S76 Journal of Cardiac Failure Vol. 16 No.

8S August 2010

Epidemiology, Prevention
244
Pro-B-Type Natriuretic Peptide Predicts Mortality and Cardiovascular Events
in the General Community: Comparison to Other BNP Biomarkers
Fima Macheret1, Paul McKie1, Guido Boerrigter1, Lisa Costello-Boerrigter1, Lahr
Brian2, Denise Heublein1, Sandberg Sharon1, Alessandro Cataliotti1, Richard
Rodeheffer1, John C. Burnett Jr.1; 1Cardiorenal Research Laboratory, Mayo Clinic,
Rochester, MN; 2Division of Health Sciences, Mayo Clinic, Rochester, MN
Introduction: Pro-B-type natriuretic peptide 1-108 (proBNP1-108) is a 108-amino
acid peptide produced by the heart and cleaved into active B-type natriuretic peptide
1-32 (BNP1-32) and inactive amino-terminal proBNP 1-76 (NT-proBNP1-76).
Recently, we used a novel, highly-specific assay for proBNP1-108 that does not
detect BNP1-32 or NT-proBNP1-76, to determine that proBNP1-108 circulates in all
humans and may be the predominant BNP form in heart failure (HF). Because
proBNP1-108 has been shown to be elevated in those with heart failure, we hypothe-
sized that proBNP1-108 would sensitively and specifically detect HF and predict those
at increased risk of mortality and cardiovascular (CV) events at least as well as pro-
cessed BNP1-32 or NT-proBNP1-76. Methods: Cohort study (n 5 2042) was a random
sample of Olmsted County, MN, residents, 45 years old or older. Each subject had
clinical examination, 2-D Doppler Echo, and plasma BNP measurement. We used elec-
tronic records to assess death and CVevents. Univariate and multivariable time-to-event
analyses determined the associations between plasma proBNP1-108 and survival free
of death or CV events. Results: Over an 11-year period, proBNP1-108 (upper quartile
compared to lower quartile) was significantly associated with mortality and a composite
endpoint of HF, MI, stroke, or atrial fibrillation (HR 2.16, p ! .001), independent of
clinical and echocardiographic abnormalities. ProBNP1-108 was comparable to both
NT-proBNP1-76 (Roche) and BNP1-32 (Biosite). Conclusions: Our paradigm-shifting
study proves that unprocessed proBNP1-108 is a robust predictor of both death and fu-
ture CV events in the general community over 11 years. Thus, proBNP1-108 may be
used to determine who in the general population is at highest CV risk and requires ag-
gressive primary prevention. Importantly, the biological implication is that while
proBNP1-108 is present in normal plasma, there may be cardiac overproduction of
proBNP1-108 or a deficiency of peripheral proBNP1-108 processing either concomi-
tant with or responsible for CV disease.
Diseases, Mayo Clinic, Rochester, MN; 2Division of Biostatistics, Mayo Clinic,
Rochester, MN; 3Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN
Introduction: Atrial natriuretic peptide (ANP) is synthesized and secreted by the
heart. Its cardiorenal protective properties include vasodilatation, natriuresis, suppres-
sion of the renin-aldosterone system, inhibition of both cardiomyocyte hypertrophy
and cardiac fibroblast activation. The ANP gene (NPPA) is located on chromosome
1 in tandem with the B-type natriuretic peptide (BNP) gene. The single nucleotide
polymorphism (SNP) rs5065 is mapped to the stop codon of exon 3 and the minor
allele encodes an ANP with two additional arginines at the C-terminus. The
rs5065 frequencies vary widely depending on ethnicity. The effect of rs5065 on car-
diovascular phenotype is still controversial. Hypothesis: We sought to identify bio-
chemical and clinical phenotypes associated with the rs5065 SNP in an USA
general adult population with primarily Northern and Western European ancestry.
Methods: Rs5065 genotype was determined in a clinically well-characterized ran-
dom sample of the general population age $45 living in Olmsted County, MN,
USA (n 5 1623). Plasma levels of ANP, BNP, NT-proBNP and ProBNP1-108
were determined. In-depth echocardiography and clinical characterization were per-
formed. Results: Genotype frequencies for rs5065 were TT: 75.1%, TC: 23.7%, and
CC: 1.2%. All subsequent analyses are TT vs TC + CC. The two groups had similar
plasma ANP and NT-proBNP levels, but they were different in terms of proBNP 1-
108 (20 vs 23 pg/ml, p 5 0.017) and BNP values (23.2 vs 27.6 pg/ml, p 5 0.008).
After adjustment for age and gender, the C-allele was associated with cerebrovascular
accident (CVA) (OR 2.63; 95% CI, 1.12 to 6.18; p 5 0.026), myocardial infarction
(MI) (OR 1.70; 95% CI, 1.05 to 2.75; p 5 0.032), and left ventricular ejection frac-
tion (LVEF) !40% (OR 2.38; 95% CI, 1.13 to 4.99; p 5 0.023). Conclusions: The
ANP genetic variant, rs5065 is associated with increased risk for CVA, MI and re-
duced LVEF. It is also associated with elevated levels of BNP and proBNP1-108, bio-
markers for increased cardiovascular morbidity and mortality. Our findings identify
the minor allele of rs5065 as a marker of increased cardiovascular risk in the general
USA population. The related pathophysiological mechanisms remain to be deter-
mined.

245 247
The Prevalence and Outcome of Diabetic Cardiomyopathy: A Population Based
Inciting Events in Takotsubo Cardiomyopathy: Is Emotional Stress Always the
Study in Olmsted County, MN
Culprit?
Aaron M. From, Joshua Slusser, Douglas Mahoney, Richard Rodeheffer, Horng H.
Sarika K. Desai, Jayanta R. Das, Jerold Shinbane, Bojan Cercek, Suhail Dohad;
Chen; Mayo Clinic, Rochester, MN
Cardiovascular Thoracic Institute, University of Southern California Keck School
of Medicine, Los Angeles, CA; Heart Institute, Cedars Sinai, Los Angeles, CA
Background: Diabetic cardiomyopathy defined as either systolic or diastolic dys-
function in otherwise healthy diabetic persons is not clearly understood. The prev-
Background: Takotsubo Cardiomyopathy (TC) is recognized by a characteristic left
alence and outcome of this disease in a community-based population has never
ventricular (LV) apical ballooning on cardiac imaging without significant coronary
been defined. Methods: Cross-sectional survey of 2,042 randomly selected resi-
artery disease (CAD) precipitated by a stressful event. Aim: To identify and analyze
dents of Olmsted County, Minnesota, aged 45 years or older from June 1997
the inciting events preceding TC. Methods: A retrospective analysis of hospital re-
through September 2000. All patients underwent Doppler echocardiographic as-
cords, between 2005-2009, at 2 major teaching hospitals in Los Angeles County.
sessment of systolic and diastolic function. Diabetic cardiomyopathy was defined
All cases were confirmed to have LV apical ballooning on LV function analysis
as a person with diabetes mellitus and any systolic dysfunction (defined as
with noncontributory CAD. Results: A total of 100 patients (mean age 68, 89% fe-
EF !50%) or diastolic dysfunction (defined as an E/A ratio #0.75 or $2.0 or
male) met all criteria for TC. Of the 42% of patients with primary TC, presenting to
an E/e’ ratio is $10) without a history of coronary disease, hypertension, significant
the emergency department (ED) with chest pain, troponin elevation, and EKG
valvular disease or congenital heart disease. The main outcomes measure was all-
changes and 58% patients presented to the hospital with alternative diagnoses and
cause mortality. Results: The diagnosis of diabetic cardiomyopathy was made in 23
subsequently developed TC (secondary TC).
persons, corresponding to a population prevalence rate of 1.1% (95% confidence
interval [CI] 0.7% to 1.6%) in the community. Mortality of patients with
Diabetic Cardiomyopathy was nearly 20% during the 9.2 + / 1.5 year follow- Primary TC Secondary TC
up. Mortality among patients with Diabetic Cardiomyopathy was similar to diabetic
persons with left ventricular dysfunction who had hypertension or coronary disease n 5 42 n 5 58
(RR 5 0.424, 95% CI 5 0.146 to 1.230; p 5 0.114) after adjustment for age and
Inciting Event
sex. Among all diabetic patients 18 (11%) had systolic dysfunction and 101 (60%)
Emotional Stress 19 (45.2%) 0
had diastolic dysfunction. Among non-diabetic patients 71 (4%) had systolic dys-
Physical Stress 2 (4.8%) 0
function and 806 (43%) had diastolic dysfunction. Diabetes mellitus was associated
Post surgical 2 (4.8%) 18 (31.1%)
with a 1.5 fold increase in any left ventricular dysfunction (OR 5 1.50 (95% CI 5
Sepsis 1 (2.4%) 14 (24.1%)
1.05 to 2.14; p 5 0.026) and a 1.4 fold increase in diastolic dysfunction (OR 5 1.40
Upper respiratory infection 3 (7.2%) 8 (13.8%)
(95% CI 5 0.98 to 1.98; p 5 0.062) after adjustment for age, gender, coronary dis-
Substance Abuse 2 (4.8%) 4 (6.9%)
ease and hypertension. Conclusions: Diabetic Cardiomyopathy is common in the
Subarachnoid hemorrhage 0 5 (8.6%)
community. Mortality among diabetic patients with left ventricular dysfunction is
Pulmonary embolus 0 1 (1.7%)
high regardless of the presence of hypertension or coronary disease. Furthermore,
Trauma 1 (2.4%) 1 (1.7%)
diabetes mellitus is independently associated with left ventricular dysfunction after
Syncope 1 (2.4%) 3 (5.2%)
adjustment for age, gender, coronary disease and hypertension.
Unidentified 11 (26.2%) 4 (6.9%)
EKG
ST elevation 20 (48%) 16 (28%)
Non ST elevation 22 (52%) 42 (72%)
246
Association of NPPA rs5065 Genetic Variant With Increased Cardiovascular
Risk in the General USA Population Conclusion: Inciting events differ in patients with primary versus secondary TC. Of
Valentina Cannone1, Guido Boerrigter1, Lisa C. Costello-Boerrigter1, Alessandro the patients with primary TC, emotional or physical stress was an inciting event in
Cataliotti1, Kent R. Bailey2, Brian Lahr2, Denise M. Heublein1, Richard J. 50%, whereas in patients with secondary TC, 69% of patients had a surgical proce-
Rodeheffer1, Timothy M. Olson3, John C. Burnett1; 1Division of Cardiovascular dure or infection with or without sepsis as the inciting event.