Alterations in the Peripheral Circulation in Heart Failure

Pathophysiologic Insights

One of the important insights that has emerged from studies on the peripheral circulation in HF is that endothelial dysfunction plays a significant role in the pathogenesis, symptomatic status, and prognosis in HF. It contributes to the impaired coronary and systemic perfusion and reduced exercise capacity in patients with HF. The endothelium is a monolayer of cells that cover the luminal side of the heart and all blood vessels, from the aorta to the capillaries. Historically, the endothelium was considered a relatively inert “border” between the blood and surrounding tissues. However, over the past two decades the endothelial cells, building blocks of the endothelium, were found to exert an extremely diverse range of activities implicated in cardiovascular biology and pathology. Indeed, the endothelium regulates vasomotor function, hemostatic status, angiogenesis, the balance of prooxidant and antioxidant, and proinflammatory and antiinflammatory processes. Adjacent endothelial cells can exhibit differential signaling to modulate functional properties of specialized cardiomyocytes (e.g., “pacemaker cells”). All these activities are highly relevant to the clinical status of the patients with compromised cardiac function, who are vulnerable to even minor shifts in hemodynamic and homeostatic state. Of note, the vast majority of research data in HF have focused on HF with impaired systolic function with previously limited information available on HF with preserved ejection fraction (HFpEF). However, evidence for the role of endothelial dysfunction in HFpEF is growing ( see also Chapter 11 ). For example, Lee and colleagues showed that patients with HFpEF have impaired macrovascular and microvascular functions as compared with age- and sex-matched controls. Cardiac endothelial dysfunction plays a key role in HFpEF leading to cardiomyocyte dysfunction, unfavorable left ventricular (LV) concentric remodeling and resulting diastolic dysfunction.

Although the term endothelial dysfunction is used throughout the chapter, there is a continuum from endothelial activation to endothelial “dysfunction” and endothelial “damage.” Endothelial activation usually refers to a physiologic response to various stimuli (including inflammatory cytokines), such as bleeding and infection, aiming to preserve homeostatic stability of the host (protective changes). Endothelial “activation” may involve increased expression and shedding of some surface adhesion molecules, release of von Willebrand factor, and fibrinolytic factors. A crucial aspect of “activation” is that it is reversible upon cessation of the activating agent(s). In contrast, endothelial dysfunction refers to the situations of sustained excessive (e.g., increased reactive oxygen species [ROS] production) or depressed (e.g., impaired vasodilation) endothelial performance. Given that endothelial “dysfunction” could follow chronic “activation” (e.g., by prolonged and inappropriate activation by inflammatory cytokines), there is clear overlap between the two states. In terms of blood flow control, a major pathologic feature of endothelial dysfunction (in the context of cardiovascular disorders) is a functional deficiency of endothelial nitric oxide synthase (eNOS). This results in the reduced bioavailability of nitric oxide and excessive formation of ROS within the vascular wall and leads to endothelial dysfunction. Dysfunction may be reversible, whereas endothelial damage refers to the extreme degree of endothelial dysfunction characterized by premature apoptosis/death of endothelial cells. Increased shedding of the circulating endothelial cells and high plasma concentrations of von Willebrand factor are considered markers of endothelial damage. Such damage is unlikely to be reversible.

Although the endothelium serves as a critical regulator of different aspects of vascular biology, such as hemostasis and inflammation, its ability to produce nitric oxide is pivotal for the different endothelial-dependent functions related to the development and progression of HF. In addition to the regulation of the hemodynamics, nitric oxide acts as a potent modulator of myocardial oxygen consumption in the failing heart. The reduced availability of nitric oxide in HF stems either from its reduced production by eNOS or accelerated nitric oxide degradation by ROS ( Fig. 14.1 ). Downregulation of constitutively expressed eNOS by the endothelium is a characteristic feature of endothelial dysfunction that can be related to LV impairment. Paradoxically, the chronic production of nitric oxide by inducible nitric oxide synthase (iNOS) in HF exerts detrimental effects on ventricular contractility and circulatory function. However, direct evidence for a pathogenic role of iNOS in human HF remains limited. Treatment with NOS inhibitors has no effect on the contraction of the failing heart or β-adrenoceptor sensitivity of ventricular myocytes.

Mice lacking eNOS have abnormal cardiac nitric oxide production, impaired myocardial glucose uptake, and pathologic concentric LV remodeling, whereas eNOS overexpression reduced severity of HF. Targeted overexpression of the eNOS gene within the vascular endothelium in mice has attenuated cardiac and pulmonary dysfunction and led to dramatic improvement in survival during severe HF. On the other hand, Scherrer-Crosbie et al. have demonstrated that eNOS-deficient mice have increased end-diastolic diameter and end-diastolic volume and depressed contractility, fractional shortening, and survival when compared with wild-type mice after 4 weeks of coronary artery ligation. Interestingly, the capillary density was lower in postinfarction eNOS-deficient mice compared with wild-type animals, indicating a role for nitric oxide in postinfarction capillary preservation. Reduced eNOS activity leads to the hypertrophic growth of cardiomyocytes in vitro and eNOS deficiency in mice was associated with impaired myocardial angiogenesis. Although eNOS mRNA is reduced in LV tissue of patients with end-stage HF, iNOS mRNA is upregulated and associates with impaired myocardial relaxation. iNOS is located primarily and invariably in the endothelium and smooth muscle cells of the myocardial vasculature, and its expression is associated with the condition of HF per se rather than related to HF etiology. Patients with advanced HF have increased circulating levels of proinflammatory cytokines. Several studies have shown that proinflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) stimulate nitric oxide synthesis in cardiac myocytes by inducing iNOS expression. Nitric oxide induced by cytokines leads to sustained reduced myocardial contractility and negative chronotropic effects on cardiac myocytes.

An excess in ROS causes endothelial dysfunction by accelerating nitric oxide inactivation (see also Chapter 8 ). The family of multisubunit nicotinamide adenine dinucleotide phosphate (NADPH) oxidases is a major contributor to the increase in superoxide anion production and oxidative stress is upregulated in HF. Depression of the endothelial function and eNOS activity may directly lead to increased ROS release, thus maintaining a vicious circle of oxidative stress. In a rat model of diastolic HF, the increase in cardiac eNOS expression by the eNOS enhancer, AVE3085 (which is an activator of eNOS transcription), is accompanied by the reduction in NADPH oxidase, as well as attenuation of cardiac hypertrophy, fibrosis, and diastolic dysfunction.

Antioxidant capacity is also diminished in HF. In animal experiments, activity of different superoxide dismutase (SOD) isoforms is present in the failing myocardium and gene transfer of extracellular SOD significantly improves endothelial function. Increased xanthine-oxidase and reduced extracellular SOD activity is closely associated with increased vascular oxidative stress in HF patients, indicating increased oxidative burden and loss of vascular oxidative balance as possible contributors to endothelial dysfunction in HF.

There are in vivo and in vitro data for impaired arginine (eNOS substrate) transport in human HF. This is mediated by the biochemical system y ⁺ carrier, which is principally represented by the CAT-1 transporter. The arginine uptake and mitochondrial expression of the CAT-1 arginine transporter are significantly reduced in HF. Williams and colleagues have shown that higher mitochondrial l -arginine availability achieved by transfection of a mitochondrially targeted CAT-1 significantly improved cardiomyocyte response to mitochondrial stresses, reduced oxidative stress, and improving survival. In addition, circulating levels of asymmetric dimethylarginine (ADMA; an endogenous inhibitor of eNOS and circulating proinflammatory cytokines) are increased in HF, further contributing to endothelial dysfunction and accelerated apoptosis of endothelial cells. In patients with ischemic chronic HF elevated plasma, ADMA levels tend to be related to higher New York Heart Association (NYHA) functional classes, increased N-terminal (NT)-proBNP levels, and worse clinical outcomes. A strong correlation has been demonstrated between eNOS downregulation and endothelial apoptosis. Of some interest, the β-blocker carvedilol suppresses the caspase cascade and excessive human umbilical vein endothelial cell apoptosis induced by the serum from HF patients or addition of TNF-α.

Inflammatory changes are common in patients with HF, with numerous studies reporting high concentrations of cytokines (e.g., TNF-α and IL-6) and C-reactive protein (CRP) (see also Chapter 7 ). These biomarkers strongly correlate with HF severity and are strong and independent predictors of mortality. In animal models, inflammation is not an innocent bystander but is rather an active participant in HF development and progression. A dysfunctional endothelium also facilitates a proinflammatory status in HF by release of inflammatory factors, such as pentraxin 3 (see also Chapter 33 ). Endothelial activation of nuclear factor-κB, a key proinflammatory transcriptional factor, is more prominent in patients with severe HF undergoing heart transplantation. Of note, pentraxin 3 levels independently predict cardiac death or HF-related rehospitalization. Despite the strong evidence of a detrimental impact of inflammation in HF outcome, data on specific biologic therapies against TNF-α (i.e., using etanercept and infliximab) have been generally disappointing (see also Chapter 7 ).