Novel drug therapy for hypertension-induced heart failure with persevered ejection fraction and hypertensive cardiomyopathy

Abstract

Hypertension (HT), with a high mortality and worldwide prevalence, has been considered as the largest risk factor contributing to various cardiovascular disorders. Heart failure (HF) with preserved ejection fraction (HFpEF) is a type of HF that features in preserved left ventricular (LV) systolic function and deteriorated diastolic function, and it is highly associated with chronic HT. Although there have been a diversity of both pharmacological and surgical therapies targeting HT across the globe up-till-now, not all patients admitted to HT and received any of these therapeutics have successfully achieved optimal blood pressure (BP) management. Therefore, a novel therapeutic strategy for HT treatment is in emerging need. Traditional pharmacological therapies such as diuretics, calcium channel blockers (CCB), inhibitors of renin-angiotensin II-aldosterone system (RAAS) (i.e. angiotensin-converting-enzyme inhibitors) and suppressors of sympathetic nerve activity (SNA) (i.e. beta-blockers) have all been manipulated experimentally and clinically to overcome HT; conventional surgical therapies such as renal denervation, splanchnic denervation and spinal cord stimulation have had effect on BP control by targeting against enhanced SNA induced by HT. Although HT treatment from the above therapeutics has acquired huge success, inconsistent efficacy, adverse effects, operative and postoperative morbidity of these surgical therapies still leave the issue unsolved. On the other hand, many of these surgical therapies have not been proved to be capable of treating HT-induced HFpEF. In this case, my study tried to solve the problem by aiming to 1) establish a large animal HT model; to 2) discover the possible underlying mechanism of HT-induced HFpEF and associated HT cardiomyopathy (hCMP) in HT model; and to 3) assess the effect of glucagon-like peptide 1 receptor agonist (GLP1RA) on HT and HT-induced HFpEF. My study used a combination of angiotensin II (Ang II) and deoxycorticosterone acetate (DOCA) to induce HT status in porcine model. After a successful establishment of HT, observations from BP recording, invasive hemodynamic assessment and echocardiographic assessment were made of increased BP, LV diastolic dysfunction and myocardial remodeling. Biomarker assessment of HT model revealed an elevation in both myocardial and splanchnic veno-arterial norepinephrine (NE) gradient, and in splenic tissue NE content. Administration of a commercially available GLP1RA, Liraglutide (Victoza, Novo Nordisk), was performed in HT model. Significant decrease in BP, improvement in LV diastolic function, restoration in myocardial morphology and reduction in inflammation status were found in GLP1RA-treated animals. I then tried to unravel the underlying mechanism of GLP1RA’s effect. Systemic and local NE assessment showed that GLP1RA had an ability to decrease the NE spillover and splenic NE concentration derived from chronic HT. ELISA, Western blots and immunohistochemical assessment demonstrated that GLP1RA could decrease the circulating inflammatory cytokines and local immune cell infiltration. Together with reduced SNA and inflammation brought by GLP1RA administration, this drug therapy had the potential in cardiac function improvement and HT-induced HFpEF prevention. My findings illustrated that enhancement in SNA, and abnormal augmentation in inflammation and inflammatory response were key driving forces in HT and HT-induced HFpEF. GLP1RA provided a novel insight in treating this particular cardiovascular disease.