Donna Burgess

Cardiac magnetic resonance imaging of myocardial contrast uptake and blood flow in patients affected with idiopathic or familial dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) is characterized by left ventricular (LV) enlargement with systolic dysfunction, other causes excluded. When inherited, it represents familial dilated cardiomyopathy (FDC). We hypothesized that IDC or FDC would show with cardiac magnetic resonance (CMR) increased myocardial accumulation of gadolinium contrast at steady state and decreased baseline myocardial blood flow (MBF) due to structural alterations of the extracellular matrix compared with normal myocardium. CMR was performed in nine persons affected with IDC/FDC. Healthy controls came from the general population (n = 6) or were unaffected family members of FDC patients (n = 3) without signs or symptoms of IDC/FDC or any structural cardiac abnormalities. The myocardial partition coefficient for gadolinium contrast (lambda(Gd)) was determined by T1 measurements. LV shape and function and MBF were assessed by standard CMR methods. lambda(Gd) was elevated in IDC/FDC patients vs. healthy controls (lambda(Gd) = 0.56 +/- 0.15 vs. 0.41 +/- 0.06; P = 0.002), and correlated with LV enlargement (r = 0.61 for lambda(Gd) vs. end-diastolic volume indexed by height; P < 0.01) and with ejection fraction (r = -0.80; P < 0.001). The extracellular volume fraction was higher in IDC patients than in healthy controls (0.31 +/- 0.05 vs. 0.24 +/- 0.03; P = 0.002). Resting MBF was lower in IDC patients (0.64 +/- 0.13 vs. 0.91 +/- 0.22; P = 0.01) than unaffected controls and correlated with both the partition coefficient (r = -0.57; P = 0.012) and the extracellular volume fraction (r = -0.56; P = 0.019). The expansion of the extracellular space correlated with reduced MBF and ventricular dilation. Expansion of the extracellular matrix may be a key contributor to contractile dysfunction in IDC patients.

Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy

BACKGROUND Lamin A/C mutations are a well-established cause of dilated cardiomyopathy (DCM), although their frequency has not been examined in a large cohort of patients. We sought to examine the frequency of mutations in LMNA, the gene encoding lamin A/C, in patients with idiopathic (IDC) or familial dilated cardiomyopathy (FDC). METHODS Clinical cardiovascular data, family histories, and blood samples were collected from 324 unrelated IDC probands, of whom 187 had FDC. DNA samples were sequenced for nucleotide alterations in LMNA. Likely protein-altering mutations were followed up by evaluating additional family members, when possible. RESULTS We identified 18 protein-altering LMNA variants in 19 probands or 5.9% of all cases (7.5% of FDC; 3.6% of IDC). Of the 18 alterations, 11 were missense (one present in 2 kindreds), 3 were nonsense, 3 were insertion/deletions, and 1 was a splice site alteration. Conduction system disease and DCM were common in carriers of LMNA variants. Unexpectedly, in 6 of the 19 kindreds with a protein-altering LMNA variant (32%), at least one affected family member was negative for the LMNA variant. CONCLUSIONS Lamin A/C variants were observed with a frequency of 5.9% in probands with DCM. The novel observation of FDC pedigrees in which not all affected individuals carry the putative disease-causing LMNA mutation suggests that some protein-altering LMNA variants are not causative or that some proportion of FDC may be because of multiple causative factors. These findings warrant increased caution in FDC research and molecular diagnostics.

Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.

Background: More than 20 genes have been reported to cause idiopathic and familial dilated cardiomyopathy (IDC/FDC), but the frequency of genetic causation remains poorly understood.

Mutations of Presenilin Genes in Dilated Cardiomyopathy and Heart Failure

Two common disorders of the elderly are heart failure and Alzheimer disease (AD). Heart failure usually results from dilated cardiomyopathy (DCM). DCM of unknown cause in families has recently been shown to result from genetic disease, highlighting newly discovered disease mechanisms. AD is the most frequent neurodegenerative disease of older Americans. Familial AD is caused most commonly by presenilin 1 (PSEN1) or presenilin 2 (PSEN2) mutations, a discovery that has greatly advanced the field. The presenilins are also expressed in the heart and are critical to cardiac development. We hypothesized that mutations in presenilins may also be associated with DCM and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. A total of 315 index patients with DCM were evaluated for sequence variation in PSEN1 and PSEN2. Families positive for mutations underwent additional clinical, genetic, and functional studies. A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single PSEN2 missense mutation (Ser130Leu) was found in two other families. Both mutations segregated with DCM and heart failure. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death. The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis. Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers. These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart failure and implicate novel mechanisms of myocardial disease.

Comparative responsiveness of short-form 12 and Minnesota living with heart failure questionnaire in patients with heart failure☆

BACKGROUND The Short-Form 12 (SF-12) and Living With Heart Failure Questionnaire (LHFQ) are commonly used to measure quality of life (QOL) in heart failure outcomes research. Their comparative responsiveness, however, has not been documented. METHODS AND RESULTS A prospective cohort study was conducted among patients attending a university-based heart failure clinic between April 1997 and September 1998. All patients received comprehensive heart failure care management. QOL of patients was assessed by the SF-12 and LHFQ at baseline and 3 months. Of 87 patients completing follow-up, the mean change score was 10.1 for the LHFQ and 5.8 for the SF-12 (both Ps < .001). The change scores of the instruments were correlated (r = 0.61; P < .001). The SF-12 had a greater ability than the LHFQ to statistically detect change in physical health but was less sensitive to changes in mental health. The LHFQ performed better than the SF-12 in the ability to distinguish the differences in perceived global health transition. CONCLUSION The LHFQ is more responsive than the SF-12 to changes in QOL. The SF-12 should not be used alone to measure the changes in QOL of patients with heart failure.

Physical and Psychological Symptom Profiling and Event-Free Survival in Adults With Moderate to Advanced Heart Failure

&NA;Heart failure (HF) is a heterogeneous symptomatic disorder. The goal of this study was to identify and link common profiles of physical and psychological symptoms to 1-year event-free survival in adults with moderate to advanced HF. Methods:Multiple valid, reliable, and domain-specific measures were used to assess physical and psychological symptoms. Latent class mixture modeling was used to identify distinct symptom profiles. Associations between observed symptom profiles and 1-year event-free survival were quantified using Cox proportional hazards modeling. Results:The mean age of the participants (n = 202) was 57 ± 13 years, 50% were men, and 60% had class III/IV HF. Three distinct profiles, mild (41.7%), moderate (30.2%), and severe (28.1%), that captured a gradient of both physical and psychological symptom burden were identified (P < .001 for all comparisons). Controlling for the Seattle HF Score, adults with the moderate symptom profile were 82% more likely (hazard ratio, 1.82; 95% confidence interval, 1.07–3.11; P = .028) and adults with the severe symptom profile were more than twice as likely (hazard ratio, 2.06; 95% confidence interval, 1.21–3.52; P = .001) to have a clinical event within 1 year than patients with the mild symptom profile. Conclusions:Profiling patterns among physical and psychological symptoms identifies HF patient subgroups with significantly worse 1-year event-free survival independent of prognostication based on objective clinical HF data.