New Mechanisms to Prevent Heart Failure with Preserved Ejection Fraction Using Glucagon-like Peptide-1 Receptor Agonism (GLP-1 RA) in Metabolic Syndrome and in Type 2 Diabetes: A Review

Figures

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  Figure 1. Mechanical and paracrine effects of increased epicardial adipose tissue (EAT) on myocardial structure and function (adapted from [102,105,106]). * = Additional potential contributors to pericardial restraint in obesity HFpEF: increased LV and RV volumes, increased left and right atrial volumes, blood volume expansion, mediastinal/abdominal extrinsic restraint, pulmonary hypertension with abnormal RV–PA coupling). Abbreviations: LV = left ventricle, RV = right ventricle, PA = pulmonary artery, IL = interleukin TNF = tumor necrosis factor, HF = heart failure.

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  Figure 2. Preventive effects of the counter-regulatory renin angiotensin system (non-classic renin angiotensin pathway) on obese HFpEF. Activation of the AT2R and the MASR with angiotensin 1–9 and angiotensin 1–7, respectively, achieves protective effects on obese HFpEF by counteracting the classic effects of the RAS pathway activation. Additionally, GLP-1 RA also promotes activation of the counter-regulatory renin angiotensin system. Abbreviations: ACE = angiotensin converting enzyme 1, ACE2 = angiotensin converting enzyme 2, NEP = neutral endopeptidase, AT1R = angiotensin receptor type 1, AT2R = angiotensin receptor type 2, MASR = G-protein–coupled receptor Mas, SNS = sympathetic nervous system, PSNS = parasympathetic nervous system, VSMC = vascular smooth muscle cell.

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  Figure 3. Mechanisms of GLP-1 RA on prevention of pathologic cardiac hypertrophy by (A) regulating the expression of the Ang II/AT1R/ACE2 pathway by inhibiting Ang II-induced RhoA/ROCK2 activation (which regulates MYPT1 and MLC phosphorylation) and (B) by activating the AMPK/mTOR/p70S6K pathway (adapted from Refs. [153,155]). Interrupted line = inhibition. Abbreviations: GLP-1 RA = glucagon-like peptide 1 receptor agonism, GLP-1R = glucagon-like peptide 1 receptor, cAMP = cyclic adenosine 3′,5′-monophosphate, PKA = protein kinase A, Ang II = angiotensin II, ROCK2 = Rho kinase 2, MYPT1 = Myosin phosphatase target subunit 1, MLC = myosin light chain, RAAS = renin angiotensin aldosterone system, AT1R = angiotensin receptor type 1, AT2R = angiotensin receptor type 2, ACE2 = angiotensin converting enzyme 2, AMPK = Adenosine monophosphate (AMP)-activated protein kinase, mTOR = mammalian target of rapamycin, p70S6K = p70 ribosomal S6 protein kinase, ANP = atrial natriuretic peptide, BNP = brain natriuretic peptide, β-MHC = β myosin heavy chain.

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  Figure 4. Mechanisms to prevent HFpEF using a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in obesity (as well as in metabolic syndrome and in obese type 2 diabetes). The protective effects of GLP-1 on HFpEF may be attributed to the effects on obesity and its consequences on its ability to inhibit Ang II-induced RhoA/ROCK2 activation, which, in turn, regulates MYPT1 and MLC phos-phorylation, thus preventing pathologic myocardial remodeling and HFpEF. Interrupted line = in-hibition. Abbreviations: LV = left ventricle, LA = left atrium, RAS = renin angiotensin system, AMPK = AMP-activated protein kinase, mTOR = mammalian target of rapamycin, PKA = protein kinase A, ROCK = Rho-associated coiled-coil containing kinase.