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S10 Journal of Cardiac Failure Vol. 23 No. 8S August 2017
Rapid-Fire Abstracts I
Aggregated Light Chain Increases Brain Natriuretic Peptide Expression and
Induces Oxidative Stress Response in Cardiomyocytes
Stephen J. Tam, Lauri Li, Mark Renz, Philip J. Dolan, Tarlochan Nijjar, Erich Goldbach,
Gene G. Kinney, Wagner Zago; Prothena Biosciences Inc, South San Francisco,
Introduction: Light chain (AL) amyloidosis, the most common form of systemic
amyloidosis, is characterized by the accumulation of aggregated, misfolded immunoglobulin light chain (LC) protein (amyloid) in one or more organs. Amyloid deposition
in the heart (observed in ~70% of patients) and other organs leads to organ dysfunction and may result in death, most often because of cardiac involvement. No therapies
are approved for AL amyloidosis, and current approaches do not directly target the
misfolded LC protein, which is the underlying cause of organ dysfunction. NTproBNP measures are used clinically to assess patient prognosis and potential response
to treatment and have been recommended by the Amyloidosis Research Consortium
for use as a surrogate end point predictive of survival in clinical trials. In AL amyloidosis, the elevation in NT-proBNP levels is believed to occur in response to a direct
cytotoxic effect of LC species to cardiomyocytes via the p38 MAPK signaling pathway.
This response contrasts that in congestive heart failure, in which NT-proBNP is regulated by mechanical strain and neurohormones. Hypothesis: Aggregated LC directly
affects cardiomyocyte homeostasis by influencing the transcriptional regulation of
BNP precursor gene (prepro-BNP) and through elevation of an oxidative stress response marker. Methods: Primary rat cardiomyocytes were incubated with a mixture
of soluble and insoluble LC aggregates derived from a number of LC sequences described in patients with AL amyloidosis. Both prepro-BNP transcription and secreted
NT-proBNP protein were assessed by quantitative real-time PCR and MSD
electrochemiluminescence, respectively. LC aggregate cellular binding was assessed
by MSD electrochemiluminescence. Cellular oxidative stress was assessed by measuring oxidative stress marker Hmox-1 transcription using quantitative real-time PCR
measurement and reactive oxygen species levels using the hydrogen peroxideactivated bioluminescence assay. Results: LC treatment of rat primary cardiomyocytes
was associated with cellular binding and significantly increased transcription of preproBNP and secretion of NT-proBNP. The effect was dependent on LC sequence, dose,
and incubation time. LC aggregates also induced a rapid and significant elevation of
Hmox-1 and hydrogen peroxide, indicative of cellular insult driven by oxidative stress.
Conclusions: We showed that a heterogeneous mixture of aggregated and nonaggregated
LC, which recapitulates the presumed extracellular milieu in patients with AL amyloidosis, promoted prepro-BNP and Hmox-1 transcriptional activation and secreted
NT-proBNP protein production. These results support previous findings that NTproBNP levels are modulated directly by LC-induced cardiotoxicity and may explain
the robust correlation between NT-proBNP levels and survival in patients with AL
Contribution of Central Abnormalities to Exertional Dyspnea and Ventilatory
Response in Heart Failure with Preserved Ejection Fraction
Masaru Obokata, Thomas P. Olson, Yogesh N.V. Reddy, Barry A. Borlaug; Mayo Clinic,
Rochester, Minnesota
Introduction: Exercise intolerance is attributed to cardiac and peripheral abnormalities in heart failure with preserved ejection fraction (HFpEF). However, no study has
evaluated the relationships between hemodynamics, dyspnea and ventilatory response in HFpEF. Methods and Results: Subjects with invasively-diagnosed HFpEF
(n = 50) and participants with dyspnea but no identifiable cardiac pathology (controls, n = 24) underwent invasive catheterization at rest and during exercise with
simultaneous expired gas analysis and spiroergometry. Compared to controls, subjects with HFpEF displayed higher exercise pulmonary capillary wedge pressures (PCWP)
and pulmonary artery pressures, greater Borg perceived dyspnea and fatigue scores,
and increased respiratory rate relative to exercise intensity (Figure). Exercise PCWP
was directly correlated with Borg dyspnea and effort scores (r = 0.31 and r = 0.39, both
P < .01). The ratio of dead space ventilation to tidal volume (VD/VT) was greater in
HFpEF during exercise (0.25 ± 0.09 vs. 0.33 ± 0.11, P = .002), and this was correlated with exercise PA pressures (r = 0.42, P = .0003). Compared to controls, HFpEF
subjects displayed lower increase in VT during peak exercise (ΔVT 831 ± 464 vs.
454 ± 233 ml, P = .001). Peak VT was inversely correlated with exercise PCWP (r = −0.38,
P = .0007). Peak VO2 was markedly impaired in HFpEF subjects (8.1 ± 2.4 vs.
14.2 ± 4.0 ml/kg/min, P < .0001) and varied inversely with exercise PCWP (r = −0.65,
P < .0001). Conclusions: Central hemodynamic derangements that develop during exercise in people with HFpEF are correlated with subjective symptoms of dyspnea,
impaired tidal volume reserve, and increased dead space ventilation relative to tidal
volume, supporting the relevance of central hemodynamics as a key mediator of disability in HFpEF and important therapeutic target.
In-Hospital Mortality in Hospitalized Patients with Congestive Heart Failure in
Relation to Serum Potassium Levels in the US: National Inpatient Sample Analysis
Sijan Basnet1, Dilli R. Poudel1, Sushil Ghimire1, Biswaraj Tharu2, Rashmi Dhital3;
Reading Health System, West Reading, Pennsylvania; 2Maharajgunj Medical Campus,
Tribhuvan University, Kathmandu, Nepal; 3Universal College of Medical Sciences,
Tribhuvan University, Bhairhawa, Nepal
Introduction: Alteration in serum potassium levels has been found to affect the mortality risk among patients with congestive heart failure (CHF). Methods: We utilized
the National Inpatient Sample database. We selected patients (≥18 years and nonpregnant) admitted with CHF in US hospitals from 2009 to 2011. We substituted code
for CHF (428) based on International Classification of disease-9 (ICD-9) with Clinical Classification Software-Diagnoses of 108. We added ICD-9 codes 404.03, 404.11,
404.13, 404.91, 404.93 and 402.11 to include all etiologies of heart failure. The ICD-9
codes for hypokalemia is 276.8 and hyperkalemia is 267.7. STATA version 13.0 (College
Station, TX) was used for analysis. Multivariate analysis of mortality among CHF patients was done while controlling for age, sex, race, smoking, obesity, dyslipidemia,
diabetes, hypertension and Charlson comorbidity index. Results: Our total study population was based on 2,660,609 discharge records. Hypokalemia was found to be
associated with increased mortality risk (OR: 2.025) and hyperkalemia was associated with decreased mortality risk (OR: 0.935) in comparison to normokalemia (Table 1).
Similar association was seen with etiologies (Acute coronary syndrome, Ischemic heart
disease, valvular heart disease, hypertensive heart disease, cardiomyopathy, atrial fibrillation) and subtypes (systolic, diastolic and combined) of CHF with serum potassium
levels (Tables 2 and 3). Discussion: Our study is the first to establish relationship of
risk of mortality between subcategories of serum potassium levels with different etiologies and subtypes of CHF. Thus, regardless of the etiology or subtype of heart failure,
hypokalemia increases mortality and hyperkalemia is associated with mortality benefit.
Table 1. Multivariate analysis with logistic regression of mortality among CHF
patients with hyperkalemia and hypokalemia with reference to normokalemia.
(Controlled for age, sex, race, smoking, obesity, dyslipidemia, diabetes,
hypertension, Charlson comorbidity index)
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