Secondary Prevention Strategy of Cardiovascular Disease Using Endothelial Function Testing

Abstract

Over the past decades, secondary prevention of cardiovascular (CV) disease has improved and considerably reduced mortality rates. However, there remains a high-rate of new or recurrent CV events in those with established atherosclerotic vascular diseases. Although most of the prevailing therapies target the conventional risk factors, there is notable interindividual heterogeneity in adaptation to risk factors and response to therapies, which affects efficacy. It is desirable to have a methodology for directly assessing the functional significance of atherogenesis, and for managing individual patients based on their comprehensive vascular health. Endothelial function plays a pivotal role in all stages of atherosclerosis, from initiation to atherothrombotic complication. Endothelial function reflects the integrated effect of all the atherogenic and atheroprotective factors present in an individual, and is therefore regarded as an index of active disease process and a significant risk factor for future CV events. Moreover, improvement in endothelial function is associated with decreased risk of CV events, even in the secondary prevention setting. The introduction of endothelial function assessment into clinical practice may trigger the development of a more tailored and personalized medicine and improve patient outcomes. In this review, we summarize current knowledge on the contribution of endothelial dysfunction to atherosclerotic CV disease in the secondary prevention setting. Finally, we focus on the potential of an endothelial function-guided management strategy in secondary prevention. (Circ J 2015; 79: 685–694)

Over the past decades, secondary prevention measures have greatly improved and considerably reduced cardiovascular (CV) mortality.¹ However, there remains a high-rate of new or recurrent CV events in those with established coronary and other atherosclerotic vascular diseases.² The difficulty in identifying individual risk can be highlighted as a factor associated with the high prevalence of recurrent CV disease. Although a number of CV risk factors have been established and effective treatments for atherosclerotic CV disease (ASCVD) have been developed, there is a notable interindividual heterogeneity in response to risk factors and therapies, which affects efficacy. It is desirable to have a methodology for directly assessing the functional significance of atherogenesis at each stage.

Endothelial function reflects the balance of all atherogenic and atheroprotective factors present in an individual. Dysfunctional endothelium is associated with unfavorable physiological vascular changes such as vasomotor tone alterations, thrombotic dysfunction, smooth muscle cell proliferation and migration, as well as leukocyte adhesion, and plays a pivotal role in the initial development and progression of atherosclerotic plaque, and subsequent atherosclerotic complications.^3,4 Endothelial dysfunction can, therefore, be regarded as both an index of active disease process through the course of ASCVD, and a significant risk factor for future CV events.⁵ Thus, the introduction of endothelial function assessment into clinical practice may instigate the development of more tailored medicine.

In this review, we update the evidence supporting the role of endothelial function assessment in patients with established ASCVD, and focus on the potential of an endothelial function-guided management strategy in the secondary prevention setting.

Role of Endothelial Dysfunction in CVD

Atherosclerosis begins early in life, and progresses over decades. Endothelial dysfunction contributes to atherosclerotic disease progression in all stages.^3,6 Dysfunctional endothelium is also responsible for increased plaque vulnerability.⁷ Impaired endothelial function is associated with an increased inflammatory response, thrombogenicity, and enhanced local expression of matrix metalloproteinases, which are rendered prone to develop a fracture in the protective fibrous cap of plaques, and coronary thrombosis.^3,8 Moreover, apoptosis of endothelial cells could contribute to desquamation of endothelial cells in areas of superficial erosion, which can foster coronary thrombosis.⁹

In addition to its association with atherosclerosis, endothelial dysfunction has been implicated in other conditions that lead to CV events, such as coronary spasm,¹⁰ heart failure with preserved ejection fraction,¹¹ cardiomyopathy,¹² atrial fibrillation,¹³ and left atrial¹⁴ and venous¹⁵ thrombus formation. Thus, endothelial dysfunction is a systemic manifestation and represents comprehensive CV health (Figure 1). Effective identification of vulnerable patients with severe endothelial dysfunction is important to improve prognosis.

Figure 1.

Systemic manifestation of endothelial dysfunction in the vulnerable patient with vulnerable endothelium.

Local and Systemic Factors Damaging the Endothelium

Atherosclerosis is a diffuse disease with focal complications in different vascular beds. The precise mechanisms by which a specific site is rendered more prone to the development of symptomatic disease and CV events are not known. Endothelial function status is not determined solely by an individual risk factor burden, but is rather an integrated index of all factors (Table 1).¹⁶ Although the entire systemic vasculature is exposed to the atherogenic effects of systemic risk factors, similarly, local risk factors, such as flow-generated endothelial shear stress,¹⁷ angioplasty,¹⁸ and local inflammation play a role in regional endothelial dysfunction and plaque formation. Iatrogenic vascular injury, including balloon angioplasty and stent implantation, disrupts endothelial cells, which promotes in-stent thrombosis and restenosis. Restoration of healthy vascular endothelial cells is an important step in the prevention of subsequent coronary events. Locally derived endothelial cells and bone-marrow derived circulating endothelial progenitor cells (EPCs) have been suggested to participate in re-endothelialization.^18,19 EPCs may have an important function as an endogenous repair mechanism by replacing denuded parts of the artery and regenerating low-grade endothelial damage. Dysfunctional EPCs are also considered part of endothelial dysfunction.²⁰ Atherosclerotic plaque progression results from a complex interaction between local and systemic atherogenic and atheroprotective factors. Both local and systemic atherosclerotic disease manifestations vary depending on the stage, location, and other factors affecting the integrity of the vascular wall.

Table 1. Local and Systemic Risk Factors for Atherosclerosis

Known risk factors
Local	Systemic
Hemodynamic forces (eg, shear stress)	Conventional risk factors (modifiable)
Vascular injury (eg, balloon angioplasty, stent implantation)	Smoking
	Hypertension
Local inflammation	High LDL-C
Local oxidative stress	Low HDL-C
Impaired local endothelial repair	High triglycerides
	Diabetes, metabolic syndrome, insulin resistance
	Non-conventional risk factors
	Male sex
	Older age
	Race
	Genetic factors
	Inflammation
	Lp-PLA2
	Lipoprotein(a)
	Homocysteine
	Environmental exposures
	Depression, mental stress
	Low physical activity, sedentary behaviors
	Obesity
	Dietary factor
	Menopause, postmenopausal hormone therapy
	Noise
	Others
Unknown risk factors

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp-PLA2, lipoprotein-associated phospholipase A2.

Assessment of Endothelial Function

Development of clinical tests that evaluate endothelial function has paralleled the growing understanding of the biology of the vascular endothelium. Endothelial function can be measured by assessing various physiologic functions, which include regulation of vascular tone, expression of adhesion molecules and maintenance of an antithrombotic microenvironment. In general, loss of regulation and activity of vasoactive substances, in particular nitric oxide (NO), indicates a broadly dysfunctional phenotype across many properties of the endothelium; suppression of platelet aggregation, inflammation, oxidative stress, vascular smooth muscle cell migration and proliferation, and leukocyte adhesion.²¹ Thus, endothelium-dependent vasodilation is the most widely used clinical endpoint to assess and reflect the multiple aspects of endothelial function in humans.

Coronary Endothelial Function Assessment

The widely accepted method of evaluating coronary endothelial function involves intra-arterial administration of endothelium-dependent vasodilatory substances (eg, acetylcholine). The vasodilatory agent delivered into the coronary arteries results in measurable vasodilatation and an increase in coronary blood flow in normal subjects through activation of endothelial cells and stimulation of NO release, whereas in patients with endothelial dysfunction, it induces vasoconstriction and lack of increase in coronary blood flow via direct activation of muscarinic receptors on vascular smooth muscle cells. Changes in vessel diameter assessed by quantitative coronary angiography represent epicardial coronary endothelial function, whereas changes in coronary blood flow assessed by Doppler flow wire represent coronary microvascular endothelial function (Table 2). More recently, noninvasive methods of assessing coronary endothelial function have been developed, such as transthoracic Doppler echocardiography, computed tomography imaging, magnetic resonance imaging, and positron emission tomography.^22,23

Table 2. Methods Used to Assess Endothelial Function

Method	Coronary or Peripheral artery	Vascular bed	Measurements	Stimulus	Invasive
Coronary epicardial vasoreactivity	Coronary	Conduit	Vessel diameter	Infusion of endothelial dependent vasodilator	+
Coronary microvascular vasoreactivity	Coronary	Resistance	Blood flow	Infusion of endothelial dependent vasodilator	+
FMD	Peripheral (brachial artery)	Conduit	Vessel diameter	Reactive hyperemia	−
RH-PAT	Peripheral (finger microvasculature)	Resistance	Plethysmogram	Reactive hyperemia	−

FMD, flow-mediated vasodilatation; RH-PAT, reactive hyperemia-peripheral arterial tonometry.

Peripheral Endothelial Function: FMD and RH-PAT

It has been reported that endothelial dysfunction in peripheral arteries had comparable prognostic value to coronary endothelial dysfunction,²⁴ and several noninvasive methods for the assessment of peripheral endothelial function have been developed. Reactive hyperemia after artery occlusion is used as a trigger to detect endothelium-dependent vasodilation in most of the noninvasive methods. Brachial flow-mediated vasodilatation (FMD) and reactive hyperemia-peripheral arterial tonometry (RH-PAT) are some of the widely used noninvasive methods, and are based on the same principle of reactive hyperemia (Table 2). To evaluate the endothelium-dependent vasodilation capacity, the brachial artery diameter proximal to the antecubital fossa is measured in the FMD technique at rest and during reactive hyperemia, which is achieved by rapid release of a pneumatic pressure cuff after inflation to suprasystolic pressure for 5 min. In the RH-PAT technique, the pulse wave amplitude of the finger is measured. Thus, FMD assesses conduit artery vasodilation, and RH-PAT assesses microvessel vasodilation. Both of these techniques have been reported to correlate well with coronary artery endothelial function.^10,25,26 However, the Framingham Heart Study reported that the relationship between RH-PAT and FMD is not statistically significant, and concluded that the 2 methods have differing relationships with CV risk factors.²⁷ NO bioavailability has a substantial role in both,^28,29 but other substances, such as prostaglandin, adenosine, and hydrogen peroxide, can also affect vasodilation in response to shear stress and ischemia.³⁰ There are 2 techniques of measuring brachial FMD, using an occluding cuff placed distal or proximal to the imaged artery. FMD with distal occlusion is more NO-dependent than FMD with proximal occlusion or RH-PAT. Interestingly, FMD with proximal occlusion provides higher predictive value for CV events than FMD with distal occlusion.³¹ Furthermore, microvascular function measured by blood flow or shear stress response after ischemia possesses independent predictive value from endothelial function in conduit arteries, and such responses are not solely NO mediated.^32–36 FMD and RH-PAT might reflect different and complementary aspects of vascular function. Other methods used for peripheral endothelial function assessment include laser Doppler flowmetry, biochemical markers (asymmetrical dimethylarginine, etc), endothelial microparticles, and EPCs.²³

Clinical Evidence of the Association of Endothelial Function With Atherosclerotic Disease

Plaque Vulnerability

Atherosclerotic lesions prone to acute thrombotic complications because of plaque rupture or superficial endothelial erosion are known as “vulnerable plaques”. Recent clinical studies demonstrated that coronary endothelial dysfunction was associated with vulnerable plaque characteristics than those with normal endothelial function (Table 3). Lavi et al reported that coronary segments with attenuated endothelial function were associated with a larger necrotic core of plaque.³⁷ Choi et al reported that epicardial coronary artery segments with endothelial dysfunction had more lipid deposition,³⁸ macrophages and microchannels of plaque, consistent with vasa vasorum proliferation.³⁹ In addition to invasive coronary endothelial function assessment, peripheral endothelial dysfunction as assessed by FMD was reported to be associated with larger necrotic core content of plaque and higher frequency of thin-cap fibroatheroma.⁴⁰

Table 3. Clinical Evidence of the Association of Endothelial Function With Coronary Plaque

Study	Population	n	Endothelial function assessment	Plaque assessment	Results
Coronary plaque vulnerability
Lavi et al37 (2009)	Nonobstructive CAD	30	Coronary epicardial vasoreactivity	VH-IVUS	Local coronary endothelial dysfunction associated with greater necrotic core
Choi et al38 (2013)	Nonobstructive CAD	32	Coronary epicardial vasoreactivity	NIRS	Coronary epicardial endothelial dysfunction associated with lipid core plaques
Sawada et al40 (2013)	CAD	111	FMD	VH-IVUS	Lower FMD associated with more necrotic core and higher prevalence of TCFA
Choi et al39 (2014)	Nonobstructive CAD	40	Coronary epicardial vasoreactivity	OCT	Coronary epicardial endothelial dysfunction associated with macrophages and microchannels in coronary plaques
Coronary plaque progression
Yoon et al41 (2013)	Nonobstructive CAD	35	Coronary epicardial vasoreactivity	IVUS	In segment with endothelial dysfunction, coronary plaque progressed
Gössl et al4 (2014)	Nonobstructive CAD	22	Coronary epicardial vasoreactivity	IVUS	In segment with endothelial dysfunction, coronary plaque progressed

CAD, coronary artery disease; FMD, flow-mediated vasodilatation; NIRS, near-infrared spectroscopy; OCT, optical coherence tomography; TCFA, thin-cap fibroatheroma; VH-IVUS, virtual histology-intravascular ultrasound.

Plaque Progression

Endothelial dysfunction is not only a marker for CV risk but also a contributor to the progression of atherosclerosis. A randomized study of endothelin-A receptor antagonist was reported recently by Yoon et al.⁴¹ In addition to its vasoconstrictive properties, endothelin has mitogenic properties, and plays an important role in the development of endothelial dysfunction and progression of atherosclerosis.⁴² Plaque volume change was evaluated by intravascular ultrasound in patients with nonobstructive coronary artery disease (CAD) at baseline and 6-month follow-up, and in the coronary artery segments with endothelial dysfunction, significant plaque progression had occurred at the 6-month follow-up, but not in segments with normal endothelial function. Moreover, plaque progression was attenuated by endothelin-A receptor antagonist. Those results indicate the important role of coronary endothelial dysfunction in CAD progression. Similarly, Gossel et al reported that coronary plaque progressed more in segments with endothelial dysfunction than in segments with normal endothelial function.⁴ Thus, coronary segments with endothelial dysfunction represent vulnerable segments.

Stent Thrombosis and In-Stent Restenosis

To our knowledge, no direct clinical evidence of the association between endothelial dysfunction and in-stent thrombosis has been reported. Compared with bare-metal stents, drug-eluting stents reduce the incidence of in-stent restenosis, but also increase the risk of in-stent thrombosis, possibly mediated by their effects on the endothelium. It has been reported that drug-eluting stents are associated with a hypersensitivity reaction, delayed healing, and incomplete endothelialization, which may contribute to the increased risk of late and very late stent thrombosis compared with bare-metal stents.⁴³ Moreover, in patients with CAD on dual antiplatelet therapy, peripheral endothelial function as assessed by RH-PAT is associated with residual platelet reactivity that may also contribute to an increased risk of in-stent thrombosis.⁴⁴ Both systemic and local endothelial dysfunction may be modifiable factors in the prevention of in-stent thrombosis, and several stent technologies are being developed in an attempt to decrease the risk of late thrombotic events, including bioabsorbable polymers, nonpolymeric stent surfaces, bioabsorbable stents, and an EPC capture stent.

Possible mechanisms involved in the pathogenesis of in-stent restenosis include platelets and inflammatory cell activation by procedural vascular injury with subsequent local release of cytokines and growth factors, leukocyte adherence, smooth muscle cell proliferation, and extracellular matrix synthesis. Dysfunctional endothelium may be partly responsible for in-stent restenosis, and several prospective studies using FMD have reported that endothelial dysfunction is an independent predictor of in-stent restenosis.^45,46

Validity of Endothelial Function Testing for Event Prediction

In 2000, we reported the first evidence of the long-term prognostic significance of coronary endothelial vasodilator dysfunction on atherosclerotic disease progression and CV events.⁴⁷ In addition, the independent association between coronary microvascular endothelial dysfunction and the risk of future CV events has been reported.^48,49 However, in order to use an endothelial function-based secondary prevention strategy, endothelial function tests must be minimally invasive or noninvasive. A large number of studies have reported the prognostic value of FMD and PAT in both the primary and secondary prevention setting, and several meta-analyses have demonstrated the tests independent prognostic value.^50,51 Studies that reported the prognostic value of these tests in patients with established ASCVD are listed in Table 4.^46,52–70 Importantly, these studies demonstrated the utility of endothelial function assessment not only in chronic CAD patients but also in patients with acute coronary syndrome (ASC) or ischemic heart failure.

Table 4. Clinical Evidence of the Association of Noninvasive Endothelial Function Assessment With CV Events in the Secondary Prevention Setting

Study	Population	Follow-up	n	Method	Clinical endpoints	Events	Results
Frick et al53 (2005)	Patients with chest pain (CAD 79%)	39 months (mean)	398	FMD	Cardiac death+MI+angina+coronary revascularization+progression of coronary plaque	44	FMD predicts CV events
Rubinshtein et al70 (2010)	Patients with chest pain	70 months (median)	270	PAT	CV death+MI+coronary revascularization+cardiac hospitalization	98	PAT predicts CV events
Matsuzawa et al64 (2013)	Patients with chest pain (CAD 84%)	34 months (mean)	528	PAT	CV death+MI+UA+coronary revascularization+HF+peripheral vascular events	105	PAT predicts CV events
Chan et al52 (2003)	CAD	34 months (mean)	152	FMD	CV death+MI+UA+coronary revas cularization+stroke+TIA+carotid endarterectomy+peripheral vascular events	22	FMD predicts CV events
Bosevski et al55 (2007)	DM+CAD	12 months (mean)	82	FMD	CV death+MI+angina+stroke+ worsening HF	46	FMD predicts CV events
Akcakoyun et al46 (2008)	CAD	12 months (mean)	135	FMD	CV death+MI+UA+stroke	30	FMD predicts CV events
					In-stent restenosis	16	FMD predicts in-stent restenosis
Corrado et al56 (2009)	CAD	12 months (mean)	58	FMD	CV death+MI+UA+angina	9 (all angina)	FMD predicts angina recurrence
Kitta et al58 (2009)	CAD	31 months (mean)	251	FMD	Cardiac death+MI+coronary revascularization+stroke	42	Persistent low FMD over 6 months predicts CV events
Matsue et al63 (2014)	CAD (LDL <100 mg/dl with statins)	32 months (median)	213	PAT	Coronary death+MI+angina+ coronary revascularization	22	PAT predicts CV events in patients successfully treated with statins
Nakamura et al65 (2013)	CAD	52 months (mean)	547	FMD	Cardiac death+MI+UA+stroke	69	FMD predicts CV events
Ikonomidis et al67 (2014)	CAD	34 months (mean)	111	PAT	MI	12	PAT predicts MI
Karatzis et al54 (2006)	NSTE-ACS	25 months (mean)	98	FMD	CV death+MI+UA+stroke	20	FMD on the 2nd day after admission predicts CV events
Guazzi et al57 (2009)	MI (STEMI 20%, NSTEMI 80%)	14 months (mean)	179	FMD	MI+coronary revascularization+ HF+cerebral vascular events	45	FMD within 5 days after onset of MI predicts CV events
Wang et al60 (2009)	STEMI	12 months (mean)	101	FMD	Cardiac death+MI+UA+coronary revascularization+HF+stroke	29	FMD on the 5th day after PCI predicts CV events
Careri et al62 (2013)	NSTE-ACS	32 months (median)	60	FMD	CV death+MI+UA+angina	14	FMD at 3 months after NSTE- ACS predicts CV events
Mei et al68 (2014)	NSTEMI	22 months (mean)	172	FMD	Cardiac death+MI+angina+TVR	37	FMD predicts CV events
Shechter et al59 (2009)	Ischemic HF NYHA class IV	14 months (mean)	82	FMD	Death+MI+worsening HF	30	FMD predicts CV events
Takishima et al61 (2012)	Ischemic HF	33 months (mean)	245	FMD	Cardiac death+worsening HF	33	Persistent low FMD over 6 months predicts CV events
Watanabe et al66 (2013)	Ischemic HF	19 months (mean)	47	FMD	CV death+MI+coronary revascularization+congestive HF	9	Standardized FMD by autonomic nervous activity predicts CV events
Hasin et al69 (2015)	HF with LVAD (Ischemic 44%)	18 months (median)	18	PAT	Death+thrombotic event+ bleeding+HF+renal failure+ arrhythmia	69*	Decrease in RH-PAT after LVAD implantation compared to pre LVAD implantation predicts adverse events

*Multiple events were counted per patient. CAD, coronary artery disease; CV, cardiovascular; FMD, flow-mediated vasodilatation; HF, heart failure; LVAD, left ventricular assist device; MI, myocardial infarction; NSTE-ACS, non-ST-elevation acute coronary syndrome; NSTEMI, non-ST-elevation myocardial infarction; NYHA, New York Heart Association; PAD, peripheral arterial disease; PAT, peripheral arterial tonometry; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; TIA, transient ischemic attack; TVR, target vessel revascularization; UA, unstable angina.

Patients With Chest Pain

In a study of patients with chest pain undergoing coronary angiography (79% had CAD),⁵³ FMD, which was performed on the day after angiography, had significant predictive value for CV events. Similarly, another study of 528 patients with chest pain (84% had CAD) demonstrated that RH-PAT before coronary angiography predicted future CV events over a mean follow-up of 34 months.⁶⁴ Interestingly, the prognostic value of RH-PAT was independent of coronary atherosclerotic plaque. Endothelial dysfunction itself can cause myocardial ischemia, even in the absence of relevant coronary stenosis. Importantly, Rubinshtein et al reported that RH-PAT was an independent predictor of CV events in patients with chest pain but without apparent obstructive CAD.⁷⁰

Stable CAD

There is growing evidence of the significant predictive value of peripheral endothelial function assessment in stable CAD patients. Notably, although the therapeutic approach in diabetic patients with CAD continues to be a clinical challenge, even in this high-risk population, peripheral endothelial dysfunction predicted prognosis of CV events.⁵⁵ It has been reported that even with statin therapy, 9% of patients with chronic CAD proceeded to a second CV event at 5 years of follow-up,⁷¹ and therefore many patients are not completely protected by their current therapeutic regimens. Matsue et al demonstrated that, in CAD patients successfully treated with statins, RH-PAT predicted subsequent CV events, indicating the usefulness of endothelial function assessment in identifying residual risk in CAD patients under statin therapy.⁶³ Furthermore, the overall survival of patients with CAD has been suggested to be largely independent of the degree of coronary luminal stenosis.⁷² In a study of 442 patients with CAD, peripheral endothelial dysfunction, as assessed by RH-PAT, predicted the risk of CV events independently of traditional risk factors and coronary plaque complexity as assessed by the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) Score.⁶⁴

ACS

After ACS, patients are at higher risk for recurrence of CV events compared with patients with chronic CAD.⁷³ Several studies have reported that endothelial function assessment performed 2–5 days after the onset of ACS predicted subsequent CV events.^54,57,60 On the other hand, in a study of non-ST-elevation ACS patients by Careri et al, FMD was measured <12 h after admission and at 3-month follow-up, and it was reported that FMD at 3 months after the acute event was a significant predictor, but FMD within 12 h was not. Thus, although endothelial dysfunction seems to be present in most patients with ACS, it is reversible.

Heart Failure

Ischemic cardiomyopathy, a terminal stage of CAD, is a major challenge to the health system because it continues to contribute significantly to healthcare costs and to the degree of disability. Shechter et al⁵⁹ reported the significant prognostic value of FMD in patients with New York Heart Association Class IV ischemic heart failure. Moreover, we recently reported a study of patients with severe heart failure undergoing implantation with a continuous flow left ventricular assist device.⁶⁹ Endothelial function as assessed by RH-PAT declined after device implantation, and this decline was associated with subsequent adverse CV events.

Endothelial dysfunction in epicardial and/or microcirculatory coronary arteries has an important involvement in myocardial ischemia and coronary atherosclerosis progression in every stage of the disease.^74,75 Notably, in accordance with this pathological feature, previous clinical studies have demonstrated the significant prognostic value of noninvasive endothelial function assessment for CV events in every stage of CAD progression, including patients without any vascular disease, chronic CAD patients, ACS patients, and ischemic heart failure patients, as mentioned before. Furthermore, in patients with chronic CAD,⁵⁸ ACS,⁶² or ischemic heart failure,⁶¹ improvement in peripheral endothelial function has been reported as associated with a significant reduction in future CV events. Thus, endothelial function is predictive for CV events and reversible through the course of CAD.

Link Between Endothelial Function and Clinical Outcome

As mentioned earlier, improvement in endothelial dysfunction is associated with better CV outcomes. Thus, endothelial function can be not only a diagnostic and prognostic marker but also a therapeutic target. Table 5 is a brief summary of the effect of interventions on endothelial function and CV outcomes.^74,75 Effective management of atherosclerotic disease includes pharmacologic treatment of specific risk factors and lifestyle modifications, such as smoking cessation, weight loss, diet change, and increased physical activity, all of which reportedly improve endothelial function. Contrarily, the effect of glucose-lowering therapy on endothelial function is still controversial, which is consistent with results of CV outcomes from large clinical trials.⁷⁵ Cholesteryl ester transfer protein (CETP) is considered an attractive therapeutic target for increasing high-density lipoprotein cholesterol. However, torcetrapib, a CETP inhibitor, unexpectedly increased CV events.⁷⁶ It was suggested that sustained and marked worsening of endothelial function might, at least in part, explain the increased mortality associated with torcetrapib treatment.⁷⁷ Importantly, most studies of interventions for CV risk factors show consistent effects on both endothelial function and CV outcomes, again suggesting a link between them.

Table 5. Treatment Effects on Endothelial Function and CV Outcomes⁷⁴

	Endothelial function	Cardiovascular outcomes
Smoking cessation	+	+
Physical activity	+	+
Weight management	+	+
Statins	+	+
RAAS blockers	+	+
3rd generation β-blockers	+	+
Glucose-lowering therapy	±	±
CETP inhibitor, torcetrapib	−	−

+, improvement; ±, controversial; −, worsening. CETP, cholesterol ester transfer protein; RAAS, renin-angiotensin-aldosterone system. Reproduced with permission from Matsuzawa Y, et al.⁷⁴

Endothelial Function-Guided Secondary Prevention

ASCVD is a generalized process and a systemic disease that involves multiple organs, especially heart, brain, kidney, and peripheral arteries.⁷⁸ Clinical manifestations tend to coexist, and the presence of atherosclerosis in one area increases the likelihood of developing atherosclerosis in another. Although invasive coronary revascularization can anatomically dilate local coronary stenoses and is effective for patients with chronic CAD, especially for patients with severe coronary stenosis, multivessel disease, and ischemic heart failure, it fails to treat physiological vascular disorders such as endothelial dysfunction in the systemic vasculature. Thus, adjunctive treatments directed at atherosclerosis, including interventions for risk factors, in addition to revascularization of flow-limiting stenoses, are quite important to reduce CV mortality. Anatomical plaque assessment, such as coronary artery plaque burden, provides information on the degree of atherosclerotic plaque progression, whereas endothelial function testing assesses functional disease activity, such as the direction of atherosclerosis (Figure 2). Given its valuable features, as a mirror of ASCVD status and outcomes, and being reversible with interventions, comprehensive systemic therapy guided by individual endothelial function measurements using noninvasive methods might be feasible and effective. Figure 3 shows a potential strategy using noninvasive assessment of endothelial function for secondary prevention of CV events in patients with established CAD. The endothelial function-guided prevention strategy, with pharmacological therapies, lifestyle modification, etc, might be beneficial in providing a tailored treatment according to the specific manifestation of atherosclerosis in a given patient, and we suggest modifying therapies and searching for other risk factors, including nontraditional risks, in patients who present with endothelial dysfunction even after implementation of optimal therapies along current guidelines. However, it should be noted that endothelial function measurements are not yet recommended by the latest guidelines for risk assessment.^79,80 Currently, evidence is not sufficient to establish an endothelial function-based primary or secondary prevention strategy. Prospective randomized studies are needed to elucidate whether endothelial function-guided therapies provide benefits in improving outcomes for patients with risk factors and for patients with established ASCVD. Such studies may lead us into a new era of individualized medicine in cardiology based on endothelial function assessment.

Figure 2.

Endothelial function through the course of coronary artery disease. Endothelial function is predictive for cardiovascular events and reversible through the course of coronary artery disease. Anatomical plaque assessment suggests the degree of atherosclerotic plaque progression, whereas endothelial function assessment reflects functional disease activity.

Figure 3.

Potential secondary prevention strategy for cardiovascular disease using noninvasive endothelial function testing. DM, diabetes mellitus; RAAS, renin-angiotensin-aldosterone system.

Conclusions

A growing body of evidence suggests that noninvasive assessment of endothelial function may provide important information for individual patient risk and guidance of therapy at different stages of atherosclerotic disease. However, more solid clinical evidence on the utility of endothelial function-guided treatment strategy in preventing CV diseases is required before it can be widely adopted in daily clinical practice.

Disclosures

Funding: A.L. is supported by the National Institute of Health (NIH Grants HL-92954 and AG-31750), the Mayo Foundation. Conflict of Interest: A.L. declared consulting for Itamar Medical.

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