Vascular Repair and Regeneration in Cardiometabolic Diseases

David A. Hess; Subodh Verma; Deepak Bhatt; Ehab Bakbak; Daniella C. Terenzi; Pankaj Puar; Francesco Cosentino

Disclosures

Eur Heart J. 2022;43(6):450-459. 

In This Article

Abstract and Introduction

Abstract

Graphical Abstract

During cardiometabolic based chronic disease, dysglycemia and excess adipocity induce a differentiate imbalance in the bone marrow that contribute to overproduction of inflammatory cells and impaired mobilization of progenitor cells that mediate endogenous mechanisms for vessel repair and regeneration.

Chronic cardiometabolic assaults during type 2 diabetes (T2D) and obesity induce a progenitor cell imbalance in the circulation characterized by overproduction and release of pro-inflammatory monocytes and granulocytes from the bone marrow alongside aberrant differentiation and mobilization of pro-vascular progenitor cells that generate downstream progeny for the coordination of blood vessel repair. This imbalance can be detected in the peripheral blood of individuals with established T2D and severe obesity using multiparametric flow cytometry analyses to discern pro-inflammatory vs. pro-angiogenic progenitor cell subsets identified by high aldehyde dehydrogenase activity, a conserved progenitor cell protective function, combined with lineage-restricted cell surface marker analyses. Recent evidence suggests that progenitor cell imbalance can be reversed by treatment with pharmacological agents or surgical interventions that reduce hyperglycaemia or excess adiposity. In this state-of-the-art review, we present current strategies to assess the progression of pro-vascular regenerative cell depletion in peripheral blood samples of individuals with T2D and obesity and we summarize novel clinical data that intervention using sodium-glucose co-transporter 2 inhibition or gastric bypass surgery can efficiently restore cell-mediated vascular repair mechanisms associated with profound cardiovascular benefits in recent outcome trials. Collectively, this thesis generates a compelling argument for early intervention using current pharmacological agents to prevent or restore imbalanced circulating progenitor content and maintain vascular regenerative cell trafficking to sites of ischaemic damage. This conceptual advancement may lead to the design of novel therapeutic approaches to prevent or reverse the devastating cardiovascular comorbidities currently associated with T2D and obesity.

Introduction

Introduction to Chronic Cardiometabolic Disease

Link Between Chronic Cardiometabolic Disease and Cardiovascular Comorbidities

The clinical outcomes of ischaemic cardiovascular diseases (CVD), including coronary and peripheral artery disease, myocardial infarction, heart failure and stroke, are often considered unavoidable complications that compromises quality of life in patients with type 2 diabetes (T2D) and obesity. CVD was responsible for nearly 18 million global deaths in 2015,[1,2] and collectively CVD remains the leading cause of death worldwide.[3,4] It is estimated that 420 million individuals are living with diabetes and 2 billion individuals are considered overweight, 650 million of which are affected by obesity [body mass index (BMI) >30 kg/m2]. Due to the increased prevalence of T2D and obesity in an ageing population worldwide, and despite improved pharmacologic and surgical intervention, the incidence of CVD is expected to continue to rise over the next decade.[5] The global financial burden of treating diabetes was estimated at $1.31 trillion in 2015,[6] and CVD comorbidities were responsible for nearly one-third ($437 billion) of the cost of therapy.[7] Thus, there exists a compelling need to better understand the pathophysiological interrelationship between T2D, obesity and the subsequent development of CVD.

In a recent review, Mechanick et al.[8] conceptualized that ischaemic CVD represents the endpoint of an accumulation of clinical risk factors including hyperglycaemia and insulin resistance during T2D and the elevation of systemic inflammation during obesity. Because T2D and obesity are often highly entangled, comorbid states, chronic dysglycaemia, and increased adiposity can be considered primary drivers of vascular damage that overwhelm endogenous vessel repair mechanisms.[9–13] This unmanaged cycle of excessive vascular damage combined with gradually compromised vessel regenerative response can intensify atherosclerotic plaque instability and elevate the risk of experiencing ischaemic macrovascular events,[14] including myocardial infarction and stroke. Therefore, strategies to stimulate the recovery of endogenous blood vessel repair represent a novel target to prevent and treat CVD progression[15] (See Graphical Abstract).

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