© Springer International Publishing Switzerland 2015
Adel Berbari and Giuseppe Mancia (eds.)Arterial Disorders10.1007/978-3-319-14556-3_2929. Therapeutic Options: Lifestyle Measures and Pharmacological Approaches
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Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 2QQ, UK
Keywords
AtherosclerosisArteriosclerosisPharmaceuticsLifestyle interventions29.1 Introduction
Preventing cardiovascular disease by lifestyle and therapeutic intervention is a broad topic, which encompasses an enormous amount of published research. This chapter shall focus largely on the primary prevention of atherosclerosis and arteriosclerosis. Although frequently confused, these are in reality distinct disorders, differing in their underlying pathophysiology. As such preventative therapeutic strategies are likely to differ.
29.2 Atherosclerosis
The main risks factors for atherosclerotic disease have been firmly established by a wealth of research over the last 60 years. These include smoking, hypertension, hyperlipidaemia and diabetes mellitus, each of which can be addressed by both lifestyle and pharmacological interventions.
29.2.1 Lifestyle
Modification of the major lifestyle risk factors is potentially a very powerful form of intervention, which can benefit a substantial proportion of the population. However, there are significant challenges in implementation at an individual level, and some interventions may be better addressed through government-led public health initiatives, e.g. forcing companies to reduce the amount of salt and trans fats added to food, increasing taxes and banning cigarette advertising. Recent research suggests that such measures can have a significant benefit to the population [1].
29.2.2 Smoking
Smoking is a well-established risk factor for atherosclerosis; it causes a number of vascular changes including endothelial dysfunction, which contribute to both the formation and acceleration of atheroma. There are many epidemiology cohort studies that link cigarette smoking to atherosclerosis and to cardiovascular diseases per se. Current cigarette smoking gives a ~50 % risk of atherosclerosis compared to a non-smoker; an even greater increase in risk of atherosclerosis is found in smokers who also suffered from diabetes and/or hypertension [2]. This is supported by a 50-year observational cohort study of British doctors finding greater mortality among smokers compared to non-smokers [3].
Intervention studies show that quitting reduces the chances of cardiovascular disease [4]. It can be said that a patient who has smoked for a long time may never fully decrease their risk to that of a non-smoker, and there is mixed evidence on how advantageous the benefits of quitting are [5]. Smokers commonly gain weight initially after smoking cessation; an increased BMI is a risk factor for cardiovascular disease itself. Despite this, ex-smokers perform better on an exercise stress test than current smokers, indicating that the positive health and fitness benefits of quitting smoking outweigh the negative health effects of an increased BMI [6].
In ex-smokers who have smoked for a long period of time, there is still a significant increased risk of mortality even after quitting compared to never smokers. For example, individuals who have smoked more than 20 years have a significant excess of cardiovascular deaths 10–29 years after quitting compared to individuals who smoked for less than 19 years [4]. Nevertheless, there is a fall in mortality risk from coronary heart disease in the first 19 years after quitting, but after this the risk is almost unchanged. On average, former cigarette smokers have a greater risk of cardiovascular disease than never smokers but a smaller risk than current smokers. Smoking, therefore, has a dose-dependent effect.
The progressive popularity of e-cigarettes raises the question of how safe smokeless tobacco actually is [7]. Unfortunately, there are relatively few studies on the matter, but a meta-analysis of the available data, including case control and cohort studies, concluded that there was an increased risk of cardiovascular disease, 40 % excess risk, in smokeless tobacco (e-cigarettes and chewing tobacco) users compared to non-smokers. In smokeless tobacco users there was less evidence of atherosclerotic plaques than in smokers but more than in non-smokers. There is also a lot of evidence to suggest that passive smoking can be almost as damaging as active smoking [8], but like smoking, this is dose dependent.
There are many measures that can help increase rates of quitting, including social and pharmacological measures. In a meta-analysis of randomised clinical trials, all three licensed quitting therapies, bupropion (an antidepressant), varenicline (a nicotine receptor partial agonist) and nicotine replacement, were effective [9]. Bupropion and varenicline do not increase cardiovascular disease, but nicotine replacement studies showed an elevated risk compared to the other two; relative risk is 2.29 for non-serious cardiovascular events, but for serious cardiovascular events, none of the methods increase the risk [10].
29.2.3 Alcohol
There is a paradox revolving around alcohol consumption. Alcohol has a linear relationship with blood pressure; the more alcohol consumed, the greater the person’s blood pressure. However, alcohol consumption has a U-shaped relationship with cardiac deaths. So although alcohol raises blood pressure, mild to moderate drinking is seemingly protective against cardiovascular events.
The French paradox is a well-known phenomenon, in which the French, although not consuming perhaps the healthiest diet (high in saturated fats) and drinking a lot of red wine, have a much lower risk of cardiovascular disease. A lower cardiovascular risk is seen with moderate alcohol intake of all forms, but alcohols rich in polyphenols appear to have a particularly protective effect. In a meta-analysis of prospective cohort studies, it was found that the relative risk of drinkers of alcohol to non-drinkers for cardiovascular disease mortality was 0.75. The authors concluded that mild–moderate alcohol intake was associated with reduced cardiac death and stroke deaths [11].
Those who consumed between 2.5 and 14.9 g alcohol a day were protected against all cardiovascular events, but those who consumed more than 60 g/day were at a greater risk of stroke than non-drinkers. Alcohol consumption lowers the risk of ischemic stroke but slightly raises the risk of haemorrhagic strokes, giving an overall reduction in risk of stroke in those who drink moderately [11].
In some in vitro studies, the effects of gin and wine on LDL levels and oxidation were observed, and while both reduced oxidation, wine had the greater effect [12]. Red wine also reduces inflammation, gin does so too but to a lesser extent.
29.2.4 Salt
One of the well-known dietary risk factors towards atherosclerosis is salt (NaCl) intake. High sodium intake is associated with hypertension, a leading risk factor for atherosclerosis. In 2010 it was estimated that 1.65 million people died as a consequence of excess NaCl intake [13], and daily intake of salt is above recommended guidelines in almost all countries [14].
The INTERSALT study showed that the amount of sodium excretion was positively correlated with systolic pressure. Sodium intake was also positively correlated with raised diastolic pressure, but this was also related to confounding factors such as body mass index and alcohol intake [15]. In England from 2003 to 2011, there was a population fall in blood pressure of 2.7/1.1 mmHg and corresponding drop in rates of stroke and ischemic heart disease of about 40 %, which may have been related to an concomitant fall in salt consumption [16]. In a meta-analysis the authors concluded that high salt intake was associated with an increased risk of stroke [17].
There are many interventional studies of the short-term effect of reduced salt on blood pressure; a meta-analysis of randomised clinical trials shows that a modest reduction of salt intake, 4.4 g/day, for 4 weeks can cause a significant decrease in blood pressure, a mean fall of 4.18/2.06 mmHg. This was associated with no adverse effects on lipid and hormone level [18]. Other studies have reported similar results [19]. A fall in blood pressure was seen with salt reduction across all ethnicities [20]. Theoretically a fall in blood pressure should result in a reduction in atherosclerosis and cardiovascular events. This has been reported in some small studies [21], but a recent meta-analysis suggested that the data were still inconclusive and that more randomised trials were still required [22].
There is evidence that nationwide intervention could be beneficial. From 2001 to 2011 the amount of salt in UK bread has been reduced [23]. This corresponds with the reduction in daily salt intake seen over this time period. Thus, public health initiatives, e.g. reduction of salt in readymade foods, could lead to a significant decrease in population blood pressure and resultant cardiovascular disorders.
29.2.5 Potassium
From the INTERSALT study there appears to be an inverse relationship between potassium concentration and sodium concentration in the urine [24]. A high sodium to potassium ratio was associated with an increased systolic and, although less strong an association, increased diastolic pressure [15]. Potassium supplementation is linked to a reduction in postprandial brachial artery flow-mediated dilatation (FMD) [25]. An increased potassium intake is associated with a drop in blood pressure in both epidemiological studies and clinical trials; the mechanism behind this decrease in blood pressure is unclear [26]. However, it may be related to swelling and softening of the endothelium leading to an increase in nitric oxide a vasodilator, whereas sodium causes the stiffening of endothelium cells resulting in less nitric oxide production and thus an increased blood pressure [27].
29.2.6 Diet
Much has been written about the potential cardiovascular and anti-atherosclerotic benefits of many different diets. Men who follow a Mediterranean diet, rich in unsaturated fats, tomatoes and fresh fruit/vegetables, appear to be less at risk from coronary artery disease and death from cardiovascular disease [28]. The dietary approaches to stop hypertension, or DASH diet, is rich in fruit, vegetables and low-fat dairy product and is low in saturated fat and total fat. The DASH diet was found to lead to a reduction in blood pressure [29].
Those who eat large amounts of fruit and vegetables have a reduced risk of myocardial infarction and other cardiovascular diseases, with adjustment for history of diabetes, hypertension or high cholesterol; there was a relative risk for CVD of 0.45 between the extremes of vegetable intakes [30]. The effect of low-carbohydrate, high-protein diets on a wide range of surrogate phenotypes and biomarkers has been widely investigated, but a recent meta-analysis suggested that they may have no effect of mortality [31]. However, they appear effective in aiding weight loss in the long term [32].
29.2.7 Exercise
Exercise is associated with a reduced risk of atherosclerosis and cardiovascular disease. However, some studies have reported that high levels of exercise can actually be associated with cardiovascular disease.
Perhaps the most famous epidemiology study on the relationship between (self-reported) exercise and mortality and cardiovascular disease is the Harvard alumni study. This showed that those who undertake more exercise have an extra 1.5 years of life compared to those who did not. However, participation in light exercise did not correlate with mortality, whereas participating in moderate activity and vigorous activity was associated with reduced mortality [33] and reduced carotid arterial thickness. Interestingly, however, the Harvard alumni study also found an association between high levels of vigorous activity and slightly higher risk of cardiac death (a U-shaped curve) [34].
Vigorous exercise is known to be a protector against carotid artery calcification (an indicator for atherosclerosis) as well as decreasing the relative risk of cardiovascular diseases as a whole [35]. At least 120 min a week of moderate activity is all that is necessary for a clinically relevant benefit [36]. Exercise as a primary prevention method should be started in the young for the best results [37].
29.3 Pharmacological
29.3.1 Hypertension Treatment
Hypertension is a major risk factor for atherosclerosis. There is a linear relationship between blood pressure and cardiovascular risk and as such there are no hard and fast limits as to what is a ‘safe’ blood pressure to have [40]. The main classes of antihypertensive drugs in current common use are diuretics, beta blockers, ACE inhibitors, calcium channel blockers and alpha blockers. There has been considerable debate as to whether decreasing blood pressure is of most importance or whether there are differences between drug classes.
The largest study to compare classes and drugs was the ALLHAT study. This compared ACE inhibitors (lisinopril), calcium channel blockers (amlodipine), diuretics (chlorthalidone) and alpha blockers. The alpha blocker (doxazosin) arm of the ALLHAT terminated early due to a twofold higher risk of congestive heart failure for patients on doxazosin compared to chlorthalidone [41]. This was largely based on a clinical diagnosis of heart failure not lab defined results and debate continues as to the clinical benefits/harm of alpha blockers, but mostly they are not now used first line. All other agents reduced the risk of the trial’s primary outcomes of fatal CHD or nonfatal myocardial infarction and secondary outcomes of all-cause mortality, fatal and nonfatal stroke, combined CHD and combined CVD. However, thiazide diuretics were slightly more effective both at lowering blood pressure and reducing clinical events as well as being the most accepted as well as being low cost [42].
Beta blockers were not included in the ALLHAT study, and a meta-analysis by Lindhlom et al. showed that atenolol was inferior to other agents in preventing CVD and that there was a lack of evidence to support their first-line use [43]. This, and the results of the ASCOT study, which showed that atenolol plus thiazide was inferior to a calcium channel antagonist and ACE inhibitor in reducing total and cardiovascular mortality, led to the demotion of beta blockers to fourth line [44]. However, it is unclear as to whether some newer beta blockers, e.g. nebivolol, which have vasodilating properties may be as effective as other agents in reducing events. Certainly nebivolol lowers central blood pressure and left ventricular mass more effectively than traditional agents [45, 46].
In patients who are black, thiazide diuretics have a more noticeable effect compared to other drugs tested in the ALLHAT study at preventing cardiovascular events, such as myocardial infarction and stroke, or renal events [47].
Combination therapy may be preferable to single therapy. This is due in part to synergism between the two therapies but also because one drug’s side effects offset that of the other, as well as lower doses of both being needed [26]. Studies comparing combination versus initial monotherapy are ongoing.
29.3.1.1 Hyperlipidaemia
There is a well-established positive relationship between LDL cholesterol, and inverse relationship between HDL cholesterol, and atherosclerosis. The most effective drug class for lowering LDL cholesterol are statins, and they are one of the most commonly prescribed pills.
There is overwhelming evidence that statins decrease the risk of cardiovascular events. In a meta-analysis of studies, statins reduced the risk of myocardial infarction by 39.4 % and stroke by 23.8 % in elderly patient who have had no pre-existing cardiovascular diseases; therefore, statins may be a very good primary prevention method [48]. In a meta-analysis of adults with both no past history of cardiovascular disease (CVD) and those with a past history of CVD, statins gave an odds ratio of all-cause mortality of 0.86 compared to controls, as well as relative risks of CVD 0.75, CHD 0.73 and stroke 0.78 (all both fatal and nonfatal) [49]. Statins are also known to have few adverse effects, although they may slightly increase the risk of diabetes mellitus [50]. Benefits of statins are rapid as assessed by improvements in FMD [51].
Niacin or vitamin B has been examined for its use in raising HDL levels. In some clinical trials niacin appears to give a reduction in the risk of cardiovascular disorders and major coronary heart disease (but does not cause a reduction in stroke risk) [52, 53]. When niacin and statins are combined, there is an even greater increase in the number of HDLs present in the blood [54]. However, this evidence remains controversial and some studies are to the contrary [55]. Therefore, the effectiveness of niacin requires further study. Niacin may even increase risk in some high-CVD-risk individuals [56].
A variety of other cholesterol modifying have been, or are, in current development. CEPT inhibitors such as torcetrapib were developed to raise HDL cholesterol, but development has now largely ceased as torcetrapib was linked with an excess cardiovascular mortality [57] and other related agents appeared not to improve surrogate end points [58]. PCSK9 antagonists offer more promise and initial data suggest impressive reductions in LDL cholesterol [59]. However, these are given by infusion, which may limit their widespread applicability for primary prevention of atherosclerosis.
Diabetes Mellitus
Suffering from diabetes greatly increases the risks of cardiovascular disease. Diabetic patients without previous myocardial infarction have as high a risk of myocardial infarction as non-diabetic patients with a history of previous myocardial infarction [60].
Diabetics benefit as much if not more so than non-diabetics by targeting other cardiovascular risk factors. Diabetics may gain a greater benefit from blood pressure and cholesterol treatment than nondiabetics [61]. Therefore, it is of benefit to treat other risk factors in diabetics rather than focusing exclusively on tight glycaemia control. Indeed, multifactorial, long-term, aggressive treatment reduces risk of cardiovascular and microvascular events by 50 % compared to conventional treatment [62]. However, interventions in obese and overweight diabetics focusing on weight loss do not reduce the risk of cardiovascular disease [63].
The UK PDS study showed that reducing glucose reduced the risk of ‘any diabetes-related end point’ by 12 % but did not significantly reduce macrovascular complications [64, 65]. Likewise, subsequent randomised trials failed to show cardiovascular benefit of intensive glycaemic control, as did a recent meta-analysis of published trial data [66]. Nevertheless, intensive control does appear to reduce microvascular events [66]. There is still a debate about whether cardiovascular outcome varies between classes of hypoglycaemic agent. A recent meta-analysis suggested that sulphonylureas have a relative risk of 1.27 for cardiovascular death and 1.18 for cardiovascular events [67]. Metformin appears safe, but does not reduce events when added to insulin, compared to insulin alone [68]. The combination with incretins also appears not to increase events.
29.4 Arteriosclerosis
Arteriosclerosis is a general thickening and stiffening of the arteries with the loss of elasticity, caused by mainly fatigue fracture of the elastic fibres within the arterial wall. It is an independent risk factor for cardiovascular disease and mortality [69]. The literature surrounding arteriosclerosis is difficult to assess because stiffness of a vessel is dependent on the pressure at which stiffness is measured; i.e. blood pressure is a confounding factor, as may also be the case for heart rate. Therefore, any intervention that changes heart rate or blood pressure may indirect effect stiffness without altering isobaric stiffness. Stiffness is often accessed in a variety of different ways, which are not always comparable. The gold standard is the aortic pulse wave velocity (aPWV), as it has the most evidence of independent predictive value, and so studies employing aPWV should be given more weighting. An addition issue is that many of the published studies are very small and no doubt underpowered. All of these factors make interpreting the published data challenging.
29.5 Lifestyle
29.5.1 Smoking
Smoking is associated with atherosclerosis, but there is also some evidence to suggest that smoking is also associated with arteriosclerosis and arterial stiffness. Epidemiological data suggest that smoking in youth may be associated with increased aPWV [70, 71] and other studies have reported a positive association between aPWV and smoking in adults [72, 73]. However, the data are inconsistent [74, 75] and longitudinal data do not support a strong role for smoking [76–80].
There is little evidence concerning smoking cessation. One study did report a lowering of brachial-ankle pulse wave velocity after 12 months cessation, but brachial-ankle index increased [81]. There is also some evidence to suggest that flavonoids such as those found in chocolate and grape juice may have a protective effect against arterial stiffness in smokers [82].
29.5.2 Alcohol
Moderate, chronic alcohol consumption is associated with a lowered risk of cardiovascular disease, compared to no alcohol consumption and heavy alcohol consumption. In women there is evidence that moderate alcohol consumption is linked to decreased arterial stiffness in a J-shaped correlation; drinking between 4 and 20 glasses a week reduces arterial stiffness but greater than 21 results in an increase in arterial stiffness [83]. A similar association was seen in men; when adjusted for other factors effecting PWV, this association was unchanged [84].
29.5.3 Diet
There is epidemiological evidence that salt intake is related to arterial stiffness. Avolio et al. completed a study comparing arterial distensibility between rural Chinese and urban Chinese populations. This study found that those individuals in rural communities have less age-related arterial stiffening, likely due to differences in salt consumption between the two groups, with the rural group consuming less sodium than the urban group, resulting in a lower blood pressure [85]. Similar results were seen in studies comparing urban and rural pygmies, showing the impact of environment vs. genetics on arterial stiffness [86].
Consuming a low-salt diet results in a lower AASI (ambulatory arterial stiffness index), whereas high-salt intervention results in a raised AASI [87]. The effect of salt consumption is not purely a long-term progressive effect; salt can also have an acute effect on arterial stiffness. A high-sodium meal can increase arterial stiffness for a short time period as assessed by augmentation index (AIx) [88]. Interestingly, however, this study did not find an association between blood pressure and acute salt consumption. This is backed by a study of salt consumption in the Portuguese which used the gold standard aPWV to conclude that the association with salt consumption was, independently of blood pressure [89], linked to arterial stiffness. In clinical trials salt reduction may have a greater impact on black people’s pulse wave velocity than whites or Asians [20].
29.5.4 Exercise
There is mixed evidence as to whether exercise is of benefit against arterial stiffness. The evidence remains largely inconclusive over how much and what sort of exercise should be undertaken. High-intensity exercise may be harmful rather than beneficial.
In heart failure patients with reduced ejection fraction, 8 weeks of exercise increases arterial compliance [90]. Resistance training may be linked to arterial stiffness, but this is more likely to be restricted to high-intensity resistance training [90]. Long-distance endurance training may be associated with pathological structural remodelling of arteries [91]. However, again this is generally only with high-intensity training.
However, both endurance and resistance training have in some studies led to a significant decrease in arterial stiffness as well as blood pressure in pre-hypertensive students [92]. Exercise is associated with increased total systemic arterial compliance [93]. Exercise can be combined with weight loss to increase the endothelial-dependent flow-mediated dilatation (FMD) in patient with coronary heart disease greater than that of weight loss alone [94]. Therefore, exercise appears to be beneficial provided it is not undertaken to excess. However, in the majority, it is unclear as to whether isobaric stiffness is affected. Larger randomised studies, with adequate controls/blinding and correction for changes in blood pressure, are clearly required.
29.6 Pharmacology
A number of small studies have assessed the effect of antihypertensive drugs on measures of arterial stiffness including aPWV. Many of these suggest that aPWV is lowered, but it is difficult to know the effect on isobaric stiffness. One meta-analysis suggested that ACE inhibitors in particular may reduce aPWV independently of blood pressure. However, this was based on data from only 294 subjects [95]. Several head-to-head comparisons suggest that beta blockers may reduce stiffness more than other drugs and that vasodilating agents may be even better [96], but again sample sizes are very small [97, 98]. There is also a lack of data concerning the long-term effects of BP lowering per se. If fatigue fracture of the elastic elements is largely driven by pulsatile load and heart rate, then lowering average pressure, pulsatility and heart rate may retard age-related arterial stiffening, but this hypothesis remains to be formally tested.
Matrix proteins are another target for therapies designed to alter stiffness. ALT711 is an advanced glycation end point (ACE) breaker meaning that it has the potential to reverse the stiffening of arteries due to cross-linking of elastic elements. This hypothesis was supported by an animal data [99], and early human studies reported a lowering of reduced left ventricular stiffness and systolic pressure compared to placebo [100]. However, development was discontinued and no other similar agents are currently available for trials.
Statins may have pleomorphic effects beyond simply cholesterol lowering, including improving endothelial function and acting as a modest but clinically apparent anti-inflammatory. There have also been many studies demonstrating that statins decrease arterial stiffness [101]. However, these invariably included only tiny numbers of subjects, and the much larger CAFE sub-study of ASCOT did not find any difference in estimated aPWV between those randomised to a statin compared to placebo, all be it in a hypertensive population.
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