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.

Mechanisms and effects of vasomotor endothelial function in heart failure.

Vasomotor endothelial dysfunction is featured by reduced endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production. It can also be contributed by diminished arginine availability and its impaired intracellular function, as well as upregulation of the endogenous eNOS inhibitor, asymmetric dimethylarginine (ADMA) . In heart failure, these abnormalities lead to the reduced coronary blood flow reserve, increased myocardial oxygen consumption, impaired cardiac function, angiogenesis, enhanced cardiac remodeling, and fibrosis. BFR , Blood flow reserve; EC , Endothelial cell; LV , left ventricular.

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 ).

Endothelial Dysfunction and Clinical Outcomes in Heart Failure

Evidence of clinical significance of vasomotor endothelial dysfunction in patients with HF is provided by several prospective outcome studies ( Table 14.1 ). All these studies consistently demonstrate an independent relationship between the degree of endothelial dysfunction and the risk of negative outcome. This relationship was true across a population of patients ranging from mild HF (NYHA class I) with relatively preserved cardiac contractility to those with advanced disease (NYHA class IV) with severely depressed LV function. Systemic levels of the natural eNOS inhibitor, ADMA, which are elevated in systolic HF, independently predict a reduced effective renal plasma flow. This potentially makes endothelial dysfunction partly responsible for the progressive deterioration of renal function seen in many patients with HF.

Although the severity of vasomotor endothelial dysfunction may vary among patients with ischemic or nonischemic cause of HF, the predictive power of endothelial dysfunction on prognosis does not depend on the HF etiology. Once developed, endothelial dysfunction bears similarly high risk of unfavorable events in both ischemic and nonischemic HF. Moreover, endothelial dysfunction of coronary arteries in patients after cardiac transplantation also independently predicts the risk of future cardiovascular events and death. Endothelial dysfunction may be also accountable for some cases of suboptimal response to cardiac resynchronization therapy. The association of clinical improvement after cardiac resynchronization therapy and magnitude of endothelium-dependent vasodilation is independent from the factors commonly used to select patients for treatment, such as QRS complex duration, LV ejection fraction, or degree of LV dyssynchrony. Improvement in exercise tolerance after cardiac resynchronization therapy is accompanied by improvements in endothelial vasodilatory capacity, although a causative relationship between the changes cannot be established. Recently, endothelial dysfunction has been shown to be of prognostic significance in patients with HFpEF. However, the clinical significance of the endothelial dysfunction in HF is somewhat limited by relatively small populations of the studied patients, as well as the short- to middle-term duration of follow-up.

Circulating Markers of Endothelial Dysfunction in Heart Failure

The impairment of endothelial function in HF is not limited to vasomotor capacity but apparently affects all the diverse aspects of the endothelial activity, including proinflammatory activation of endothelial cells and failure of the antioxidant defense system ( Fig. 14.2 ). Among multiple regulatory proteins produced by the endothelium, several have emerged as useful blood markers of endothelial activation or damage. In respect to the HF, increased levels of plasma markers of endothelial activation (e.g., E-selectin) and damage (e.g., von Willebrand factor) are commonly seen ( Table 14.2 ). However, most of these studies compared data obtained from patients with HF with those from healthy individuals. Consequently, it is difficult to differentiate precisely the scale to which the endothelial changes are attributable to the HF per se or to comorbidities and risk factors (such as hypercholesterolemia), which are often seen in patients with HF and known to be associated with endothelial perturbation. The influence of comorbidities and risk factors on endothelial function may partly explain why levels of von Willebrand factor and E-selectin do not always correlate with measures of HF severity, such as LV ejection fraction, BNP, HF functional status, or exercise tolerance. This viewpoint is also supported by lack of significant differences in parameters of plasma markers of endothelial activation and damage between patients with acute decompensated and chronic HF. Furthermore, increased concentrations of E-selectin and von Willebrand factor in HF were reported in patients with concomitant diabetes but not in diabetes-free patients.

Diversity of endothelium-related abnormalities in HF. Endothelial dysfunction in HF parallels enhanced oxidative stress, which contributes to accelerated nitric oxide (NO) degradation, and proinflammatory activation of endothelial cells (ECs) . Activated endothelium produces different inflammatory molecules, such as pentraxin, and also attracts inflammatory cells (leukocytes) in the vascular wall, thus completing the vicious circle on proinflammatory changes. In addition, dysfunctional endothelium shifts toward a prothrombotic phenotype, associated with increased production of von Willebrand factor, tissue factor, tissue type plasminogen activator (t-PA) , and reduced expression of ADAMTS 13. eNOS , Endothelial NO synthase; E-sel , soluble E-selectin; HF , heart failure; iNOS , inducible NO synthase; NFκB , nuclear factor-κB; P-sel , soluble P-selectin; ROS , reactive oxygen species.

TABLE 14.2

Plasma Markers of Endothelial Function in Heart Failure

Study	Study population	EF, % (Inclusion Criteria/Actual)	Etiology	Controls	Marker	Results
Kistorp et al.	195 CHF with diabetes 147 CHF without diabetes	≤45/30 ± 8 in diabetic group, 30 ± 8 in nondiabetic group	74% IHF in diabetic group, 51% IHF in nondiabetic group	116 healthy	E-selectin	↑ diabetes group ↔ in nondiabetic
					vWF	↑ diabetes group ↔ in nondiabetic
Chong et al.	35 with AHF 40 with CHF	≤40/30 (21–33) in AHF, 30 (29–33) in CHF	63% IHF in AHF group, 83% IHF in CHF group	32 healthy	E-selectin	↑ in AHF and CHF ↔ AHF vs. CHF
					vWF	↑ in AHF and CHF ↔ AHF vs. CHF
					sTM	↑ in AHF and CHF ↑ AHF vs. CHF
Vila et al.	59 CHF	Not specified	Not specified	59 healthy	vWF	↑
					thrombospondin-1	↓
Chong et al.	137 CHF	≤45/30 (25–35)	61% IHF	106 healthy	E-selectin	↔
					vWF	↔
Chong et al.	30 with AHF 30 with CHF	≤40/30 (22–32) in AHF group, 30 (29–34) in CHF	70% IHF in AHF group, 80% IHF in CHF group	20 healthy	E-selectin	↑ in AHF and CHF ↔ AHF vs. CHF
					vWF	↑ in AHF and CHF ↔ AHF vs. CHF
					CECs	↑ in AHF and CHF ↔ AHF vs. CHF
Leyva et al.	39 CHF	Not specified/22 ± 12 in IHF, 26 ± 16 in DCM	59% IHF	16 healthy	E-selectin	↑ (↔ IHF vs. DCM)
Chong et al.	30 CHF	<40/31 (29–35)	77% IHF	20 healthy	vWF	↑
					sTM	↔
					CECs	↑

 

↑, Increased; ↓, decreased; ↔, no changes; AHF, acute heart failure; CECs, circulating endothelial cells; CHF, chronic heart failure; DCM, dilated cardiomyopathy; EF, ejection fraction; IHF, ischemic heart failure; sTM, soluble thrombomodulin; vWF, von Willebrand factor.

Counts of circulating endothelial cells, another index of endothelial damage, are increased to similar degree in subjects with acute and chronic HF and correlate with other measures of endothelial damage/dysfunction (e.g., levels of von Willebrand factor and E-selectin and FMD). In relation to clinical parameters, circulating endothelial cell counts parallel plasma levels of BNP but not LV contractility or HF functional class.

Endothelin-1 is a very powerful vasoconstrictor, and overproduction is related to the pathogenesis of various cardiovascular diseases. Although produced by endothelial cells, the role of blood endothelin-1 levels—a marker of endothelial dysfunction—has significant limitations. First, its generation is not exclusive to the endothelium, and it is also produced by vascular smooth muscle cells. Second, this regulatory protein predominantly acts in a paracrine manner being released toward the location of the vascular smooth muscles rather than to the arterial lumen. Nevertheless, endothelin-1 overexpression is implicated in endothelial dysfunction, and its plasma levels correlate with degree of impairment of the endothelium-mediated vasodilation. Plasma endothelin-1 levels are increased in HF patients and inhibit endothelial activity by stimulation of ADMA production, at least in experimental HF. Consequently, increased endothelin-1 activity in HF represents one of the mechanisms responsible for endothelial dysfunction. In experimental work, pharmacologic inhibition of the endothelin-1 pathway significantly improved vasomotor endothelial function. In addition, in patients with HF, vasomotor endothelial function improved following administration of small doses of an endothelin A receptor blocker. However, endothelin receptor blockers failed to demonstrate any significant clinical benefits in randomized clinical trials conducted on patients with HF.

Prothrombotic Transformation of the Endothelium in Heart Failure

Chronic HF is an independent and major risk factor for venous thromboembolism (VTE) and confers a considerable prothrombotic risk in both inpatient and outpatient settings. The annual incidence of VTE is 1.7% to 2.7% in HF compared with approximately 0.1% in the general population. The frequency of PE in patients with HF ranges from 0.9% to 39% and deep vein thrombosis (DVT) varies from 10% to 59%. Three large, well-designed, double-blinded, placebo-controlled studies of hospitalized medical patients at risk of VTE showed that 25% to 50% of these admissions were due to HF. Although the genesis of prothrombotic risk in HF is multifactorial and includes low cardiac output, dilation of cardiac chambers, and stasis of blood in peripheral vascular beds, endothelial damage/dysfunction is considered an important contributor to this process.

The prominent antithrombotic characteristics of healthy endothelial cells are changed dramatically in the dysfunctional endothelium. For example, the abundance of inflammatory cytokines in HF triggers endothelial expression of tissue factor, a trigger of the extrinsic coagulation cascade. Active endothelial production of tissue factor results in downstream activation of factor Xa and leads to cleavage of prothrombin to form thrombin. In acute HF, high tissue factor levels are significantly correlated with inflammatory markers and are highly increased in those who died during the follow-up period. In addition, tissue factor is a significant predictor of poor prognosis in chronic HF.

Platelet abnormalities in observed HF are also partly attributable to endothelial impairment. A dysfunctional endothelium triggers expression of platelet-activating factor, which facilitates platelet adhesion to endothelial cells and upregulates production of von Willebrand factor. Dysfunctional endothelial cells release large amounts of von Willebrand factor, further promoting platelet activation and adhesion. Activity of ADAMTS13, a key von Willebrand factor–cleaving protease pivotal in the pathogenesis of prothrombotic thrombogenic purpura and hemolytic thrombogenic syndrome, is decreased in HF, being negatively correlated with BNP levels, NYHA class, and endothelial dysfunction. In addition, high levels of the tissue type plasmin activator antigen (tPA), predominantly produced by endothelial cells, are independently predictive of a poor prognosis in HF.

Treatment of Endothelial Dysfunction in Heart Failure

Pharmaceutical Agents and Endothelial Function

Given the general acceptance of the importance of endothelial dysfunction in the pathogenesis and outcome of HF, the endothelium became a target for various therapeutic interventions. Activation of the renin-angiotensin-aldosterone axis seen in HF negatively affects function of endothelial cells and disturbs nitric oxide downstream signaling ( Fig. 14.3 ). Favorable effects of angiotensin-converting enzyme (ACE) inhibitors on the endothelium in HF are achieved via different mechanisms, including reduction in production of vasoconstrictor prostanoids, upregulation of eNOS, and inhibition of endothelial cell apoptosis (see also Chapter 37 ). The clinical effectiveness of inhibitors of the renin-angiotensin-aldosterone system, such as ACE inhibitors or spironolactone, in HF appears to be partly attributable to their beneficial effects on the vascular endothelium.

Effects of therapeutic interventions on characteristics of endothelial function in patients with systolic heart failure. ACE , Angiotensin-converting enzyme; ADMA , asymmetric dimethylarginine; EPCs , endothelial progenitor cells.

All published studies uniformly show improvement in endothelium-dependent vasomotor capacity and reduction in the blood levels of von Willebrand factor using neurohormonal antagonists in HF ( Table 14.3 ). Several studies, including the African American Heart Failure Trial (A-HeFT), have demonstrated that improvement in morbidity, mortality, and functional status in HF treated by ACE inhibitors was linked to the improvement in endothelial function. The capacity of various ACE inhibitors to restore endothelial function may differ significantly, and the prescription of higher treatment doses may be required. However, the relative impact of the endothelial effects in the overall benefit of such therapy is unclear, and there is little evidence to justify the preference of particular ACE inhibitors based on their endothelial effects.

TABLE 14.3

Clinical Studies on the Effects of Pharmaceutical Agents and Nutritional Supplements on Endothelial Function in Heart Failure

Author	Study	Number of HF Patients	EF, %	Treatment a	Duration	Results
Boman et al.	R, DB, controlled	267 (53% IHF)	25 ± 7	Carvedilol 25 mg bd or metoprolol 50 mg bd	1 year	↓vWF by carvedilol ↔vWF by metoprolol
Hornig et al.	R, PC	40 (34% IHF)	≈25	Quinaprilat, enalaprilat, IA	Acute effects	↑FMD by quinaprilat ↔FMD by enalaprilat
Hryniewicz et al.	R, PC, DB	64 (52% IHF)	25 ± 1	Ramipril 10 mg or sildenafil 50 mg or combination	Acute effects 1–4 hr	↑FMD (with all 3 treatments)
Drakos et al.	NR	11		Enalapril 10–30 mg bd	4–8 weeks	↑FMD with higher doses
Tavli et al.	NR	30 (100% IHF)	25 ± 5	Cilazapril 5 mg	3 days	↑FMD
Gibbs et al.	NR	40 (80% IHF)	30	Lisinopril 10 mg od, or BB (bisoprolol 5 mg or carvedilol 25 mg od)	6 months	↓vWF
Poelzl et al.	NR	33 (40% IHF)	≈24	Optimized dose of various ACEI and BB	3 months	↑FMD in responders defined by improvement in functional capacity
Farquharson et al.	R, DB, PC, crossover	10 (100% IHF)	31 ± 6	Spironolactone 50 mg daily	1 month	↑FBF in response to ACH (VOP)
Macdonald et al.	R, DB, PC, crossover	43 (67% IHF)	<25	Spironolactone 12.5–50 mg daily	3 months	↑FBF in response to ACH (VOP)
Abiose et al.	NR	20	24 ± 9	Spironolactone	8 weeks	↑FMD
Farquharson et al.	R, PC, DB	10 (100% IHF)	20 ± 8	Amiloride 5 mg od	1 month	↔FBF in response to ACH (VOP)
Belardinelli et al.	R, PC, DB	51 (100% IHF)	33 ± 5	Trimetazidine 20 mg tid	4 weeks	↑RA response to ACH (US)
Ito et al.	NR	12 NIHF	34	Vitamin C 1 g, IV	Acute effects	↔FMD
Hornig et al.	PC	15 (20% IHF)	21	Vitamin C 0.25 g, IA; 1 g bd, oral	Acute effects 4 weeks	↑FMD
Ellis et al.	R, PC, DB, crossover	10		Vitamin C 2 g, IV	Acute effects	↑FMD
Ellis et al.	PC	40 NIHF	<35	Vitamin C 2 g, IV; 2 g bd, oral	Acute effects 1 month	↑FMD
Erbs et al.	NR	18 (50% IHF)	25 ± 4	Vitamin C 0.5 g, IA	Acute effects	↑RA response to ACH (US)
George et al.	R, PC, DB	30		Allopurinol 300 od or bd	4 weeks	↑FBF in response to ACH (VOP) (more with 300 mg bd)
Doehner et al.	DB, PC, crossover	14 (79% IHF)	≈23	Allopurinol 300 mg od	1 week	↑FMD
Hambrecht et al.	R	40 (40% IHF)	19 ± 3	l -arginine 8 g daily	4 weeks	↑FBF in response to ACH (VOP)
Hirooka et al.	NR	20 NIHF	≈43	l -arginine 50 mg, IA	Acute effects	↑FBF in response to RH (VOP)
Chin-Dusting et al.	R, PC, DB	20 (60% IHF)	21	l -arginine 20 g daily	4 weeks	↔FBF in response to ACH (VOP)
Paul et al.	R, PC, DB	22 (100% IHF)	27 ± 7	Methyltetrahydrofolate, IV	Acute effects	↔PWA (salbutamol-mediated changes AI) ↓ADMA
Napoli et al.	R, DB, PC	16 (31% IHF)	<40	Growth hormone (4 IU, SC every other day)	3 months	↑FBF in response to ACH (VOP)
Fichtlscherer et al.	Controlled	18 (50% IHF)	25 ± 1	Etanercept 25 mg, SC, single dose	7 days	↑FBF in response to ACH (VOP)
Fuentes et al.	R, PC, DB	22 (41% IHF)		800 mg magnesium oxide bd	3 months	↑small artery elasticity index
George et al.	R, PC, DB	26		Probenecid 1 g daily	4 weeks	↔FBF in response to ACH (VOP)
Patel et al.	NR	19 (100% IHF)	27 ± 2	Dobutamine 3 μg/kg/min, IV	72 hr	↑FMD for ≥2 weeks
Freimark et al.	Controlled	20 (100% IHF)		Dobutamine, 3.5 μg/kg/min, IV, 5 hr twice a week	4 months	↑FMD
Schwarz et al.	R, PC	31 NIHF	19 ± 7	GTN 10 −9 mol/L, IA	20 min or 12 hr	↑ FBF in response to ACH (VOP)
Guazzi et al.	DB, PC	16 (63% IHF)	≤45	Sildenafil 50 mg	Acute effects	↑FMD

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