Impact of Lipid and ACE Inhibitor Therapy on Cardiovascular Disease and Metabolic Abnormalities in the Diabetic and Hypertensive Patient

Impact of lipid and ACE inhibitor therapy on cardiovascular disease and metabolic abnormalities in the diabetic and hypertensive patient

JR Sowers Division of Endocrinology, Metabolism and Hypertension, Wayne State University School of Medicine, Detroit, MI, USA

Hypertension is often accompanied by a variety of meta- abnormal more atherogenic LDL cholesterol particle. bolic abnormalities. These metabolic abnormalities Dyslipidemia interacts with associated hemodynamic include insulin resistance, dyslipidemia and abnormali- (ie, hypertension) and metabolic (ie, increased platelet ties of the coagulation-ﬁbrinolytic system predisposing aggregation and PAI-1 levels) in a multiplicative manner to a procoagulent state. The nexus for all of these potentiating cardiovascular and renal disease. Accord- abnormalities may be central (visceral) obesity. The dys- ingly, lipid therapy should be aggressive to attenuate lipidemia accompanying hypertension consists of low these medical complications of essential hypertension. HDL cholesterol, elevated triglyceride levels and an

Keywords: diabetes; cardiovascular disease; lipids; ACE inhibitors

Introduction lin levels11 (Table 1). In the Rancho Bernardo Study, those persons with type II diabetes and impaired Ischemic heart disease (IHD) impacts more than 12 glucose tolerance had higher triglycerides and lower million people, and remains the highest cause of HDL compared with normal controls.13 Similar death in the US. Lipid abnormalities, cigarette observations have been made in other populations.14 smoking and hypertension are known modifiable Genetics studies, including twin, parent–child stud- risk factors for IHD.1–7 Furthermore, the risk for IHD ies, large scale family, and candidate gene studies is markedly increased with multiple risk factors, provide substantial evidence for a genetic basis for especially if diabetes is one of those risk factors.4,5,8– the relationship between hypertension/diabetes and 12 Diabetes is often accompanied by hypertension, other accompanying metabolic abnormalities.11,15–17 which is twice as frequent in individuals with this There is higher heritability in estimates twins than metabolic disorder as in those without.9–11 This arti- in pedigrees for blood pressure (BP), very low den- cle reviews the impact of dyslipidemia and other sity lipoproteins (VLDL), LDL, and BMI.15 In one metabolic abnormalities that often accompany dia- study it was estimated that 70% of adults with betes mellitus and hypertension, and therapeutic hypertension before age 55 have siblings or parents strategies which address metabolic as well as hemo- with hypertension, and 12% of all hypertensive dynamic abnormalities. patients have familial dyslipidemic hypertension.17 Thus, both hypertension and dyslipidemic con- ditions appear to have a genetic basis, and both have Genetic basis for lipid abnormalities been linked to insulin resistance.11 The genetic accompanying diabetes/hypertension Hypertensive persons matched for age and body mass index (BMI) with normotensive individuals Table 1 Lipoprotein abnormalities seen in patients with hyper- have been reported to have lower high density lipo- tension and diabetes mellitus proteins (HDL), higher low-density lipoprotein 1. Elevated plasma levels of VLDL, LDL, and (LDL) levels, as well as increased postprandial insu- lipoprotein(a). 2. Decreased plasma HDL cholesterol. 3. Elevated plasma triglyceride levels. 4. Increased lipoprotein oxidation. 5. Increased lipoprotein glycation. 6. Increased small, dense LDL cholesterol products. 7. Decreased lipoprotein lipase activity. Correspondence: Dr JR Sowers, Director, Division of Endocrin- 8. Increased Lp(a) levels. ology, Metabolism and Hypertension, Wayne State University School of Medicine, UHC-4H 4201 St Antoine, Detroit, MI VLDL indicates very-low-density lipoprotein; HDL, high-den- 48201, USA sity lipoprotein. Impact of lipid and ACE inhibitor therapy JR Sowers 10 locus more commonly associated with poor glycemic control.29,30 Lp(a) is a complex lipo- diabetes/hypertension and accompanying dyslipide- protein particle that contains one LDL cholesterol mia (high triglycerides, low HDL cholesterol, and coupled to one molecule of apolipoprotein a (apo [a] small dense LDL particles) is closely linked to the and apo B-100 through a sulfhydryl bond). Apo(a) LDL receptor and to the insulin receptor locus.17–19 is highly homologous to plasminogen but without Indeed, in coronary sibships, three-fourths of those its protease activity.31,32 Accordingly, it does not with early coronary disease have lipid abnormalities possess the ability to catalyze the conversion of associated with the familial dyslipidemic hyperten- fibrinogen and fibrin to degradable products.31,32 sion syndrome.11,17 Sequencing of DNA has shown L(a) potentiates thrombosis because it inhibits the a point mutation for the enzyme lipoprotein lipase binding of plasminogenic binding proteins on the that contributes to high VLDL/low HDL and poss- surface of endothelial cells, thus inhibiting the con- ibly hypertension.17 In an investigation examining version of plasminogen to plasmen and thus the relationship between HDL cholesterol and the fibrinogen and fibrin degradation. Lp(a) also inhibits variable region flanking the human insulin gene, one fibrinolysis, possibly via fibrin binding attributable class of alleles was associated with a family history to the kringle repeats of apo(a), Lp(a) may delay of both diabetes and IHD.18 In children from the thrombolysis and contribute to the progression of Bogalusa cohort, postprandial insulin levels were atherosclerotic plaques.31–34 Plasma levels of Lp(a) positively correlated with fasting serum cholesterol have been observed to be elevated with increasing and VLDL.20 Thus, there is mounting evidence for a age, LDL-cholesterol levels33 and hyperglycemia.34 genetic basis for the association of insulin resistance Similar to LDL, Lp(a) can undergo oxidative modi- and dyslipidemia.21 In turn, both of these abnormali- fication and has been localized in atherosclerotic ties are associated with hypertension and type II dia- lesions,33 suggesting a direct participation.5 While it betes mellitus.9–12,22–24 seems likely that lowering of Lp(a), could decrease atherosclerotic vascular disease risk, currently there Elevated VLDL and serum triglycerides are no data to support this notion. Niacin and post- menopausal estrogen therapy, but not other lipid High serum triglyceride levels are associated with therapies have been demonstrated to lower increased IHD risk,21,25 and often elevated in associ- Lp(a),5,31,32 but additional investigation is needed to ation with insulin resistance.21 Viseral or ‘android’ determine the relevance of this effect. obesity is associated with insulin resistance, elevated VLDL, reduced HDL and an increased propen- sity to IHD.22–26 Compared with adipocytes located Post-translational modification of lipoproteins peripherally (ie, gluteofemoral), visceral adipocytes associated with diabetes mellitus display greater sensitivity to lipolytic hormones.27 Hyperglycemia contributes to acceleration of athero- The consequent increased lipolysis in visceral obes- sclerosis, in part, by resulting in glycooxidation of ity, in turn, causes increased free fatty acid (FFA) lipoprotein particles (Table 1).4,5,35–37 In the diabetic turnover into the portal and systemic circulations. state, the generation of reactive oxygen species Delivery of increased FFA to the liver inhibits hep- (ROS) or free radicals by vascular intimal macro- atic clearance of circulating insulin, and stimulates phages and vascular smooth muscle cells (VSMC) hepatic glycogenesis as well as synthesis and release results in oxidative modification of lipoproteins and of triglyceride-rich lipoprotein (VLDL).11,21 vascular structural proteins. Oxidation of LDL modi- Increased levels of FFA are, in turn, associated with fies not only the fatty acid and lipoprotein content reduced insulin sensitivity.28 This relationship is of this particle, but also the amino acid side chains explained by the observation that increases in FFA of apo B, analogous to the modification produced by oxidation elevated the mitochondrial ratio of acetyl- acetylation.35 As a result, oxidized LDL (ox-LDL) is CoA to CoA, which suppresses pruvate dihydro- no longer recognized by the classical LDL receptor, genase (PDH) directly, and phosphofructo 1-kinase but by macrophage scavenger receptors which and hexokinase activities indirectly via citrate and enhances ox-LDL uptake into vascular tissue.35,36 glucose 6-phosphate (C-6-P) accumulation, and Once taken up by foam cells, ox-LDL is poorly resultant inhibition of glucose uptake and oxi- degraded leading to further accumulation. Ox-LDL dation.28 Further, as a result of the consequent is also toxic to endothelial cells, altering both struc- decrease in insulin sensitivity, there is decreased ture and function.35,36 Ox-LDL also stimulates the activity of endothelial bound lipoprotein lipase in production of chemoattracts thereby increasing skeletal muscle and adipocytes, and it is this lipo- migration and binding of monocytes to damaged protein lipase that is responsible for the metabolism endothelium. In addition, antibodies to ox-LDL may of triglyceride rich particles. Thus, triglyceride lev- be involved in the latter stages of atheroma forma- els increase because of increased hepatic production tion.35 of triglyceride-enriched lipoproteins coupled with Glycosylation, the non-enzymatic linkage of glu- reduced peripheral metabolism of VLDL.11,21 cose to proteins also contributes to glycemia- Because of inefficient triglyceride metabolism, HDL induced alterations of lipoproteins and vascular levels demonstrate a parallel fall.11,21 structural proteins4,5,10–12,36,37 (Table 2). Similar to ox-LDL, glycated LDL, in part through glycation of Lipoprotein (a) (Lp(a)) in diabetes mellitus the apo B moiety, is taken up by a foam cell scaven- Plasma levels of Lp(a) have been reported to be elev- ger pathway and enhances atherogenity in diabetic ated in diabetic individuals particularly those with persons.36,37 Compared to normal LDL, glycated LDL Impact of lipid and ACE inhibitor therapy JR Sowers 11 Table 2 Vascular and lipoprotein effects of non-enzymatic pro- Both the intrinsic and extrinsic coagulation cascades tein glycosylation in diabetes associated with hypertension regulate the conversion of prothrombin to thrombin (Figure 1). Elevations in factor VII, a critical compo- 1. Glycosylation of collagen occurs, increasing rigidity. 2. Glycosylation increases DNA synthesis and prolifer- nent of the extrinsic pathway have been associated ation. with cardiovascular disease, and are relatively com- 3. AGE protein receptor is identifiable on macrophages. mon in diabetic persons particularly those with hyp- 4. AGE proteins enhance macrophage secretion of TNF-␣ erglycemia and hypertriglyceridemia5,46 Increases in and interleukin-1. several components of coagulation factor VIII, 5. Macrophage receptor for AGE proteins is upregulated by TNF-␣ in an autocrine manner. including the endothelially derived von Willeb- 6. rand’s factor, occur in diabetes mellitus, particularly Enhanced free radicals are generated (early glycosyl- in association with prolonged hyperglycemia, endo- ation products primarily responsible). thelial cell damage and micro- and macrovascular 7. AGE proteins are chemotactic for monocytes. 4,5,10–12,47,48 8. AGE proteins enhance PDGF secretion. disease. Levels of fibrinogen and throm- 9. AGE proteins increase endothelial cell procoagulant bin-antithrombin complexes have been reported in activity and suppress endothelial cell surface throm- patients with diabetes mellitus and hyperten- bomodulin. sion.4,5,10–12,48–50 Increased levels of fibrinogen pro- 10. AGE proteins increase endothelial cell transcytosis and longs survival of provisional clot matrix upon trans- monolayer permeability. 11. Glycosylated collagen exhibits increased protein bind- formation of fibrinogen to fibrin at sites of injured 5 ing, including LDL, and increases platelet aggregation. endothelium. Further, elevated levels of thrombin- 12. Non-enzymatically glycosylated LDL enhances macro- antithrombin complexes have been observed in dia- phage cholesterol ester synthesis and reduces degra- betic persons with enhanced thrombin generation.50 dation. Clot formation is attenuated by specific factors that inhibit one or more clotting factors (ie, TNF-␣ indicates tumor necrosis factor-a; PDGF, platelet-derived growth factor. antithrombin III (AIII), protein C and S), and by the fibrinolytic system both of which are deficient in individuals with diabetes mellitus and hyperten- sequestered in the arterial intima has a greater pro- sion.4,5,10–12,38–50 ATIII, which inhibits thrombin, Xa, pensity to become bound by glucose-mediated IXa, and XIIa, has been reported to be deficient in crosslinks to local matrix proteins.36,37 When this diabetic persons, particularly those in poor meta- occurs, the LDL particles may undergo even more bolic control.39,51 Protein C antigenic levels have extensive glycative and oxidative modification.36,37 also been reported to be low in diabetes in poor Glycated LDL, like ox-LDL, is immunogenic, for- metabolic control, and to be normalized with glyco- ming antibody-lipoproteins complexes that stimu- metabolic control.52 High levels of plasminogen acti- late foam cell formation and platelet aggregation.36,37 vator inhibitor 1 (PAI-1) have been observed in hypertensive5,48 and diabetic persons43,44,53,54 and in men with myocardial infarction at risk for reinfarc- Diabetes as a procoagulant state tion.5,55 These observations are related to the fact Hypercoagulation and disturbances of the that PAI is the major plasma inhibitor of plasmin- fibrinolytic system have been reported in association ogen activators which convert plasminogen to the with diabetes mellitus/hypertension and associated active proteolytic/fibrinolytic enzyme plasmin.5 dyslipidemias and cardiovascular disease (Table 3).4–12,38–50 A procoagulent state in diabetes and hypertension is mediated, in part, by higher than Metabolic abnormalities and endothelial normal levels of coagulation factors. Thrombus gen- dysfunction in diabetes mellitus and hypertension eration and enlargement depends on the transform- ation of fibrinogen to fibrin.5 This process occurs in There is an array of functional and anatomical three phases: proteolysis, polymerization, and stabi- abnormalities of the vascular endothelium associa- lization. Thrombin, an enzyme derived from the c- ted with diabetes mellitus, hypertension and dyslip- terminal portion of prothrombin, is necessary for all idemia (Table 4).5,10–12,22,23,56 Both hyperglycemia three phases. It is mainly responsible for four pivotal and dyslipidemia have independent toxic effects on steps: (1) potentiation of the tenase (factor Xa the vascular endothelium. Vascular segments from activity in the presence of factor VIIIa) and pro- diabetic rats demonstrate impaired endothelium- thrombinase complexes; (2) conversion of fibrino- dependent (nitric oxide (NO) mediated) relaxation, gen to fibrin monomers; (3) exposure of fibrin which can also be produced by incubating normal monomer polymerization sites; and (4) factor XIIIa- vessels in a high glucose media.57 Hyperglycemia mediated covalent crosslinking of fibrin polymers. activates protein kinase C in endothelial cells, which may account for increased production of vasoconstrictor prostaglandin, endothelia and angi- Table 3 Coagulation abnormalities seen in patients with hyper- otensin-converting enzyme (ACE),10–12,56–58 all of tension and diabetes mellitus which can directly or indirectly interfere with no mediated vasorelaxation.59 Hyperglycemia increases 1. Increased fibrinogen and PAI-1. 2. Decreased fibrinolytic activity. endothelial cell collagen IV and fibronectin syn- 3. Decreased angiotensin III, protein C and S levels. thesis, and increases the activity of enzymes 4. Elevated plasma levels of van Willebrand factor. involved in collagen synthesis.45,58 Elevated glucose levels also delays replication and increases death of Impact of lipid and ACE inhibitor therapy JR Sowers 12

Figure 1 In the intrinsic system endothelial damage or dysfunction activates factor XII, when then (in the presence of high molecular weight kininogen) converts prekallikrein into kallikrein, which in turn converts ﬁbrin-bound plasminogen into plasmin. The major inhibitor of this system includes PAI-1, which inhibits XIIa conversation of prekallikrein into kallikrein, and complement inactivator, which inhibits activation of plasminogen.

Table 4 Abnormalities of the vascular endothelium associated osis.10–12 For example, mesangial cells are derived with diabetes mellitus and hypertension from mesenchyme and share many of the same properties as VSMC.12 Like the VSMC, mesenchy- 1. Elevated expression, synthesis, and plasma levels of endothelin-1. mal cells are regulated in an autocrine/paracrine 12 2. Diminished prostacyclin release. fashion in conjunction with endothelial cells. 3. Decreased release of endothelium-derived relaxing fac- Hyperglycemia can produce non-enzymatic glycos- tor (NO) and reduced responsiveness to NO. ylation of glomerular basement membrane proteins 4. Impaired fibrinolytic activity. such as fibronectins, collagen type IV and luminin 5. Increased endothelial cell procoagulant activity. 12 6. Increased endothelial cell surface thrombomodulin. leading to loss of permselectivity. The glomerular 7. Impaired plasmin degradation of glycosylated fibrin. endothelial cells are separated from mesangial cells 8. Increased levels of advanced glycosylated end pro- by a basement membrane, and passage of substances ducts. between these two cells is readily accomplished. In states of hyperglycemia and hyperlipidemia, endo- NO indicates nitric oxide. thelial damage can result in release of growth factors endothelial cells,60 in part, by enhancing glycooxid- (ie, endothelia, platelet derived and insulin-like growth factor) which can enhance mesangial cell ation.36 proliferation and matrix overproduction.12,65–68 Hypercholesterolemia, and perhaps hypertriglyceridemia, impair endothelium-dependent relax- These metabolic abnormalities may also interfere with the production of NO and vasodilatory prosta- ation.61,62 In diabetes there is decreased conversion glandins which inhibit mesangial cell growth and of cholesterol ester-enriched VLDL to LDL, and the 12,69 resulting large and abnormal cholesterol ester- matric production. Thus, it is not surprising that treatment of hyperglycemia70 and hypercholestero- enriched VLDL is injurious to endothelial cells fol- lemia67,68 favorably impact on diabetic glomeru- lowing receptor-mediated uptake.63 Recently, it has been reported that in hypertension not associated losclerosis. with impaired carbohydrate metabolism or dyslipidemia, there is preservation of endothelium-depen- Dyslipidemia therapy dent vasodilation.64 Thus, it appears to be the meta- Aggressive therapy of hypercholesterolemia (ie, LDL bolic abnormalities accompanying diabetes and Ͼ130 mg/dl) in persons with established ischemic hypertension which play a major role in develop- IHD or other atherosclerotic disease (secondary ment of endothelial dysfunction. prevention) is well supported by data from several recent studies.71–74 These clinical trials have shown Contributions of metabolic abnormalities to renal that lowering of LDL cholesterol in persons with glomerular disease established atherosclerotic disease reduces angio- Pathophysiologically, diabetic glomerulosclerosis graphic progression of coronary artery disease, car- has many features analogous to vascular atheroscler- diovascular events and total mortality. Further, a Impact of lipid and ACE inhibitor therapy JR Sowers 13 recently reported study,75 using an HMG-CoA mation in balloon-injured carotid arteries can be reductase inhibitor, demonstrated a decrease in IHD abolished by a bradykin antagonist or by inhibition events and total mortality in individuals with sig- of NO synthesis using N-nitro-L-arginine methyl nificant risk factors including hypercholesterolima ester (L-NAME). Other anti-atherogenic properties of but without established disease (primary ACE inhibitors may relate to blockade of Ang II prevention). Therefore, it is reasonable to extrapo- stimulated protein synthesis and proto-oncogene late to the diabetic patient, especially those with expression (Figure 2).77–83 Nevertheless, more data hypertension, as a ‘high risk’ patient that may are needed to determine if these protective experi- require very aggressive primary prevention therapy mental effects of ACE inhibitors extend to human for their dyslipidemia, as well as their hyperglyce- disease. Current data is promising since ACE inhibi- mia70 and hypertension.9 My philosophy is to treat tors did reduce myocardial infarction-related mor- the LDL-cholesterol as aggressively as for patients bidity and mortality in the Consensus II,89 the ISIS- with established atherosclerotic vascular disease – 4,90 GISSI,91 AIRE92 and TRACE93 clinical trials in lowering the LDL-cholesterol to less than patients with significant left ventricular dysfunc- 100 mg/dl.20 My rationale for this approach is based tion. The results of ongoing trials (QUIET, HOPE, on a number of issues: (1) most type II diabetic PEACE) are designed to determine if ACE inhibitors patients have atherosclerotic vascular disease if also reduce IHD events in coronary patients without carefully evaluated; (2) the LDL particle in diabetic left ventricular dysfunction are eagerly awaited.77 persons is very abnormal/atherogenic, being small, dense and glycooxidized; (3) there are often other Acknowledgements components to their dyslipidemia (ie, increased Lp(a), elevated VLDL and low HDL) which may The author wishes to thank Paddy McGowan for her enhance the risk of atherosclerotic and glomerulos- fine work in preparing this manuscript. clerotic disease. Finally, there is experimental evi- 67,68 dence that lowering of LDL-cholesterol with a References HMG-CoA reductase inhibitor may afford protection against progression of diabetic renal disease. 1 Lipid Research Clinics Program. 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