Antihypertensive treatment in ischemic heart disease: is there an ideal pill?

Almazov Federal Heart, Blood
and Endocrinology Centre
Saint Petersburg

Antihypertensive treatment in ischemic heart disease: is there an ideal pill?

by E. V. Shlyakhto, Russia

The coexistence of arterial hypertension and ischemic heart disease results in more than a simple summation of their clinical features. Mutual activation of common pathophysiological mechanisms leads to increased levels of morbidity and mortality in this group of high-risk patients. This is characterized not only by progression of atherosclerosis and stabilization of high blood pressure, but also by the occurrence of a number of concomitant problems such as arrhythmias and heart failure. All of this places additional demands on the choice of treatment for hypertensive patients with ischemic heart disease. When choosing a treatment for these patients the whole complexity of the problem should be considered: atherosclerosis, angina, fibrosis, arrhythmia, dyslipidemia, and other metabolic disorders. Drug therapy should be individualized and take into account the heightened risk for cardiovascular events. Recent data suggest that the use of certain groups of medication raises many questions, but administration of ACE inhibitors, statins, and acetylsalicylic acid seems to have undeniable benefits.

Medicographia. 2013;35:418-425 (see French abstract on page 425)

Despite the significant progress made by medical science in the last several decades, ischemic heart disease (IHD) is still the leading cause of death in the majority of countries worldwide. With improvement of technology, the availability of invasive treatment methods, and extension of pharmacological treatment options, the IHD mortality rate has decreased, but the incidence of cardiovascular risk factors—particularly obesity, hypertension, and hyperlipidemia—is rapidly increasing. Statistics from 2010 revealed that hypertension was present in 34% of the adult population, with obesity found in 33%, the metabolic syndrome in 34%, and 59% having no daily physical activity.1

Hypertension as a risk factor for ischemic heart disease

In 2002-2003, Khot et al analyzed the incidence of traditional risk factors (hypertension, diabetes mellitus, hyperlipidemia, and smoking) among 122 458 patients with evident IHD. They reported the absence of risk factors in only 10% to 15% of patients; in all others, at least one of the risk factors was present.2 The presence of hypertension ranged from 21% to 60% across different age groups.2,3 There is no doubt that risk factors significantly affect the course of atherosclerosis, including the state of coronary plaques, and that the risk of complications is increased with the presence of risk factors. Hypertension is known to be not only the major risk factor for stroke and heart failure, but also for IHD. According to the results of the INTER-HEART study, which involved participants in 52 countries, hypertension is a more significant additional risk factor for myocardial infarction than diabetes. In patients aged 40 to 90 years, for every 20/10-mm Hg elevation in blood pressure, the risk of fatal coronary events doubles.4 Hypertension accelerates the development and progression of atherosclerosis, and stable blood pressure elevation can lead to destabilization of the coronary plaque and development of acute coronary syndrome. Hypertension can lead to myocardial ischemia even in the absence of coronary atherosclerosis.

Pathophysiological mechanisms in arterial hypertension and ischemic heart disease

The pathophysiological association of hypertension with IHD is probably due to two main mechanisms: endothelial dysfunction, which is an early stage of atherosclerosis, and increased afterload leading to myocardial hypertrophy.

Early atherogenesis is characterized by endothelial damage caused by high arterial pressure leading to impairment of nitric oxide production and release, and simultaneous accumulation of free radicals and mediators of inflammation in the vascular wall. Inflammation and activation of the renin-angiotensin- aldosterone (RAS) system and sympathetic nervous system are common pathophysiological processes for arterial hypertension and IHD. In particular, angiotensin II maintains elevated blood pressure and leads to atherosclerosis progression due to vasoconstriction and vascular remodeling. It is also known to stimulate hypertrophy of cardiomyocytes and smooth muscle cells by the direct activation of type 1 receptors, and to increase expression of inflammatory factors and cytokines. Aside from this, RAS activation leads to the accumulation of low-density lipoproteins in the vascular wall.5

The metabolic syndrome

Hypertension is one of the components of the metabolic syndrome, which affects about one-third of the population and is becoming increasingly prevalent. Several studies report a correlation between the metabolic syndrome and atherosclerosis. The clustering of abdominal obesity with other components in the metabolic syndrome results in a significantly higher incidence of elevated carotid intima-media thickness. In addition to increased incidence of IHD, the metabolic syndrome is associated with a more severe disease course, and the presence of a higher number of components from the metabolic syndrome is correlated with worse IHD on coronary angiography. Patients with the metabolic syndrome are approximately four times more likely to die of IHD.6-8

◆ Adiponectin
The increased cardiovascular risk arising from the metabolic syndrome is the result of a complex interaction of individual risk factors that is not completely understood. One of the possible explanations is oxidative stress. Increased oxidative stress is known to be strongly associated with atherosclerosis development and progression. Furthermore, visceral adipose tissue is a source of a large number of biologically active substances, including RAS components, inflammatory factors, interleukins, adiponectin, and others. Obesity is characterized by low serum adiponectin levels (hypoadiponectinemia). The severity of hypoadiponectinemia correlates with coronary lesions, and plasma adiponectin levels can be used to identify patients prone to coronary artery disease. It is of interest that adiponectin can limit the damage from myocardial infarction during acute injury. In ischemia-reperfusion mice, adiponectin deficiency was found to increase myocardial infarct size by up to 78%, and changes were also found in tumor necrosis factor–α levels resulting in increased apoptosis of myocytes and stromal cells. Treatment of these mice with adiponectin led to a reduction in the infarcted zone.9,10 In humans, adhesion of monocytes to aortic endothelial cells is inhibited by adiponectin through reduction of the expression of vascular cell adhesion molecule 1, E-selectin, and intercellular adhesion molecule 1 on the surface of endothelial cells.11 Adiponectin inhibits the transformation of human macrophages into foam cells by inhibiting the class A macrophage scavenger receptor.

One possible role of adiponectin in atherosclerosis may relate to its ability to decrease lipid accumulation in the subendothelial space, which is the earliest step in atherosclerotic plaque formation. In addition, a single nucleotide polymorphism at position +276 in the adiponectin gene is known to be linked with IHD. T/T polymorphism is associated with a lower risk of developing coronary artery disease than G/G or G/T variants of the genes. Adiponectin has been shown to activate the peroxisome proliferator-activated receptor–α pathway and to increase expression of AdipoR1 in IHD. Expression of adiponectin receptors is 30% lower than normal in the subcutaneous fat of obese patients, and expression normalizes following weight loss. It is well established that adiponectin plays an important role in type 2 diabetes, hypertension, multiple sclerosis, and dyslipidemia, the most significant of which is its insulin-sensitizing effect. Adiponectin blood levels are lower in diabetic patients than in nondiabetic individuals, and higher plasma levels of adiponectin minimize the risk of developing type 2 diabetes. Adiponectin is negatively related to blood glucose and insulin levels.10,12

Left ventricular hypertrophy

Another important link between hypertension and IHD has been attributed to left ventricular hypertrophy (LVH), one of the forms of myocardial remodeling. Myocardial hypertrophy impairs myocardial relaxation and coronary perfusion during diastole. LVH is known to be an independent strong predictor of adverse cardiovascular events, including death from IHD, congestive heart failure, sudden cardiac death, and stroke.13 Data from the Framingham Heart Study showed that males with electrocardiographic signs of LVH had an eightfold increase in cardiovascular mortality and a six fold increase in the rate of sudden death compared with those who did not have LVH.14

So far, there is no clear opinion as to the reasons for the close association between hypertension, LVH, and IHD. Both experimental and clinical evidence confirms that high blood pressure stimulates the development of atherosclerosis.15,16 In addition, LVH is associated with changes in the density, structure, and tone of coronary arteries. Despite the fact that absolute coronary blood flow is elevated in the hypertrophied heart, a decrease in capillary density and coronary reserve is observed, even in the absence of coronary atherosclerosis.17,18

In accordance with experimental data, hypertrophied myocardium is more susceptible to electrical instability during ischemia/ reperfusion. During reperfusion after global ischemia, the ability to restore contractility is impaired in hypertrophied hearts, and levels of lactate dehydrogenase and creatine kinase are increased. A number of hypotheses have been put forward to explain the high sensitivity of the hypertrophied myocardium to ischemia/reperfusion injury, which include mitochondrial damage, lactate accumulation, disturbance of glycolysis, as well as oxidative stress and an increase in oxygen free radicals.16

Elevated systemic blood pressure is one reason for the development of endothelial dysfunction and degenerative changes of the peripheral arteries associated with elasticity loss and an increase in vascular stiffness. Such changes lead to elevation of central blood pressure, causing additional strain and further remodeling of the left ventricle. These changes are especially significant in patients with isolated systolic hypertension, as a simultaneous decrease in diastolic blood pressure can worsen perfusion pressure in the coronary arteries. Both structural and functional changes in the peripheral arteries make a significant contribution to the phenomenon of blood pressure variability, which, in turn, leads to further hypertrophy and coronary flow impairment.19,20

LVH is also associated with an increased risk of sudden cardiac death, which is usually due to fatal ventricular arrhythmias. The electrophysiological mechanisms are not fully understood, but experimental data suggest a prolongation of the action potential and changes in the ionic fluxes in hypertrophied cardiomyocytes. The presence of fibrosis foci is typical of LVH in arterial hypertension, and leads to the appearance of zones of impaired conductivity.21 Fibrosis also contributes to the dispersion of the duration of action potentials and to the formation of reentry. The frequency and severity of tachyarrhythmia is probably increased in the presence of LVH. Belichard et al demonstrated in 1987 that the duration of ventricular tachycardia paroxysms caused by coronary occlusion was significantly higher in spontaneously hypertensive rats than in control normotensive animals.22 This phenomenon was due exclusively to myocardial hypertrophy and not to elevated blood pressure. Similar results confirming the high rate of ventricular fibrillation in ischemia in hypertrophied myocardium were produced by other authors.16 Fibrosis of the myocardium and the phenomenon of high blood pressure variability probably contribute to the occurrence of another form of arrhythmia; namely, atrial fibrillation (AF), which is the most prevalent type of rhythm disturbance. At present, hypertension is the most frequent independent modifiable risk factor for AF. The relative risk of AF in hypertension is lower than in other diseases (eg, heart failure or valvular heart diseases), but because of the high worldwide prevalence of arterial hypertension, it is the main risk factor for AF.23 Investigations into the pathogenesis of AF have confirmed a strong association between AF and RAS activation.24

Treatment of arterial hypertension and concomitant ischemic heart disease

The close association between arterial hypertension and IHD, the presence of common pathophysiological mechanisms, and the widespread prevalence of a number of concomitant problems (systolic and/or diastolic myocardial dysfunction, AF, ventricular arrhythmia) demand special attention with regard to choice of antihypertensive medication. Modern risk stratification criteria refer patients with arterial hypertension and concomitant cardiovascular disease to the very-high-risk group. It is well known that achievement of goal blood pressure levels in this particular category of patients is a serious problem. The debate concerning appropriate blood pressure lowering (“the lower, the better”) in this category of patients has been going on for more than 30 years. At the end of the 1970s, Steward demonstrated a five fold increase in the relative risk of myocardial infarction in patients with diastolic blood pressure below 90 mm Hg compared with those in whom it remained within the 100-109 mm Hg range.25 There is still no definitive explanation for this “J-curve” phenomenon.

It is believed that excessive diastolic blood pressure reduction leads to the worsening of coronary perfusion and thus induces adverse coronary events. Most experts do not recommend diastolic blood pressure lowering to below 60 mm Hg.

According to the majority of the current guidelines, the target blood pressure level in hypertensive patients with concomitant cardiovascular diseases is 130/80 mm Hg; this demands more aggressive treatment and early administration of combination therapy. The presence of coexisting IHD requires medications with the following effects: (i) a decrease in the severity of symptoms (eg, angina pectoris); (ii) prevention of atherosclerosis progression; and (iii) modification of other factors that induce or worsen ischemia.

The general principles of nonpharmacological treatment in patients with arterial hypertension and IHD do not differ significantly from those in the general population of hypertensives. Regular physical activity improves inotropic function, decreases blood pressure, afterload, and arterial stiffness, and leads to an increase in coronary reserve.26

◆ β-Blockers
β-Blockers have been used in cardiology for more than 40 years, and according to many reports, they contribute significantly to blood pressure lowering, decrease cardiovascular morbidity and mortality, and positively affect clinical manifestations in patients with IHD. So at first glance, β-blockers could be an optimal treatment for this particular group of patients. However, it is well known that the use of β-blockers may be limited by a number of adverse events and poor tolerability: fatigue, weakness, sexual dysfunction, cold in the extremities, etc. Moreover, a large pool of data has demonstrated the negative effects of β-blockers on metabolism— first and foremost, on glycemic control. Finally, the results of an analysis of data from the REACH registry (Reduction of Atherothrombosis for Continued Health) published at the end of 2012 produced a strong response.27 Having analyzed data from 44 708 patients (31% with a history of myocardial infarction, 27% with other forms of IHD, and 42% with only risk factors for coronary artery disease), the authors of this study suggested that β-blocker administration was not associated with a decrease in cardiovascular event rates within a follow up period of 44 months in the myocardial infarction group. Moreover, in some subgroups of patients, use of β-blockers was associated with a higher rate of cardiovascular events. These data are not currently supported by randomized clinical trials, but they do suggest that the rapid progress of medical science and the emergence of new drugs and therapies have resulted in a change in the established views on the treatment of such patients. Nevertheless, current guidelines state that patients with stable angina pectoris, a history of myocardial infarction, and systolic dysfunction of the left ventricle should receive β-blockers as part of their complex treatment regimen.

◆ Calcium channel blockers
Another well-studied group of medications is the calcium channel blockers. They appear to be good substitutes for β-blockers in the treatment of angina in hypertensive patients; however, they are not recommended for secondary prevention because of their inability to prevent ventricular dilatation and heart failure. Nondihydropyridine agents should not be used in patients with systolic heart failure, and short-acting dihydropyridine calcium channel blockers should be avoided in patients with acute myocardial infarction, pulmonary edema, or significant left ventricular dysfunction.26

◆ RAS blockade
As mentioned, the RAS system plays a key role in the pathogenesis of arterial hypertension, atherosclerosis, type 2 diabetes, heart failure, and kidney damage. Thus, the groups of drugs that block RAS activity, namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), attract much attention. The level of RAS activity is believed to be a strong predictor of cardiovascular complications and death. For example, in untreated hypertensive patients, high plasma renin levels are associated with a more than twofold increase in cardiovascular morbidity, and in patients with severe IHD, they are associated with a high mortality level.28,29 Aside from its potent vasoconstrictor effect, angiotensin II affects cell growth and sodium and water metabolism, and modulates sympathetic activity. It also promotes endothelial dysfunction, inflammation, oxidative stress, and insulin resistance, and decreases the reactivity of pancreatic β-cells.30

The pressor effect of angiotensin II is predominantly due to its binding to type 1 receptors in the heart, peripheral arteries, kidneys, adrenal glands, brain, and adipocytes. The angiotensin II/type 1 receptor complex suppresses renin production, stimulates aldosterone release, enhances cardiomyocyte contractility, hypertrophy, and fibrosis, and increases vascular tone and sodium reabsorption. It is thought that binding of angiotensin II to type 2 receptors promotes cardioprotection and nephroprotection due to vasodilation caused by nitric oxide release and antiproliferative and anti-apoptotic activity mediated by kinins.31 Both ACE inhibitors and ARBs are effective antihypertensive medications. Both classes prevent cardiovascular complications, which makes them the basic drugs for the treatment of high-risk patients. Leading European and American experts recommend these medications for patients with concomitant cardiovascular diseases.

◆ Angiotensin receptor blockers
In 2006, the results of a meta-analysis were published suggesting that ARBs can increase the risk of myocardial infarction. In the LIFE trial (Losartan Intervention For Endpoint reduction in hypertension) involving more than 9000 patients, losartan therapy was associated with a 5% increased rate of myocardial infarction (statistically insignificant) compared with atenolol-based therapy, despite the lower levels of blood pressure obtained in the losartan group.32 In SCOPE (Study on COgnition and Prognosis in the Elderly), compared with the control group, candesartan treatment was associated with a 10% increased incidence of fatal and nonfatal myocardial infarction, which also did not achieve statistical significance.33 The results of VALUE (Valsartan Antihypertensive Long-term Use Evaluation) in 15 245 patients demonstrated a significant 19% increase (P=0.02) in the rate of myocardial infarction in patients receiving valsartan 160 mg compared with those receiving amlodipine 10 mg.34

It should be noted that all of the aforementioned trials included hypertensive patients at very high risk, 80% of whom had evident cardiovascular disease. In total, 9 of the 11 major clinical trials on ARBs reported an increased rate of myocardial infarction, and in 2 of these (VALUE and CHARM [Candesartan in Heart failure Assessment of moRtality and Morbidity]), the difference was statistically significant.

This paradox can be explained by the excessive stimulation and overexpression of angiotensin type 2 receptors.35 As a result of angiotensin type 1 receptor blockade, ARBs can cause an increase in angiotensin II levels that leads to the excessive stimulation of type 2 receptors. It is thought that such stimulation has adverse effects due to enhanced cell growth, fibrosis, hypertrophy, a proinflammatory effect, and stimulation of atherogenesis.13,36-38 Experimental data report that excessive stimulation of type 2 receptors leads to cardiomyocyte contractile dysfunction, and in humans, this phenomenon is associated with hypertrophy. It was also demonstrated that activation of type 2 receptors inhibits hypoxia-induced neovascularization, which is an important compensatory mechanism in chronic myocardial ischemia.13 In 2005, Alfakih et al in the UK revealed an association between increased expression of angiotensin type 2 receptors and early development of IHD.39 These data suggest that ARBs can cause plaque injury and rupture.35

◆ ACE inhibitors
ACE inhibitors are not associated with increased levels of angiotensin II. Besides ACE inhibition, the drugs are accompanied by increased levels of some ACE-dependent substrates; eg, bradykinin, substance P, and enkephalins. This phenomenon provides ACE inhibitors with additional physiological and clinical properties: increased vasodilation, decreased thrombogenesis, and the slowing down of atherogenesis and tissue proliferation. Bradykinin suppresses platelet aggregation and decreases the level of plasminogen activator inhibitor-1, which is a potent fibrinolysis inhibitor and can independently predict the mortality rate after myocardial infarction.40 Thus, long-term use of ACE inhibitors improves peripheral vasodilatation mediated by bradykinin and stimulates the release of tissue plasminogen activator to levels achieved during systemic thrombolysis.41 Bradykinin is also the main mediator of ischemic preconditioning, a unique phenomenon that allows cardiomyocytes to avoid damage during ischemia, decreases the size of infarction, and prevents ventricular arrhythmia. ACE inhibitors have been shown to improve endothelial function in peripheral and coronary arteries. One of the suggested mechanisms for this is their effect on gene expression, which leads to the enhanced activity of cyclo-oxygenase-2, and consequently to prostacyclin and prostaglandin E2 production, without increasing thromboxane A2.35 In contrast, ARBs have practically no effect on endothelial dysfunction, which is known to be an early marker of atherosclerosis.

Although the beneficial effects of ACE inhibitors on post infarct left ventricular remodeling have been unequivocally demonstrated in both animal models and clinical trials, the acute infarct–limiting effect of these drugs has been controversial. Recent evidence suggests that a genetically-determined decrease in ACE activity is associated with a significant reduction in infarct size.42 By contrast, increased ACE activity in mice was found to be associated with a trend toward increased infarct size and blunted preconditioning-mediated infarct limitation. Oral administration of ramiprilat at a dose of 50 μg/kg during 1, 4, and 10 weeks resulted in a significantly reduced infarct size in a rat model of myocardial ischemia-reperfusion.43 It should be noted, however, that the infarct-limiting effect of ACE inhibitors has been called into question by other investigators. This controversy could stem from the use of different routes of drug administration in different studies and differences in the doses of drugs and their pharmacokinetic profiles.

In our own experiments, we investigated the infarct-limiting and antiarrhythmic effects of captopril and zofenopril in the rat model of myocardial ischemia-reperfusion in vivo.44 Both ACE inhibitors were administered intravenously and the mean blood pressure and heart rate were monitored throughout the experiments. Baseline blood pressure and heart rate values were no different among the groups. Intravenous administration of ACE inhibitors at a dose of 2.5 mg/kg resulted in a significant blood pressure decrease (by 40% to 45% from baseline). The ACE inhibitor–induced decrease in blood pressure persisted throughout the entire experiment. No changes in heart rate were observed after ACE inhibitor infusion. The anatomical area at risk was no different between the groups. In comparison with controls, infarct size was significantly smaller in the group of animals treated with zofenopril, and there also tended to be a decrease in the captopril group. These data indicate that zofenopril significantly limited the infarct size when administered 30minutesprior to ischemia. The enhanced infarct-limiting effect could be explained by the presence of an SH group in the chemical structure of zofenopril, as well as by its greater ability to inhibit tissue ACE.45

◆ Ischemic preconditioning
Ischemic preconditioning (IPC) is a phenomenon of increased myocardial tolerance to ischemia-reperfusion injury occurring after single or multiple brief episodes of ischemia-reper fusion.46 We were interested in investigating whether a sub-threshold preconditioning stimulus could be strengthened by the concomitant administration of the ACE inhibitor spirapril. IPC was elicited by a single 5-minute episode of ischemia followed by 5 minutes of reperfusion. IPC significantly reduced infarct size, but spirapril alone failed to limit the infarct size.

However, a combination of the preconditioning stimulus and a nonhypotensive dose of spirapril resulted in significant attenuation of infarct size compared with IPC alone, which is suggestive of a potentiation of the protective effect of IPC by the ACE inhibitor. These data are in agreement with the findings of Miki et al, who showed that captopril could enhance the infarct-limiting effect of a single 2-minute IPC stimulus in rabbits.47 This effect was abolished by the concomitant administration of the B2-receptor blocker HOE 140, which indicates that ACE inhibitor–induced potentiation of IPC is bradykinin dependent.

◆ Metabolic effects
Another important issue with regard to RAS blockade concerns the beneficial metabolic effects of RAS blockers. A number of clinical trials have observed beneficial effects of RAS blockade on cardiovascular morbidity and mortality in both hypertensive and normotensive patients with the metabolic syndrome. RAS blockade is known to have positive effects on insulin resistance, glucose tolerance, lipid profiles, and oxidative state. In an animal model of insulin resistance and RAS overactivity, administration of RAS blockers improved insulin sensitivity, stimulated glucose transport into muscle, and reduced oxidative stress. Similar results were shown in other experimental studies in which RAS blockade was associated with increased numbers of GLUT-4 transporters and increased glucose uptake.6,48 Moreover, analysis of HOPE (Heart Outcomes Prevention Evaluation) demonstrated a 32% reduction in the incidence of new-onset diabetes in patients treated with an ACE inhibitor.

◆ Statins
When discussing the treatment of hypertensive patients with IHD, one cannot avoid mentioning the statin group of drugs. The addition of lipid-lowering medications to RAS inhibitors is a widely-accepted treatment strategy in this category of patients. There are several possible interactions between cholesterol and angiotensin II: (i) as they affect endothelial function, they may interact to promote the development and progression of atherosclerosis; (ii) hypercholesterolemia, particularly high levels of low-density lipoprotein, leads to the up regulation of vascular ACE and angiotensin II type 1 receptors; and (iii) angiotensin II promotes oxidation and vascular uptake of low density lipoprotein cholesterol.

Aside from lowering cholesterol levels, statins are known to modify endothelial function and atherogenesis, stabilize atherosclerotic plaques, and reduce inflammation and thrombus formation. These pleiotropic properties of statins may have important clinical implications in addition to their lowering of serum cholesterol levels.49

Important data on statins came from ASCOT-LLA (the lipid lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial), which was a double-blind placebo-controlled trial of atorvastatin in 10 305 hypertensive patients originally enrolled in the blood pressure–lowering arm of ASCOT and with baseline total cholesterol concentrations of below 6.5 mmol/L. ASCOT-LLA was stopped prematurely after a 3.3-year follow- up because of a 36% relative risk reduction in nonfatal myocardial infarction and fatal coronary heart disease (the primary outcome) in favor of atorvastatin and a nonsignificant reduction in cardiovascular death (16%) and all-cause mortality (13%). In the 11 years after initial randomization and 8 years after closure of the lipid-lowering arm, all-cause mortality remained significantly lower in patients assigned to atorvastatin. Cardiovascular deaths were also fewer, although not significantly, and noncardiovascular deaths were significantly lower, which was attributed to a reduction in deaths from infection and respiratory illness. The study authors concluded that the pleiotropic effects of statins may play a role in these protective effects.50

Clinical data suggest that hypertensive diabetic patients who experience an acute myocardial infarction have a smaller infarct size, better global systolic function, and less hospital morbidity and mortality if they were receiving combined ACE inhibitor and statin therapy prior to the event. Thus, prior combination therapy with an ACE inhibitor and a statin has cardioprotective effects in hypertensive diabetic patients with acute myocardial infarction.51 The combination of an ACE inhibitor and a statin stops proteinuria and protects against renal dysfunction and structure impairment. Statins reduce cholesterol, are antiatherosclerotic, and improve endothelial function. ACE inhibitors are effective in controlling hypertension and cardiovascular disease, not only because of their blood pressure–lowering effect, but also as a result of their ability to block the production of angiotensin II. Further studies are warranted to confirm the beneficial impact of ACE inhibitors and statins and their potentially synergistic mode of action, as this could represent a potent and effective combination in high-risk patient populations.

◆ Future therapies
In terms of the development of new drugs and therapeutic approaches, one attractive option is the newly-discovered class of intracellular regulators, microRNAs (miRNAs). Their small size and known conserved sequences make them promising candidates in the development of new drugs. Currently, there are two major approaches in microRNA therapeutics—activation of existing miRNAs (miRNA mimetics) and blockage of miRNAs with the help of complementary oligonucleotides (antimiRs).52 The latter approach is easier and currently much more advanced; however, there are no cardiology clinical trials presently in progress using antimiRs, despite the development of many approaches and intracellular targets in this area.53 In the field of arterial hypertension and coronary artery disease, protection of the target organs—in particular, prevention of left ventricular hypertrophy—is an important task. To this end, miR-208a, the only cardiac-specific microRNA encoded in the α-MYH7 gene, is known to block cardiac hypertrophy.54 At the same time, it has been shown to have a protective effect against development of cardiac fibrosis and cardiac remodeling after ischemia and development of diastolic heart failure, as well as the ability to improve tissue and systemic energy metabolism. Other potential options are miR-21 and miR-29,52,55 which specifically target cardiac fibrosis.


In general, the choice of treatment for a hypertensive patient with a serious comorbidity such as IHD should take into account the whole complexity of the problem: atherosclerosis, angina, fibrosis, arrhythmia, dyslipidemia, and other metabolic disorders. Drug therapy should be individualized and should take into account the heightened risk for cardiovascular events. Recent data suggest that the use of certain groups of medication raises many questions, but administration of ACE inhibitors, statins, and acetylsalicylic acid seems undeniably beneficial. It is of note that hypertensive patients with concomitant IHD belong to the very-high-risk group, and as such, should all receive combination therapy as a first step in their treatment regimen.

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Keywords: cardiovascular risk; ischemic heart disease; hypertension; metabolic syndrome; renin-angiotensin system