Vascular Compliance

Vascular Compliance

An important cardiovascular disease risk factor

The vascular endothelium is a dynamic living organ, performing a myriad of functions within the living body. It serves as a barrier between the vessel wall and lumen (Avogaro 2008), modulates vascular tone, directs coagulation/fibrinolysis balance, and regulates inflammation (Cines 1998). Furchgott, Murad, and Ignarro jointly received the Nobel Prize in medicine in 1998 for their discoveries of the role of the endothelium in regulating vascular tone, and specifically the role of nitric oxide as the principle signalling molecule responsible (Nobelprize.org 2010).

Nitric oxide (NO) is viewed as the principle regulator of endothelium- controlled vasodilation (Murad 2006). Vascular compliance, a measure of endothelial dysfunction, is characterized by the impairment of endothelium-dependent vasodilation due to reduced activity of NO (through reduced synthesis and/ or increased degradation), and/or an increase in contracting factors (Lian 2010). In addition to compromised NO functionality, endothelial dysfunction is associated with up-regulation of coagulation and inflammation cascades, leading to increased expression of endothelial adhesion molecules, as well as an increase in oxidative burden (Avogaro 2008).

Vascular compliance and disease risk A decrease in vascular compliance can be influenced by the presence of certain metabolites, plasma lipids, oxidative stress, or in more general terms, anything that can inhibit NO formation or increase its degradation. Hypercholesterolemia, diabetes mellitus, and hypertension are pathological conditions that share a common root of impairing NO production (Irace 2001). Multiple studies have demonstrated compromised vascular compliance among patients with traditional cardiovascular risk factors (Lian 2010), including application of a validated methodology by Framingham Heart Study investigators (Hamburg 2011, Hamburg 2008).

Multiple, large, well- controlled studies have found compromised vascular compliance to accurately predict risk of “hard” cardiovascular endpoints, notably cardiac death, acute myocardial infarction, unstable angina, and stroke (Halcox 2002, Matsuzawa 2010, Schachinger 2000, Suwaidi 2000). It is generally accepted that endothelial dysfunction and inflammation precedes atherosclerotic vascular disease and if not remedied, continues indefinitely resulting in the clinical manifestations of plaque formation and subsequent altered blood flow (Avogaro 2008, Deanfield 2007, Drexler 1999, Koh 2005, Price 1999, Ross 1999).

Most interestingly, measure of vascular compliance appears to more accurately predict risk of subsequent cardiovascular disease among patients with low baseline Framingham- predicted risk, relative to individuals with elevated Framingham- predicted baseline risk, as assessed in a meta analytic review of 211 trials (Witte 2005). Assessment of vascular compliance represents a strategy capable of identifying the earliest signs of underlying physiological abnormality leading to overt cardiovascular and cerebrovascular pathology (Lian 2010). It appears to identify the underlying cause of chronic vascular diseases long before such a risk profile emerges through the patient developing traditional cardiovascular risk factors.

While previously reserved for research laboratory settings due to methodological limitations, simple, in- office and validated systems of vascular compliance have since become available (Itamar Medical 2010, Kuvin 2003).

Strategies of Assessment

There are several clinical tests used to evaluate endothelial function and dysfunction, all of which involve pharmacological and or physiological stimulation of NO release from the endothelium (Deanfield 2007). By determining NO bio-availability, critical information regarding vascular tone, thromboregulation, cell adhesion and proliferation can be obtained (Deanfield 2007).

Flow- mediated dilatation (FMD) represents the gold standard among many methods of vascular compliance assessment (Deanfield 2007). FMD represented the least- invasive option, until the development of an in- office technique described below. In brief, FMD employs ultrasound to measure brachial artery reactivity in response to hyperaemic flow. A blood pressure cuff is placed distal to the brachial artery and inflated to create ischaemia in the distal vascular bed for approximately 5 minutes. This induced- ischemia triggers the release of NO from the endothelium. When the cuff is released, reactive hyperaemia forces the endothelium to accommodate by dilatation. Ultrasound of the bracial artery during the process allows for quantification of the magnitude by which the artery was able to dilate. After a rest period, the process is repeated with administration of a single dose of 0.4mg nitroglycerine (spray or sublingual tablet). The response achieved during the phase with nitroglycerine administration is considered a 100% vascular compliance score. The calculated vascular compliance score represents the percentage of the nitroglcyerine- induced response achieved in the absence of nitroglycerine administration (trial run before nitroglycerine administration, the brachial artery dilated to 40% of what was achieved when nitroglycerine was administered) (Corretti 2002, Deanfield 2007).

The ability of assessment of vascular compliance to become commonplace in outpatient clinical settings was made possible through the development of peripheral arterial tonometry (PAT). The technique quantifies pulse wave amplitude during reactive hyperaemia in the fingertip, and has reproducibly demonstrated tight correlation with measures of FMD (Kuvin 2003, Lian 2010). The investigation of vascular compliance previously mentioned by the investigators of the Framingham Heart Study (Hamburg 2011, Hamburg 2008), as well as many of the 211 trials included in the meta analytic review by Witte (2005) utilize the PAT methodology.

Postprandial physiology and vascular compliance

Investigating vascular compliance affords the clinician a rare glimpse into the realm of postprandial physiology. The concept is easily identified in the area of glucose control, with impaired postprandial management of glucose defining diabetes (oral glucose tolerance test). As with glucose, the postprandial response to several important factors differs considerably among individual patients. Abnormal postprandial management of a high fat meal (postprandial hypertriglyceridemia) as well as methionine (postprandial hyperhomocysteinemia) are rarely considered clinically. Below, assessment of their impact to measures of vascular compliance is reviewed.

Hypertriglyceridemia

Elevated levels of triglyceride have been established as an independent risk factor for cardiovascular disease. Fasting triglyceride levels are predictive of disease risk, but the strength with which risk is predicted is diminished when other factors (total cholesterol, HDL- cholesterol, markers of insulin sensitivity) are simultaneously considered (Bansal 2007, Bayturan 2010). Interestingly, non fasting triglyceride levels are likewise an independent predictor of cardiovascular disease risk, and the strength with which this variable predicts risk is not appreciably altered by simultaneous consideration of other conventional risk factors (Bansal 2007). It is the lipemic response to a meal (magnitude by which a mean induces a spike in triglyceride levels) as opposed to fasting triglyceride levels that impacts vascular compliance.

Studies have shown that in populations with no history of myocardial ischemia, diabetes, hypertension, tobacco use (Bae 2001), who are physically active (Blendea 2005), and normocholesterolemic (Plotnick 1997), feeding of a single high- fat meal reduces postprandial endothelial function for up to 4 hours. See Table 1.

Hypercholesterolemia has been suggested to negatively impair endothelial function by increasing the production of reactive oxygen species that deactivate NO (Nofer 2010, Ohara 1993, Shiode 1996). As such, it is postulated that repetitive induction of postprandial hypertriglyceridemia has the ability to promote the development of atherosclerosis (Bae 2001) via increasing reactive oxygen species (Ulker 2003), induction of adhesion molecules and the stimulation of pro-inflammatory mediators (Lundman 1997, Lundman 2003).

Hyperglycemia

Hyperglycemia has the ability to induce endothelial dysfunction by activating Protein Kinase C which mediates the over-expression of adhesion molecules (E-selectin, ICAM, VCAM) (Feener 2001). In healthy normoglycemic subjects, Zhu and colleagues (2007) have shown that after ingestion of 75g glucose, FMD declined to 7.3+/- 3.4% 1 hour after consumption from a baseline value of 11.4+/-3.8%, which then returned to baseline after 4 hours. Interestingly, when 45 minutes of treadmill exercise was introduced immediately after glucose consumption, no significant decrease in FMD occurred (Zhu 2007). Similarly, it was found that when healthy individuals participated in 60 minutes of endurance exercise (elliptical, stationary cycle or treadmill) 17 hours prior to consumption of a high sugar “snack” consisting of a 59g chocolate bar and 591ml soft drink (total glucose, fructose, sucrose: 28g, 38g, 27g respectively), postprandial endothelial function was improved; however, markers of oxidative stress were unchanged (Weiss 2008).

Studies have shown that a transient increase in blood sugar has the ability to impair endothelial function (Akbari 1998, Ceriello 2002, Kawano 1999, Title 2000,), furthering the hypothesis that endothelial dysfunction may precede overt diabetes mellitus. In addition, prolonged and repeated exposure to postprandial hyperglycemia may have a role in atherosclerosis development by impairing NO production and activity (Avogaro 2008). It has been shown that the fraction of L-arginine converted to NO is actually lower in patients with diabetes mellitus when compared to healthy individuals (Avogaro 2003), shedding further light on how hyperglycemia impairs endothelial function.

Hyperhomocysteinemia

Elevated fasting levels of homocysteine have been established as an independent predictor of cardiovascular and cerebrovascular disease risk. A meta analytic review of 30 prospective and retrospective studies concluded a 25% lower fasting homocysteine level was correlated with a 11% reduced risk of ischemic heart disease and a 19% reduced risk of stroke (Homocysteine Studies Collaboration 2002).

A second meta analysis evaluated 72 case control studies and 20 prospective studies. Prospective studies demonstrated a 32% increased risk for ischemic heart disease and a 59% increased risk of stroke for each 5mmol/L increase in fasting homocysteine (Wald 2002).

Postprandial homocysteine responses appear to be more accurate predictors of vascular disease risk than fasting homocysteine levels. Eighteen patients (mean age 58+/- 8 years) with established vascular disease were recruited within three months of an acute vascular event. All patients received 5mg folic acid and 250mg vitamin B6 daily for three months. At baseline and following three months of supplementation, patients underwent assessment of fasting and postmethionine load homocysteine levels. While only two of eighteen patients presented with fasting hyperhomocysteinemia at baseline (>13.5micromol/L), all eighteen patients demonstrated postprandial hyperhomocysteinemia (defined as >40.6micromol/L six hours following administration of 100mg/kg body weight methionine). In a population of slightly younger age and sex matched controls (mean age 41 +/- 6 years), mean homocysteine levels reached 29.0micromol/L) following the methionine load test. Of interest is that following the three month supplementation period, postmethionine load responses decreased 34% (Constans 1999).

Several trials have demonstrated that a methionine load challenge detriments measures of vascular compliance. A selection of such trials is presented in Table 2.

It is postulated that hyperhomocysteinemia decreases vascular compliance by inhibition of NO synthesis, promotion of NO degradation through oxidative mechanisms, promotion of thrombogenesis, and stimulation of endothelin-1 (endogenous vasoconstrictor) release (Ross 1999, Tousoulis 2008).

Discussion

Assessment of vascular compliance allows for a novel, wholesystems view of cardiovascular health. The strategy appears most appropriate for application in settings of primary prevention, and can serve as a powerful tool to achieve/ maintain compliance with interventions best suited to improve the novel marker; diet and lifestyle modification. A very impressive body of literature has been able to establish assessment of vascular compliance as an independent cardiovascular risk factor of clinical significance. Of tremendous value, the test has reproducibly demonstrated the ability to predict perturbed aspects of postprandial physiology, an area not adequately addressed by current concepts in assessment of cardiovascular risk in otherwise healthy populations. Future reviews will further investigate clinical strategies capable of correcting abnormalities in vascular compliance scores.

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