TY - JOUR
T1 - Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening
AU - Sorop, Oana
AU - Heinonen, Ilkka
AU - van Kranenburg, Matthijs
AU - van de Wouw, Jens
AU - de Beer, Vincent J.
AU - Nguyen, Isabel T. N.
AU - Octavia, Yanti
AU - van Duin, Richard W. B.
AU - Stam, Kelly
AU - van Geuns, Robert-Jan
AU - Wielopolski, Piotr A.
AU - Krestin, Gabriel P.
AU - van den Meiracker, Anton H.
AU - Verjans, Robin
AU - van Bilsen, Marc
AU - Danser, A. H. Jan
AU - Paulus, Walter J.
AU - Cheng, Caroline
AU - Linke, Wolfgang A.
AU - Joles, Jaap A.
AU - Verhaar, Marianne C.
AU - van der Velden, Jolanda
AU - Merkus, Daphne
AU - Duncker, Dirk J.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Aims More than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC), and diabetes mellitus (DM). Although its pathophysiology remains incompletely understood, it has been proposed that these comorbidities induce systemic inflammation, coronary microvascular dysfunction, and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and, ultimately, diastolic dysfunction. Here, we tested this hypothesis in a swine model chronically exposed to three common comorbidities. Methods and results DM (induced by streptozotocin), HC (produced by high fat diet), and HT (resulting from renal artery embolization), were produced in 10 female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM+HC+HT group showed hyperglycemia, HC, hypertriglyceridemia, renal dysfunction and HT, which were associated with systemic inflammation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production, and impaired coronary small artery endothelium-dependent vasodilation. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio, and elevated passive cardiomyocyte stiffness, resulting in an increased left ventricular end-diastolic stiffness (measured by pressure-volume catheter) and a trend towards a reduced E/A ratio (measured by cardiac MRI), while ejection fraction was maintained. Conclusions The combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction.
AB - Aims More than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC), and diabetes mellitus (DM). Although its pathophysiology remains incompletely understood, it has been proposed that these comorbidities induce systemic inflammation, coronary microvascular dysfunction, and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and, ultimately, diastolic dysfunction. Here, we tested this hypothesis in a swine model chronically exposed to three common comorbidities. Methods and results DM (induced by streptozotocin), HC (produced by high fat diet), and HT (resulting from renal artery embolization), were produced in 10 female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM+HC+HT group showed hyperglycemia, HC, hypertriglyceridemia, renal dysfunction and HT, which were associated with systemic inflammation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production, and impaired coronary small artery endothelium-dependent vasodilation. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio, and elevated passive cardiomyocyte stiffness, resulting in an increased left ventricular end-diastolic stiffness (measured by pressure-volume catheter) and a trend towards a reduced E/A ratio (measured by cardiac MRI), while ejection fraction was maintained. Conclusions The combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction.
KW - Translational studies
KW - Coronary circulation
KW - Oxidant stress
KW - Endothelium/nitric oxide
KW - Heart failure
KW - PRESERVED EJECTION FRACTION
KW - HEART-FAILURE
KW - NONCARDIAC COMORBIDITIES
KW - METABOLIC SYNDROME
KW - PRESSURE-OVERLOAD
KW - MODEL
KW - INFLAMMATION
KW - MECHANISMS
KW - POPULATION
KW - STIFFNESS
U2 - 10.1093/cvr/cvy038
DO - 10.1093/cvr/cvy038
M3 - Article
C2 - 29432575
SN - 0008-6363
VL - 114
SP - 954
EP - 964
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 7
ER -