La angustia y la mismidad

One such group that is at high risk for cardiovascular disease in later life are patients with type 1 diabetes mellitus (type 1 DM). In the Framingham study, the risk of developing cardiovascular disease before the age of 55 years in diabetics was twice that for non-diabetics in men and over five times the normal rate for women (Kannel and McGee, 1979). This elevated risk, and particularly the occurrence o f morbidity and mortality at a young age, was also noted by Krolewski et al, (1987) when by the age of 55 years cardiovascular mortality, which affected both men and women equally, was as high as 35% (Figure 1.3.1). Autopsy studies have confirmed a relationship between early atherosclerosis and glycosylated haemoglobin as a marker of diabetes in young trauma victims (Strong et al, 1995). The risk of cardiovascular disease in type 1 DM is known to be greatest in patients who have developed microalbuminuria or frank diabetic nephropathy (Yudkin and Chaturvedi, 1999). A further adverse factor is that, at presentation, coronary atherosclerosis is often more severe and widely distributed in diabetic patients making it less amenable to intervention (Krishnaswami et al, 1996) and the long-term benefits from coronary artery bypass surgery are reduced compared to a non-diabetic population (The Bypass Angioplasty Revascularization Investigation (BARI), 1997).

The discovery of insulin by the Nobel Laureates Banting and Best in the 1920s and its widespread introduction as therapy for type 1 DM patients revolutionised their prognosis from the complications of diabetic ketoacidosis. However, insulin therapy has had relatively little impact on the incidence of cardiovascular disease in this

population, which remains the greatest cause of mortality. In the Diabetes Control and Complications Trial, of 1441 type 1 DM patients, intensive treatment with insulin improved glycaemic control and the incidence o f microvascular disease (The DCCT Research Group, 1993) but did not significantly alter the outcome from macro vascular events (The DCCT Research Group, 1995). These results emphasise the need to research the pathophysiology o f vascular disease in type 1 DM and to develop alternative strategies to retard atherosclerosis in this population.

5.1.3.1 Vascular dysfunction in type 1 D M

Meraji and colleagues (1987), demonstrated impaired endothelial-dependent dilatation in response to acetylcholine and histamine in aortic rings from spontaneously diabetic Wistar BB rats and confirmed the presence o f a structurally abnormal endothelium by electron microscopy. These findings have subsequently been confirmed in a variety of animal models (Lindsay et al, 1997). In young type 1 DM patients, without clinical cardiovascular disease, endothelial dysfunction has been demonstrated, in both resistance vessel (Calver et al, 1992; Elliott et al, 1993; Johnstone et al, 1993) and conduit arteries (Clarkson et al, 1996a; Lekakis et al,

1997). Huszka and colleagues (1997) demonstrated significantly reduced excretion o f nitrate/nitrite as a biochemical marker of NO production in type 1 DM patients. These findings however are not universal in that in other studies, of similar cohorts, no significant abnormality of endothelial function was seen (Halkin et al, 1991; Lambert et al, 1996; Smits et al, 1993). The reason for this discrepancy remains unclear, but may relate to differences in the patient characteristics, the small number of subject in many of these studies and other differences in methodology. Elliott and colleagues (1993), demonstrated an abnormality of resistance vessel function only in patients with microalbuminuria, suggesting that the stage of the disease is an important factor. In resistance vessel studies, differences in basal blood flow and the use of agents such as methacholine, which may be largely a non-NO dependent vasodilator (Chowienczyk et al, 1993), may explain some of the discrepancies. Finally a number of studies have demonstrated abnormalities of neurovascular control, in type 1 DM, and this might have an impact on, particularly, resistance vessel reactivity (Makimattila et al, 1997; Steel et al, 1993).

Four studies to date have examined endothelial function in the brachial artery. Lambert and colleagues (1996), demonstrated a small but insignificant difference (after correcting for vessel size) in FMD between normoalbuminuric type 1 DM patients and controls. However in this study an FMD of over 10% was found suggesting that the cuff was placed on the upper arm above the segment of artery being imaged. The response of arteries under these conditions may be different than when a smaller stimulus to a non-ischaemic artery is applied by placing the cuff below the target artery (Chapter 3). In a recent paper, Enderle and colleagues (1998) also found no significant abnormality of endothelial function in type 1 DM patients. However, these patients were selected on the basis of having a long duration of diabetes but not having developed any complications and therefore do not represent the general type 1 DM population. Furthermore, only 17 patients were assessed and this study might have been under-powered. Lekakis and colleagues (1997) and Clarkson and colleagues (1996a) have reported a significant abnormality o f FMD in young type 1 DM patients. In the latter study, endothelial dysfunction was not related to parameters of diabetic control but to the duration of diabetes and LDL-cholesterol levels. This emphasises the continuing importance o f reversible risk factors in type 1 DM. In addition to abnormalities of endothelial-dependent dilatation, elevated levels of von Willebrand factor, soluble adhesion molecules, and fibrinogen have been reported at an early stage in type 1 DM and are likely to represent generalised endothelial activation (Greaves et al, 1997; Kopp et al, 1998; Stehouwer et al,

1995). The balance of evidence supports there being an abnormality of endothelial function which occurs early in young type 1 DM subjects (Poston and Taylor, 1995).

Impaired smooth muscle response to exogenous nitrate has also been demonstrated in type 1 DM (Calver et al, 1992; Clarkson et al, 1996b). The mechanism of this abnormality is unknown but suggests a more complex and widespread abnormality than that seen in other risk factor groups. This might represent reduced sensitivity of vascular smooth muscle to exogenous nitrate or impaired metabolism of GTN to NO (Calver et al, 1992). However, the dose o f GTN that has been used is supramaximal (Section 2.2.7) and the more likely explanation is that structural changes in the arterial wall limit maximal dilatation. This is supported by recent findings in healthy volunteers, in which inhibition of NO synthesis resulted in enhanced smooth muscle sensitivity to exogenous nitrosovasodilators (Barba et al, 1999).

5.1.3.2 Mechanisms o f vascular disease in type 1 DM

The pathogenesis of vascular injury in diabetes mellitus is likely to be complex with multiple mechanisms operating (Poston and Taylor, 1995). Hyperglycaemia and the formation o f advanced glycosylation endproducts are important sources of oxygen derived free radicals (Cosentino et ah, 1997; Rubanyi and Vanhoutte, 1986; Williams et ah, 1998; which inactivate NO (Bucala et ah, 1991; Tesfamariam and Cohen, 1992) and accelerate the peroxidation of lipoproteins (Bucala et al., 1993). Increased susceptibility of LDL to oxidation has been reported in diabetics (Cominacini et al., 1994) which may be related to poor control and duration of diabetes (Feillet et al., 1998). In addition, glycosylation or impaired metabolism of L-arginine might reduce its availability for NO synthesis (Lo et al., 1994; Wu and Meininger, 1995) and lack o f essential co-factors (Hawthorne et al., 1989) or alteration in the kinetics of NO synthase (Amal et al., 1995) might further decrease NO formation and even result in the production of superoxide anion (Wever et al., 1997; Xia et al., 1996).

5.1.3.3 Role o f other risk factors

Whilst factors specific to diabetes are likely to have a major impact on the progression of cardiovascular disease epidemiological studies have demonstrated that classical risk factors continue to operate, though at a higher level (Kannel and McGee, 1979) (Figure 5.1.2). Furthermore diabetes is often associated with a clustering o f risk factors including hypertension, elevated cholesterol levels and dyslipidaemia. Thus for any given level of a risk factor the attributable risk will be higher and consequently intervention is justifiable at a lower threshold.

5.1.4 Discussion

Type 1 DM is a major risk factor for premature cardiovascular disease with abnormalities of endothelial function being apparent from an early age. Preventative strategies, which target the disease at this early stage, might have a clinical benefit on cardiovascular morbidity and mortality in later life. Such strategies might include therapeutic manoeuvres that enhance NO bioavailability, reduction in concomitant risk factors and the reduction in oxidative stress. Non-invasive testing of endothelial function is ideally suited to assess the effects o f such interventions on the vascular wall, over relatively short periods of time.

25 4

2 0

< 15-

o

8

4

5

6

7

Total-cholesterol (mmol/l)

Figure 5.1.2 Cardiovascular risk and total cholesterol levels in diabetics and non­ diabetic subjects aged 45 years. Although absolute risk is higher in the diabetic subjects classical risk factors continue to operate and a similar relationship with cholesterol exists as in non-diabetic individuals. Data derived from the PROCAM study.

5.1 Endothelial response to intravenous L-arginine in type 1 DM and