Plasma levels of tumor necrosis factor-α and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase.
OBJECTIVE
The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-α and interleukin-6), diastolic heart failure, and the possible molecular mechanism.


METHODS
Prospective case-controlled cohort and molecular studies.


METHODS
University hospital and research laboratory.


METHODS
Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure.


METHODS
Soluble plasma levels of tumor necrosis factor-α and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-α and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated.


RESULTS
Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-α and interleukin-6 than the control subjects. Significant correlations (p < .01 for each) were found for tumor necrosis factor-α and E/Em (r = .87) and E/A (r = -0.69), and for interleukin-6 and E/Em (r = .80) and E/A (r = -0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-α, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-α and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes.


CONCLUSIONS
Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions.
Department of Internal Medicine, National Taiwan University College of Medicine and Hospital Yun-Lin Branch, Yun-Lin, Taiwan, China.
Cho-Kai
CK
Wu
Jen-Kuang
JK
Lee
Fu-Tien
FT
Chiang
Chic-Hsin
CH
Yang
Shui-Wei
SW
Huang
Juey-Jen
JJ
Hwang
Jiunn-Lee
JL
Lin
Chuen-Den
CD
Tseng
Jin-Jer
JJ
Chen
Chia-Ti
CT
Tsai
D000368:Aged; D000369:Aged, 80 and over; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D016638:Critical Illness; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D054144:Heart Failure, Diastolic / Q000097:blood* / Q000235:genetics / Q000401:mortality; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012016:Reference Values; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000252:Calcium-Transporting ATPases