocardial fibrosis, left ventricular ejection fraction, and infarct size. RESULTS: By intention-to-treat analysis, patients randomly assigned to omega-3 fatty acids experienced a significant reduction of left ventricular systolic volume index (-5.8%, P=0.017), and noninfarct myocardial fibrosis (-5.6%, P=0.026) in comparison with placebo. Per-protocol analysis revealed that those patients who achieved the highest quartile increase in red blood cell omega-3 index experienced a 13% reduction in left ventricular systolic volume index in comparison with the lowest quartile. In addition, patients in the omega-3 fatty acid arm underwent significant reductions in serum biomarkers of systemic and vascular inflammation and myocardial fibrosis. There were no adverse events associated with high-dose omega-3 fatty acid therapy. CONCLUSIONS: Treatment of patients with acute myocardial infarction with high-dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond current guideline-based standard of care. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00729430.

Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in the young, although not all patients eligible for sudden death prevention with an implantable cardioverter-defibrillator are identified. Contrast-enhanced cardiovascular magnetic resonance with late gadolinium enhancement (LGE) has emerged as an in vivo marker of myocardial fibrosis, although its role in stratifying sudden death risk in subgroups of HCM patients remains incompletely understood. METHODS AND RESULTS: We assessed the relation between LGE and cardiovascular outcomes in 1293 HCM patients referred for cardiovascular magnetic resonance and followed up for a median of 3.3 years. Sudden cardiac death (SCD) events (including appropriate defibrillator interventions) occurred in 37 patients (3%). A continuous relationship was evident between LGE by percent left ventricular mass and SCD event risk in HCM patients (P=0.001). Extent of LGE was associated with an increased risk of SCD events (adjusted hazard ratio, 1.46/10% increase in LGE; P=0.002), even after adjustment for other relevant disease variables. LGE of ≥15% of LV mass demonstrated a 2-fold increase in SCD event risk in those patients otherwise considered to be at lower risk, with an estimated likelihood for SCD events of 6% at 5 years. Performance of the SCD event risk model was enhanced by LGE (net reclassification index, 12.9%; 95% confidence interval, 0.3-38.3). Absence of LGE was associated with lower risk for SCD events (adjusted hazard ratio, 0.39; P=0.02). Extent of LGE also predicted the development of end-stage HCM with systolic dysfunction (adjusted hazard ratio, 1.80/10% increase in LGE; P<0.03). CONCLUSIONS: Extensive LGE measured by quantitative contrast enhanced CMR provides additional information for assessing SCD event risk among HCM patients, particularly patients otherwise judged to be at low risk.

Hypertrophic Cardiomyopathy Registry: The rationale and design of an international, observational study of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease with a frequency as high as 1 in 200. In many cases, HCM is caused by mutations in genes encoding the different components of the sarcomere apparatus. Hypertrophic cardiomyopathy is characterized by unexplained left ventricular hypertrophy, myofibrillar disarray, and myocardial fibrosis. The phenotypic expression is quite variable. Although most patients with HCM are asymptomatic, serious consequences are experienced in a subset of affected individuals who present initially with sudden cardiac death or progress to refractory heart failure. The Hypertrophic Cardiomyopathy Registry study is a National Heart, Lung, and Blood Institute-sponsored 2,750-patient, 44-site, international registry and natural history study designed to address limitations in extant evidence to improve prognostication in HCM (NCT01915615). In addition to the collection of standard demographic, clinical, and echocardiographic variables, patients will undergo state-of-the-art cardiac magnetic resonance for assessment of left ventricular mass and volumes as well as replacement scarring and interstitial fibrosis. In addition, genetic and biomarker analyses will be performed. The Hypertrophic Cardiomyopathy Registry has the potential to change the paradigm of risk stratification in HCM, using novel markers to identify those at higher risk.

Significance of left ventricular apical-basal muscle bundle identified by cardiovascular magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

AIMS: Cardiovascular magnetic resonance (CMR) has improved diagnostic and management strategies in hypertrophic cardiomyopathy (HCM) by expanding our appreciation for the diverse phenotypic expression. We sought to characterize the prevalence and clinical significance of a recently identified accessory left ventricular (LV) muscle bundle extending from the apex to the basal septum or anterior wall (i.e. apical-basal). METHODS AND RESULTS: CMR was performed in 230 genotyped HCM patients (48 ± 15 years, 69% male), 30 genotype-positive/phenotype-negative (G+/P-) family members (32 ± 15 years, 30% male), and 126 controls. Left ventricular apical-basal muscle bundle was identified in 145 of 230 (63%) HCM patients, 18 of 30 (60%) G+/P- family members, and 12 of 126 (10%) controls (G+/P- vs. controls; P < 0.01). In HCM patients, the prevalence of an apical-basal muscle bundle was similar among those with disease-causing sarcomere mutations compared with patients without mutation (64 vs. 62%; P = 0.88). The presence of an LV apical-basal muscle bundle was not associated with LV outflow tract obstruction (P = 0.61). In follow-up, 33 patients underwent surgical myectomy of whom 22 (67%) were identified to have an accessory LV apical-basal muscle bundle, which was resected in all patients. CONCLUSION: Apical-basal muscle bundles are a unique myocardial structure commonly present in HCM patients as well as in G+/P- family members and may represent an additional morphologic marker for HCM diagnosis in genotype-positive status.

Risk stratification and outcome of patients with hypertrophic cardiomyopathy >=60 years of age.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is prominently associated with risk for sudden death and disease progression, largely in young patients. Whether patients of more advanced age harbor similar risks is unresolved, often creating clinical dilemmas, particularly in decisions for primary prevention of sudden death with implantable defibrillators. METHODS AND RESULTS: We studied 428 consecutive HCM patients presenting at ≥60 years of age and followed for 5.8±4.8 years; 53% were women. Of the 428 patients, 279 (65%) survived to 73±7 years of age (range, 61-96 years), most (n=245, 88%) with no/mild symptoms, including 135 with ≥1 conventional sudden death risk factors and 50 (37%) with late gadolinium enhancement. Over follow-up, 149 (35%) died at 80±8 years of age, mostly from non-HCM-related causes (n=133, 31%), including a substantial proportion from noncardiac disease (n=54). Sixteen patients (3.7%) had HCM-related mortality events (0.64%/y), including embolic stroke (n=6), progressive heart failure or transplantation (n=3), postoperative complications (n=2), and arrhythmic sudden death events (n=5, 1.2% [0.20%/y]). All-cause mortality was increased in HCM patients ≥60 years of age compared with an age-matched US general population, predominantly as a result of non-HCM-related diseases (P<0.001; standard mortality ratio, 1.5). CONCLUSIONS: HCM patients surviving into the seventh decade of life are at low risk for disease-related morbidity/mortality, including sudden death, even with conventional risk factors. These data do not support aggressive prophylactic defibrillator implantation at advanced ages in HCM. Other cardiac or noncardiac comorbidities have a greater impact on survival than HCM in older patients.

3-Dimensional Strain Analysis of Hypertrophic Cardiomyopathy: Insights From the NHLBI International HCM Registry.

BACKGROUND: Abnormal global longitudinal strain (GLS) has been independently associated with adverse cardiac outcomes in both obstructive and nonobstructive hypertrophic cardiomyopathy. OBJECTIVES: The goal of this study was to understand predictors of abnormal GLS from baseline data from the National Heart, Lung, and Blood Institute (NHLBI) Hypertrophic Cardiomyopathy Registry (HCMR). METHODS: The study evaluated comprehensive 3-dimensional left ventricular myocardial strain from cine cardiac magnetic resonance in 2,311 patients from HCMR using in-house validated feature-tracking software. These data were correlated with other imaging markers, serum biomarkers, and demographic variables. RESULTS: Abnormal median GLS (> -11.0%) was associated with higher left ventricular (LV) mass index (93.8 ± 29.2 g/m2 vs 75.1 ± 19.7 g/m2; P < 0.0001) and maximal wall thickness (21.7 ± 5.2 mm vs 19.3 ± 4.1 mm; P < 0.0001), lower left (62% ± 9% vs 66% ± 7%; P < 0.0001) and right (68% ± 11% vs 69% ± 10%; P < 0.01) ventricular ejection fractions, lower left atrial emptying functions (P < 0.0001 for all), and higher presence and myocardial extent of late gadolinium enhancement (6 SD and visual quantification; P < 0.0001 for both). Elastic net regression showed that adjusted predictors of GLS included female sex, Black race, history of syncope, presence of systolic anterior motion of the mitral valve, reverse curvature and apical morphologies, LV ejection fraction, LV mass index, and both presence/extent of late gadolinium enhancement and baseline N-terminal pro-B-type natriuretic peptide and troponin levels. CONCLUSIONS: Abnormal strain in hypertrophic cardiomyopathy is associated with other imaging and serum biomarkers of increased risk. Further follow-up of the HCMR cohort is needed to understand the independent relationship between LV strain and adverse cardiac outcomes in hypertrophic cardiomyopathy.

Autologous cardiomyotissue implantation promotes myocardial regeneration, decreases infarct size, and improves left ventricular function.

BACKGROUND: Cell therapy for myocardial infarction (MI) may be limited by poor cell survival and lack of transdifferentiation. We report a novel technique of implanting whole autologous myocardial tissue from preserved myocardial regions into infarcted regions. METHODS AND RESULTS: Fourteen rats were used to optimize cardiomyotissue size with peritoneal wall implantation (300 µm identified as optimal size). Thirty-nine pigs were used to investigate cardiomyotissue implantation in MI induced by left anterior descending balloon occlusion (10 animals died; male-to-female transplantation for tracking with in situ hybridization for Y chromosome, n=4 [2 donors and 2 MI animals]; acute MI implantation cohort at 1 hour, n=13; and healed MI implantation at 2 weeks, n=12). Assessment included echocardiography, magnetic resonance imaging, hemodynamics, triphenyltetrazolium chloride staining, and histological and molecular analyses. Tracking studies demonstrated viable implants with donor cells interspersed in the adjacent myocardium with gap junctions and desmosomes. In the acute MI cohort, treated animals compared with controls had improved perfusion by magnetic resonance imaging (1.2±0.01 versus 0.86±0.05; P<0.01), decreased MI size (magnetic resonance imaging: left ventricle, 2.2±0.5% versus 5.4±1.5%, P=0.04; triphenyltetrazolium chloride: anterior wall, 10.3±4.6% versus 28.9±5.8%, P<0.03), and improved contractility (dP/dt, 1235±215 versus 817±817; P<0.05). In the healed MI cohort, treated animals had less decline in ejection fraction between 2 and 4 week assessment (-3±4% versus -13±-4%; P<0.05), less decline in ±dP/dt, and smaller MI (triphenyltetrazolium chloride, 21±11% versus 3±8%; P=0.006) than control animals. Infarcts in the treated animals contained more mdr-1(+) cells and fewer c-kit(+) cells with a trend for decreased expression of matrix metalloproteinase-2 and increased expression of tissue inhibitor of metalloproteinase-2. CONCLUSION: Autologous cardiomyotissue implanted in an MI area remains viable, exhibits electromechanical coupling, decreases infarct size, and improves left ventricular function.

Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy.

BACKGROUND: Whether morphological abnormalities of the mitral valve represent part of the hypertrophic cardiomyopathy (HCM) disease process is unresolved. Therefore, we applied cardiovascular magnetic resonance to characterize mitral valve morphology in a large HCM cohort. METHODS AND RESULTS: Cine cardiac magnetic resonance images were obtained in 172 HCM patients (age, 42±18 years; 62% men) and 172 control subjects. In addition, 15 HCM gene-positive/phenotype-negative relatives were studied. Anterior mitral leaflet (AML) and posterior mitral leaflet lengths were greater in HCM patients than in control subjects (26±5 versus 19±5 mm, P<0.001; and 14±4 versus 10±3 mm, P<0.001, respectively), including 59 patients (34%) in whom AML length alone, posterior mitral leaflet length alone, or both were particularly substantial (>2 SDs above controls). Leaflet length was increased compared with controls in virtually all HCM age groups, including young patients 15 to 20 years of age (AML, 26±5 versus 21±4 mm; P=0.0002) and those ≥60 years of age (AML, 26±4 versus 19±2 mm; P<0.001). No relation was evident between mitral leaflet length and LV thickness or mass index (P=0.09 and P=0.16, respectively). A ratio of AML length to LV outflow tract diameter of >2.0 was associated with subaortic obstruction (P=0.001). In addition, AML length in 15 genotype-positive relatives without LV hypertrophy exceeded that of matched control subjects (21±3 versus 18±3 mm; P<0.01). CONCLUSIONS: In HCM, mitral valve leaflets are elongated independently of other disease variables, likely constituting a primary phenotypic expression of this heterogeneous disease, and are an important morphological abnormality responsible for LV outflow obstruction in combination with small outflow tract dimension. These findings suggest a novel role for cardiac magnetic resonance in the assessment of HCM.

Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease.

BACKGROUND: Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146). METHODS AND RESULTS: One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtration rate 15-60 mL/min per 1.73 m(2)), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 µg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95% CI -4.00 to -1.59 mL/m(2)) in the paricalcitol group compared with the placebo group (-0.70 mL/m(2) [95% CI -1.93 to 0.53 mL/m(2)], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% in paricalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, P = .03). CONCLUSIONS: Forty-eight weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. In a population where only few therapies alter cardiovascular related morbidity and mortality, these post hoc results warrant further confirmation.

Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial.

CONTEXT: Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking. OBJECTIVE: To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2). DESIGN, SETTING, AND PARTICIPANTS: Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010. INTERVENTION: Participants were randomly assigned to receive oral paricalcitol, 2 µg/d (n =115), or matching placebo (n = 112). MAIN OUTCOME MEASURES: Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function. RESULTS: Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group. CONCLUSION: Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00497146.

Hypertrophic cardiomyopathy: quantification of late gadolinium enhancement with contrast-enhanced cardiovascular MR imaging.

PURPOSE: To determine the most reproducible semiautomated gray-scale thresholding technique for quantifying late gadolinium enhancement (LGE) in a large cohort of patients with hypertrophic cardiomyopathy (HCM). MATERIALS AND METHODS: All study patients signed a statement approved by the internal review boards of the participating institutions, agreeing to the use of their medical information for research purposes. LGE cardiovascular magnetic resonance (MR) imaging was performed in 201 patients (71% male) with a mean age of 41.5 years ± 17.6 (standard deviation [SD]) by using standard techniques with administration of 0.2 mmol of gadopentetate dimeglumine per kilogram of body weight. The presence and quantity of LGE were determined first with visual assessment; then with gray-scale thresholds of 2 SDs, 4 SDs, and 6 SDs above the mean signal intensity for the normal remote myocardium; and then with 2 SDs above noise. The LGE quantifications were repeated 4 or more weeks apart to assess reproducibility. Bland-Altman analysis and correlation coefficients were used to compare the visual and various thresholding methods, with normally distributed variables expressed as means ± SDs. RESULTS: LGE was identified in 103 (51%) subjects. The mean quantity of LGE at visual analysis was 13 g ± 20 compared with 12 g ± 17 at 6 SDs, 25 g ± 23 at 4 SDs, 55 g ± 31 at 2 SDs, and 64 g ± 69 at 2 SDs above noise. All gray-scale thresholds were significantly correlated with visual assessment. The 6-SD threshold had the strongest correlation (r = 0.913, P < .0001) compared with thresholds of 2 SDs (r = 0.81) and 4 SDs (r = 0.91) above the mean and 2 SDs above noise (r = 0.53) (P < .001 for all comparisons). In addition, compared with visual assessment, the 6-SD threshold yielded less intraobserver variability (difference, 0.6 g ± 8, κ = 0.66 [P < .0001] vs 1.4 g ± 9, κ = 0.49 [P < .0001]) and less interobserver variability (difference, 5.4 g ± 18, κ = 0.20 [P < .0001] vs -18.4 g ± 18, κ = 0.08 [P < .0001]). CONCLUSION: Semiautomated LGE cardiovascular MR gray-scale thresholding with 6 or more SDs above the mean signal intensity for the visually normal remote myocardium yields the closest approximation of the extent of LGE identified with visual assessment and is highly reproducible. This objective method should be considered for quantifying LGE in patients with HCM.

Vitamin D receptor activation and left ventricular hypertrophy in advanced kidney disease.

BACKGROUND: In chronic kidney disease (CKD), left ventricular hypertrophy (LVH) is prevalent and is associated with increased cardiovascular morbidity and mortality. Vitamin D receptor (VDR) activation attenuates LVH progression in animal models. METHODS: PRIMO is a multinational, randomized, double-blinded trial with oral paricalcitol in subjects with stages 3-4 CKD, mild-to-moderate LVH and an LV ejection fraction >50%. The primary endpoint is change in the left ventricular mass index (LVMI) compared with placebo after 48 weeks of treatment. The main secondary endpoints are changes in diastolic function parameters. In this paper, we report baseline characteristics from this study. RESULTS: LVMI was 33.0 ± 7.5 g/m(2.7) for males and 30.8 ± 7.2 g/m(2.7) for females (p = 0.04). LVMI correlated with systolic blood pressure (r = 0.24), urine albumin creatinine ratio (r = 0.39), troponin T (r = 0.29), high-sensitivity C-reactive protein (r = 0.25) and plasma levels of B-type brain natriuretic peptide (r = 0.22); all p < 0.01. In multiple linear regression, each remained independently associated with LVMI. The early diastolic velocity of the lateral mitral annulus (E') was 8.1 ± 2.4 cm/s. E' was inversely correlated with age in univariate (r = -0.14, p = 0.04) and multivariable (p = 0.02) analysis. CONCLUSION: Among 227 multinational subjects with stages 3-4 CKD, baseline LVMI correlates with baseline blood pressure, urine albumin creatinine ratio and cardiac biomarkers, and baseline diastolic function correlates with age. This research was funded by Abbott Laboratories; ClinicalTrials.gov No. NCT00497146.

The use of group sequential, information-based sample size re-estimation in the design of the PRIMO study of chronic kidney disease.

BACKGROUND: Chronic kidney disease is associated with a marked increase in risk for left ventricular hypertrophy and cardiovascular mortality compared with the general population. Therapy with vitamin D receptor activators has been linked with reduced mortality in chronic kidney disease and an improvement in left ventricular hypertrophy in animal studies. PURPOSE: PRIMO (Paricalcitol capsules benefits in Renal failure Induced cardia MOrbidity) is a multinational, multicenter randomized controlled trial to assess the effects of paricalcitol (a selective vitamin D receptor activator) on mild to moderate left ventricular hypertrophy in patients with chronic kidney disease. METHODS: Subjects with mild-moderate chronic kidney disease are randomized to paricalcitol or placebo after confirming left ventricular hypertrophy using a cardiac echocardiogram. Cardiac magnetic resonance imaging is then used to assess left ventricular mass index at baseline, 24 and 48 weeks, which is the primary efficacy endpoint of the study. Because of limited prior data to estimate sample size, a maximum information group sequential design with sample size re-estimation is implemented to allow sample size adjustment based on the nuisance parameter estimated using the interim data. An interim efficacy analysis is planned at a pre-specified time point conditioned on the status of enrollment. The decision to increase sample size depends on the observed treatment effect. A repeated measures analysis model, using available data at Week 24 and 48 with a backup model of an ANCOVA analyzing change from baseline to the final nonmissing observation, are pre-specified to evaluate the treatment effect. Gamma-family of spending function is employed to control family-wise Type I error rate as stopping for success is planned in the interim efficacy analysis. LIMITATIONS: If enrollment is slower than anticipated, the smaller sample size used in the interim efficacy analysis and the greater percent of missing week 48 data might decrease the parameter estimation accuracy, either for the nuisance parameter or for the treatment effect, which might in turn affect the interim decision-making. CONCLUSIONS: The application of combining a group sequential design with a sample-size re-estimation in clinical trial design has the potential to improve efficiency and to increase the probability of trial success while ensuring integrity of the study.

Impact of vitamin D on cardiac structure and function in chronic kidney disease patients with hypovitaminosis D: a randomized controlled trial and meta-analysis.

AIMS: Vitamin D deficiency is associated with cardiovascular events in chronic kidney disease (CKD) yet the impact of supplementation is controversial. Previous active vitamin D supplementation studies did not show improvement in cardiac structure or function but the effect of native vitamin D supplementation in CKD patients with low vitamin D levels is unknown. We have addressed this question via both a randomized double-blind prospective study and a meta-analysis of three randomized placebo-controlled studies. METHODS AND RESULTS: We conducted a randomized double-blind, placebo-controlled trial of vitamin D supplementation in stable, non-diabetic, CKD three to four patients with circulating vitamin D <75nmol/L, who were receiving treatment with ACEi or ARB and had high-normal left ventricular (LV) mass. Patients were randomized to receive six directly observed doses of 100 000 IU cholecalciferol (n = 25) or matched placebo (n = 23). The primary endpoint was changed in LV mass index (LVMI) over 52 weeks, as assessed by cardiac magnetic resonance imaging. Secondary endpoints included changes in LV ejection fraction (LVEF); LV and right ventricular volumes and left and right atrial area. Vitamin D concentration increased with the administration of cholecalciferol. The change in LVMI with cholecalciferol [median (inter-quartile range), -0.25 g (-7.20 to 5.30)] was no different from placebo [-4.30 g (9.70 to 2.60)]. There was no difference in changes of LVEF; LV and right ventricular volumes and left and right atrial area. The meta-analysis of three 52-week, randomized placebo-controlled studies using active/native vitamin D supplementation showed no differences in LVMI measurements. CONCLUSION: Vitamin D supplementation does not have beneficial effects on LV mass in CKD patients.

Predictors of Major Atrial Fibrillation Endpoints in the National Heart, Lung, and Blood Institute HCMR.

OBJECTIVES: This study sought to identify predictors of major clinically important atrial fibrillation endpoints in hypertrophic cardiomyopathy. BACKGROUND: Atrial fibrillation (AF) is a common morbidity associated with hypertrophic cardiomyopathy (HCM). The HCMR (Hypertrophic Cardiomyopathy Registry) trial is a prospective natural history study of 2,755 patients with HCM with comprehensive phenotyping. METHODS: All patients received yearly telephone follow-up. Major AF endpoints were defined as requiring electrical cardioversion, catheter ablation, hospitalization for >24 h, or clinical decisions to accept permanent AF. Penalized regression via elastic-net methodology identified the most important predictors of major AF endpoints from 46 variables. This was applied to 10 datasets, and the variables were ranked. Predictors that appeared in all 10 sets were then used in a Cox model for competing risks and analyzed as time to first event. RESULTS: Data from 2,631 (95.5%) patients were available for analysis after exclusions. A total of 127 major AF endpoints events occurred in 96 patients over 33.3 ± 12.4 months. In the final model, age, body mass index (BMI), left atrial (LA) volume index, LA contractile percent (active contraction), moderate or severe mitral regurgitation (MR), and history of arrhythmia the most important. BMI, LA volume index, and LA contractile percent were age-dependent. Obesity was a stronger risk factor in younger patients. Increased LA volume, reduced LA contractile percent, and moderate or severe MR put middle-aged and older adult patients at increased risk. CONCLUSIONS: The major predictors of major AF endpoints in HCM include older age, high BMI, moderate or severe MR, history of arrhythmia, increased LA volume, and reduced LA contractile percent. Prospective testing of a risk score based on these parameters may be warranted.

Effect of the direct Renin inhibitor aliskiren, the Angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy.

BACKGROUND: Left ventricular (LV) hypertrophy, a marker of cardiac end-organ damage, is associated with an increased risk of cardiovascular morbidity and mortality. Inhibitors of the renin-angiotensin-aldosterone system may reduce LV mass to a greater extent than other antihypertensive agents. We compared the effect of aliskiren, the first orally active direct renin inhibitor, the angiotensin-receptor blocker losartan, and their combination on the reduction of LV mass in hypertensive patients. METHODS AND RESULTS: We randomized 465 patients with hypertension, increased ventricular wall thickness, and body mass index >25 kg/m(2) to receive aliskiren 300 mg, losartan 100 mg, or their combination daily for 9 months. Patients were treated to standard blood pressure targets with add-on therapy, excluding other inhibitors of the renin-angiotensin-aldosterone system and beta-blockers. Patients underwent cardiovascular magnetic resonance imaging for assessment of LV mass at baseline and at study completion. The primary objective was to compare change in LV mass index from baseline to follow-up in the combination and losartan arms; the secondary objective was to determine whether aliskiren was noninferior to losartan in reducing LV mass index from baseline to follow-up. Systolic and diastolic blood pressures were reduced similarly in all treatment groups (6.5+/-14.9/3.8+/-10.1 mm Hg in the aliskiren group; 5.5+/-15.6/3.7+/-10.7 mm Hg in the losartan group; 6.6+/-16.6/4.6+/-10.5 mm Hg in the combination arm; P<0.0001 within groups, P=0.81 between groups). LV mass index was reduced significantly from baseline in all treatment groups (4.9-, 4.8-, and 5.8 g/m(2) reductions in the aliskiren, losartan, and combination arms, respectively; P<0.0001 for all treatment groups). The reduction in LV mass index in the combination group was not significantly different from that with losartan alone (P=0.52). Aliskiren was as effective as losartan in reducing LV mass index (P<0.0001 for noninferiority). Safety and tolerability were similar across all treatment groups. CONCLUSIONS: Aliskiren was as effective as losartan in promoting LV mass regression. Reduction in LV mass with the combination of aliskiren plus losartan was not significantly different from that with losartan monotherapy, independent of blood pressure lowering. These findings suggest that aliskiren was as effective as an angiotensin receptor blocker in attenuating this measure of myocardial end-organ damage in hypertensive patients with LV hypertrophy.

Science to practice: can the combination of resting first-pass myocardial perfusion and late gadolinium-enhanced cardiovascular MR imaging help identify myocardial infarction resulting from coronary microembolization?

In this issue of Radiology, Carlsson and colleagues report on the use of acute (1 hour, n = 7) and subacute (1 week, n = 6) resting first-pass perfusion and late gadolinium-enhanced cardiovascular magnetic resonance (MR) imaging to detect myocardial hypoperfusion and microinfarction in a swine model of coronary microembolization. They found resting hypoperfusion at 1 hour that persisted at 1 week. Detection of microinfarction was not reliable at 1 hour, but microinfarction was detected and characterized at 1 week. The pattern on late gadolinium-enhanced images in their model was patchy, with small clusters randomly distributed across a large artery territory. This is distinct from the subendocardially based transmural extension patterns described with clinical myocardial infarction (MI). The degree of left ventricular (LV) systolic dysfunction did not correlate with the quantity of myonecrosis.

Association of Thrombolysis in Myocardial Infarction Myocardial Perfusion Grade with cardiovascular magnetic resonance measures of infarct architecture after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.

BACKGROUND: Primary percutaneous coronary intervention (pPCI) routinely restores normal epicardial flow among patients with ST-segment elevation myocardial infarction (STEMI). However, impairment of myocardial perfusion frequently persists. The goal of this analysis was to determine whether impaired myocardial perfusion was associated with cardiovascular magnetic resonance-defined abnormalities in infarct architecture, including infarct size (IS), infarct surface area (ISA), infarct border zone (IBZ), and infarct complexity (IC). METHODS: Thirty-one patients with STEMI treated with pPCI were included in the analysis. Cardiovascular magnetic resonance was performed within 7 days of presentation and repeated at 3 months. Infarct complexity was defined as the ratio of actual ISA to an idealized smooth ISA and normalized to IS. RESULTS: Impaired Thrombolysis in Myocardial Infarction Myocardial Perfusion Grade (TMPG) (<3) was associated with larger ISA at baseline (78.2 +/- 25.3 cm(2) vs 40.3 +/- 30.3 cm(2), P = .02) and follow-up (58.8 +/- 27.5 cm(2) vs 26.3 +/- 20.2 cm(2), P = .03) and larger IBZ at follow-up (7.8% +/- 2.7% vs 4.1% +/- 3.3%, P = .02). At follow-up, ISA, when normalized to IS, was significantly higher among patients with impaired myocardial perfusion (TMPG <3) (6.9 +/- 2.5 vs 5.9 +/- 2.4 cm(2)/%, P = .03). Thrombolysis in MI myocardial perfusion grade <3 was also associated with increased IC at follow-up (52% +/- 12% vs 33% +/- 16%, P = .01). CONCLUSIONS: Impaired TMPG is associated with larger ISA, IBZ, and increased IC. At 3 months, TMPG remained associated with ISA and IC after adjusting for IS, suggesting that impaired TMPG after pPCI is associated with infarct architecture after healing, independent of IS.

Association of TIMI myocardial perfusion grade and ST-segment resolution with cardiovascular magnetic resonance measures of microvascular obstruction and infarct size following ST-segment elevation myocardial infarction.

BACKGROUND: Impairment of coronary microvascular perfusion is common among patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). Cardiovascular magnetic resonance imaging (CMR) can identify microvascular obstruction (MO) following reperfusion of STEMI. We hypothesized that myocardial perfusion, as assessed by the Thrombolysis in Myocardial Infarction (TIMI) Myocardial Perfusion Grade (TMPG), would be associated with a CMR metric of MO in this population. METHODS: Twenty-one STEMI patients who underwent successful primary PCI were evaluated. Contrast-enhanced CMR was performed within 7 days of presentation and repeated at three months. TIMI Flow Grade (TFG), corrected TIMI Frame Count (cTFC), TMPG, MO, infarct size, and left ventricular ejection fraction (EF) were assessed. RESULTS: The median peak creatine phosphokinase (CPK) was 1,775 IU/l (interquartile range 838-3,321). TFG 3 was present following PCI in 19 (90%) patients. CMR evidence of MO was present in 52% following PCI. Abnormal post-PCI TMPG (0/1/2) was present in 48% of subjects and was associated with MO on CMR (90% MO with TMPG 0/1/2 vs. 18% MO with TMPG 3, P < 0.01). Abnormal post-PCI TMPG was also associated with a greater peak CK (median 3,623 IU/l vs. 838 IU/l, P < 0.001) and greater relative infarct size (17.3% vs. 5.2%, P < 0.01). CONCLUSION: Among STEMI patients undergoing primary PCI, post-PCI TMPG correlates with CMR measures of MO and infarct size. The combined use of both metrics in a comprehensive assessment of microvascular integrity and infarct size following STEMI may aid in the evaluation of future therapeutic strategies.

Distinct Subgroups in Hypertrophic Cardiomyopathy in the NHLBI HCM Registry.

BACKGROUND: The HCMR (Hypertrophic Cardiomyopathy Registry) is a National Heart, Lung, and Blood Institute-funded, prospective registry of 2,755 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 sites in 6 countries. OBJECTIVES: The authors sought to improve risk prediction in HCM by incorporating cardiac magnetic resonance (CMR), genetic, and biomarker data. METHODS: Demographic and echocardiographic data were collected. Patients underwent CMR including cine imaging, late gadolinium enhancement imaging (LGE) (replacement fibrosis), and T1 mapping for measurement of extracellular volume as a measure of interstitial fibrosis. Blood was drawn for the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT), and genetic analysis. RESULTS: A total of 2,755 patients were studied. Mean age was 49 ± 11 years, 71% were male, and 17% non-white. Mean ESC (European Society of Cardiology) risk score was 2.48 ± 0.56. Eighteen percent had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg. Thirty-six percent had a sarcomere mutation identified, and 50% had any LGE. Sarcomere mutation-positive patients were more likely to have reverse septal curvature morphology, LGE, and no significant resting LVOT obstruction. Those that were sarcomere mutation negative were more likely to have isolated basal septal hypertrophy, less LGE, and more LVOT obstruction. Interstitial fibrosis was present in segments both with and without LGE. Serum NT-proBNP and cTnT levels correlated with increasing LGE and extracellular volume in a graded fashion. CONCLUSIONS: The HCMR population has characteristics of low-risk HCM. Ninety-three percent had no or only mild functional limitation. Baseline data separated patients broadly into 2 categories. One group was sarcomere mutation positive and more likely had reverse septal curvature morphology, more fibrosis, but less resting obstruction, whereas the other was sarcomere mutation negative and more likely had isolated basal septal hypertrophy with obstruction, but less fibrosis. Further follow-up will allow better understanding of these subgroups and development of an improved risk prediction model incorporating all these markers.