Vascular, Vol. 20 No. 5, pp. 243–250, 2012 © 2012 Royal Society of Medicine Press. All rights reserved. ISSN: 1708-5381.

DOI: 10.1258/vasc.2012.ra0062

REVIEW ARTICLE

Cardiovascular disease: primary prevention, disease modulation and regenerative therapy Sherif Sultan*† and Niamh Hynes*† Cardiovascular primary prevention and regeneration programs are the contemporary frontiers in functional metabolic vascular medicine. This novel science perspective harnesses our inherent ability to modulate the interface between specialized gene receptors and bioavailable nutrients in what is labeled as the nutrient–gene interaction. By mimicking a natural process through the conveyance of highly absorbable receptor specific nutrients, it is feasible to accelerate cell repair and optimize mitochondrial function, thereby achieving cardiovascular cure. We performed a comprehensive review of PubMed, EMBASE and Cochrane Review databases for articles relating to cardiovascular regenerative medicine, nutrigenomics and primary prevention, with the aim of harmonizing their roles within contemporary clinical practice. We searched in particular for large-scale randomized controlled trials on contemporary cardiovascular pharmacotherapies and their specific adverse effects on metabolic pathways which feature prominently in cardiovascular regenerative programs, such as nitric oxide and glucose metabolism. Scientific research on ‘cardiovascular-free’ centenarians delineated that low sugar and low insulin are consistent findings. As we age, our insulin level increases. Those who can decelerate the rapidity of this process are prompting their cardiovascular rejuvenation. It is beginning to dawn on some clinicians that contemporary treatments are not only failing to impact on our most prevalent diseases, but they may be causing more damage than good. Primary prevention programs are crucial elements for a better outcome. Cardiovascular primary prevention and regeneration programs have enhanced clinical efficacy and quality of life and complement our conventional endovascular practice. Key words: cardiovascular regenerative medicine; anti-aging; arginine; glucose metabolism; insulin resistance; nitric oxide; co-enzyme q10

Introduction Unprecedented changes in vascular surgery practice over the last 20 years coalesced in the endovascular revolution. In the course of this insurgence, we contemplated that gene therapy would supplant endovascular technologies. However, after phase 3 human gene trials and more than three billion Euros squandered globally on research and development, all that we have attained is the realization that we are far from

Accepted February 7, 2012 *Department of Vascular and Endovascular Surgery, Western Vascular Institute, University College Hospital Galway, Newcastle Road; † Department of Vascular and Endovascular Surgery, Galway Clinic, Dublin Road, Galway, Ireland Correspondence to: Sherif Sultan, Department of Vascular and Endovascular Surgery, Western Vascular Institute, University College Hospital Galway, Ireland; e-mail: [email protected]

any groundbreaking clinical outcome. Equally, the new kid on the block, cultured stem cell therapy, has failed to deliver; its benefits are short-lived, it is costly to set up and we are a decade away from human relevance. Cardiovascular primary disease prevention and regenerative programs are the contemporary frontier in functional metabolic vascular medicine. An entirely novel science of nutrigenomics has evolved, about which we are relatively naive and ill-informed, despite its mounting credibility and innovative ventures.1 This new era of metabolic vascular nutrigenomics harnesses our inherent ability to modulate the interface between specialized gene receptors and bioavailable nutrients in what is labelled as the nutrient–gene interaction. By mimicking a natural process through the conveyance of highly absorbable receptor-specific nutrients, it is feasible to accelerate cell repair and optimize mitochondrial function and thereby achieve the ultimate cardiovascular cure.

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Methods We performed a comprehensive review of PubMed, EMBASE and Cochrane Review databases for articles relating to cardiovascular regenerative medicine, nutrigenomics and primary prevention, with the aim of harmonizing their roles within contemporary clinical practice. We searched in particular for large-scale randomized controlled trials on contemporary cardiovascular pharmacotherapies and their specific adverse effects on metabolic pathways which feature prominently in cardiovascular anti-aging programs, such as nitric oxide and glucose metabolism. The search terms included ‘Cardiovascular Disease’ AND each of the following terms separately ‘Regenerative Medicine’, ‘Primary Prevention’, ‘Nutrigenomics’, ‘L-Arginine’, ‘Nitric Oxide’, ‘Dysglycaemia’, ‘Insulin resistance’, ‘Endothelial Dysfunction’, ‘SIRT enzymes’, ‘Statin Therapy’, ‘Antihypertensives’, ‘ Beta-blockers’, ‘Diuretics’ and ‘Co-enzyme Q10’.

Discussion Sirtuin enzymes A new era of regenerative medicine is about to strike on a global scale and nutrigenomic substances that modulate the activity of sirtuin (SIRT) enzymes, have the power to be master regulators of survival during stress and extend life span, will strike our shelves in next to no time.2 Up-regulation of SIRT enzymes regulates glucose utilization, augments insulin sensitivity and boosts exercise tolerance. These imperative physiological adjustments are a frank consequence of amplified mitochondrial biogenesis. Resveratrol epitomizes the first in a novel class of SIRT activators that has been established as a safe well-tolerated vascular nutrigenomic in humans.3 No doubt, future generations accustomed to living past 100 years will gaze back at our present methodology for vascular intervention as a primitive relic of a bygone era. On the other hand, those who are currently eager to pop a pill and live to 130 years may have been born about half a century ahead of time. Coenzyme Q10 Two-thirds of American patients are probing for alternative methods to manage their diseases. What’s more, one-third do not get their prescription dispensed for fear of concealed side-effects. On the other hand, heightened patient awareness of contemporary treatment modalities does not directly correlate with improved population health. Emerging data

demonstrated that the number of patients with congestive heart failure has quadrupled over the last decade and there is mounting evidence which links this exponential rise to depleting co-enzyme Q10 levels4 as a side-effect of certain types of statins. Co-enzyme Q10, whose discovery earned its finder a Nobel Prize in 1978, is a crucial factor in the production of ATP, which is required for myocardium contractility. Coenzyme Q10 is a lipophilic molecule and this fat solubility is extremely important considering heart muscle acquires its energy from cholesterol. Telomere shortening More recently, the 2009 Nobel Prize in Medicine was awarded for the discovery of how telomere shortening is correlated with the aging process, whereby shorter telomeres are associated with shorter lives.5 Specifically, individuals with shorter telomeres have nearly triple the cardiovascular mortality rate of people with longer telomeres.6 Furthermore, adults above the age of 60 with shorter telomeres were eight times more likely to die from infectious disease.7 Studies had demonstrated that life span could be increased by five years by increasing the length of telomeres in people with shorter ones and that long-term endurance exercise training has proven to have a protective effect on the arterial wall and immune system by activating telomerase and thereby reducing telomere shortening. Nitric oxide Amino acids have been proven to play a vital role in primary cardiovascular prevention, disease modulation and regeneration. L-Arginine, which is a precursor of nitric oxide, has been shown to ameliorate blood vessel vasodilation and augment myocardium and brain perfusion. Nitric oxide is not only a potent vasodilator but reduces platelet aggregation and adhesion, monocyte–vessel wall interaction and smooth muscle cell proliferation – all important events in early atherosclerosis. Testimony to the significance of this breakthrough is the accolade of the Nobel Prize in medicine earned by its discoverer in 1998. L-Arginine has established promise in the management of cardiovascular atherosclerotic disorders by reducing blood pressure, lowering low-density lipoprotein cholesterol and reversing plaque maturity. Studies have shown that short-term administration of L-arginine improves endothelial vasodilator function of coronary or peripheral arteries in patients with cardiovascular disease.8 The improvement in vascular reactivity is due to the metabolism of L-arginine to NO, as demonstrated by an

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increase in urinary or plasma nitrogen oxides and cGMP with L-arginine therapy.9 The hypothesis that L-arginine supplementation could directly affect cardiovascular functional capacity was based on the observation of elevated plasma levels of asymmetric dimethylarginine (ADMA) in patients with cardiovascular disease.9,10 ADMA is a methylated arginine analog and an endogenous competitive inhibitor of NO synthase.11 It is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) and ADMA accumulates in conditions in which DDAH is impaired or deficient, such as the oxidative stress associated with elevated levels of cholesterol, blood glucose, triglycerides or homocysteine.10,12–14 Human studies indicate that ADMA adversely affects angiogenesis and vascular regeneration and accelerates vascular disease.15–18 ADMA correlates with the severity of arterial disease and is predictive of cardiovascular events.19,20 Infusion of ADMA gas has been shown to increase systemic resistance, reduce cardiac output and vascular compliance and lessen cerebral blood flow in humans.21,22 Studies have shown a beneficial effect of L-arginine on functional capacity in patients with peripheral arterial disease,9,23,24 as well as in patients with coronary artery disease25–27 and congestive heart failure.28 However, Wilson et al.29 observed, in a study of long-term administration of L-arginine to patients with peripheral arterial disease, that a reduced long-term improvement in functional capacity might be due to an arginine-induced derangement of the NO synthase pathway, with a paradoxical reduction in NO production. Furthermore, in another randomized clinical trial on patients after myocardial infarction, long-term therapy with oral L-arginine supplementation (6 g/day for 6 months; n=150) did not improve ejection fraction or vascular compliance, and the study was terminated prematurely for safety concerns.30 By contrast, in a larger study of shorter duration (6 g/day for 30 days; n=750), L-arginine tended to reduce major adverse cardiovascular events.31 Taken together, these studies are also consistent with a benefit of short-term administration, which is lost due to arginine tolerance when administered on a long-term basis. Methods of providing long-term benfits from L-arginine are being investigated with pharmacological approaches targeting ADMA and up-regulating the enzyme DDAH, which metabolizes it. Other investigators have identified a disturbance that occurs at the cellular level and involves the transport protein (CAT-1) that carries the amino acid 32,33 L-arginine into a cell. The CAT-1 transporter is responsible for endothelial dysfunction. Intimate interrogation of the CAT-1 transporter in vascular disease may lay the foundation for the development of novel, endothelially targeted, pharmacological-based approaches for the treatment and

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possibly prevention of vascular disease by therapeutic up-regulation of the L-arginine-NO pathway. Insulin resistance Major studies of ‘cardiovascular-free’ centenarians delineated that low sugar and low insulin are consistent findings in such individuals.34 The level of insulin sensitivity of the cell is one of the most crucial markers of life span.35 Insulin is a catabolic inflammatory hormone in the body and a pro-aging reversible factor. As we age, our insulin level increases. Those who can decelerate the rapidity of this process are promoting their cardiovascular anti-aging. Metabolic or insulin resistance syndrome affects over 60 million Americans and one in four adults over the age of 35.36 Those who are in the subclinical phase ‘age 35–45’ and clinical phase of aging ‘age 45 and above’ have a one in three chance of getting this syndrome and not knowing it. Metabolic syndrome may be the cause of up to 50% of all cardiovascular morbidities. It is an epidemic of massive proportions. Fortunately, it can be reversed with a diet high in unsaturated fat, low in protein and moderate in carbohydrate.37 Exercise, weight management and metabolic vascular nutrigenomics help to normalize blood glucose level and increase insulin sensitivity.36,38,39 Moreover, the contemporary management of type 2 diabetics has been subject to scrutiny and potentially raises some ethical dilemmas. Although the patient might appear to have a need for insulin therapy, the introduction of insulin in the context of severe insulin resistance may lead to hyperinsulinemia and consequently accelerate their metabolic vascular derangement, resulting in high morbidity and mortality. Conversely, metformin is a pro anti-aging agent that can oppress 80% of all type 2 diabetes mellitus (DM).40 Moreover, there is evidence that obesity and metabolic syndrome lead to a dysfunction of L-arginine influx, which negatively correlates to insulin resistance.39 These findings could be a premature marker of future cardiovascular complications during adulthood and raises the prospect of vascular metabolic nutrigenomic modulation using L-arginine supplements. Diabetics can be weaned off their medication through vascular metabolic nutrigenomics and with close attention to metabolic vascular intermediaries. In addition, in the context of the deranged metabolic milieu that exists for diabetic patients, they fare poorly with beta-blockers,41 diuretics42 and statins,43 and may require doubling the dose of potent antiplatelets to achieve a therapeutic effect.44 Beta-blockers,41 fluoroquinolones,45 phenothiazines46 and thiazide diuretics42 stall insulin secretion through

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diverse modalities, but aspirin,47 monoamine oxidase inhibitors48 and methyltestosterone49 boost the action of insulin and can lower blood glucose concentrations to a precarious level. Optimizing such a patient’s treatment regimen commands particularized expertise of drug interaction and proficient confidence in adjusting patient medications. Mastering this can lead to complete cessation of insulin in some of these patients, simply by altering concomitant medications that have an adverse effect on insulin metabolism. The ARIC study verified that patients indulged with beta-blockers have a 28% higher risk of developing type 2 DM.50 This was further scrutinized in the CAPPP trial51 and LIFE52 study, which both established that beta-blockers impose a 25% risk of developing type 2 DM in non-diabetic patients. These effects are arbitrated to impaired endotheliumdependent, insulin-mediated vasodilation. Furthermore, unimpeded alpha-one receptor activation instigates vasoconstriction and diminishes blood flow to the muscles, resulting in attenuation of insulin-stimulated glucose uptake in the periphery and thus creating a state of insulin resistance.

Statin saga The US Veterans Affair Healthcare System study on 345,417 veterans in 10 hospitals in Southern USA concluded that statins affect fasting and postprandial glucose concentration by inducing a state of hyperglycemia in diabetic as well as non-diabetic patients.53 This relationship between statin use and rise in glucose concentration is independent of age and use of aspirin, beta-blockers and angiotensin-converting enzyme inhibitors. Furthermore, a subanalysis of the JUPITER study showed that statin therapy can induce fullblown type 2 diabetes in women.54 This was astonishingly shown in the substudy of PROVE-IT TIMI 22, in which there was a significant increased risk of developing glycosylated hemoglobin (HbA1c) >6% in both diabetics and non diabetics.55 Moreover, Huptas et al.56 have also demonstrated that statin therapy can induce a state of insulin resistance. The most recent study from the Women’s Inititative investigated 153,840 postmenopausal women without DM.57 There were 10,242 incident cases of self-reported DM over 1,004,466 person-years of follow-up. Statin use at baseline was associated with an increased risk of DM and this association remained after adjusting for other potential confounders and was observed for all types of statin medications. The authors concluded that the increased risk for DM in postmenopausal women is a medication class effect of statins.

Statins manipulate glucose metabolism as a consequence of inhibitory effects on adipocytes. They induce insulin resistance through reduction in insulin-stimulated glucose uptake with a strong impact on glycemic control in nonobese patients. The poise of use of statins and clear upshot is dogged by the patient metabolic conditions and if statins could amend or impair insulin resistance and ultimately type 2 DM. Critical reappraisal of cholesterol lowering therapy in prevention of cardiovascular diseases, the ‘JUPITER trial’, elucidated that the results of trials do not support the use of statin treatment for primary prevention of cardiovascular diseases and raises troubling questions concerning the role of commercial sponsors.58 Prescribing a statin in old age has a 9% increase in risk of developing diabetes mellitus.59 It is another iatrogenic risk factor that must be avoided and it is mandatory to add glucose to the list required for monitoring patients on statin and is equally important as liver function tests and creatine kinase. Preiss et al.60 demonstrated, in a pooled analysis of data from the five major statin trials, an increased incidence of new onset diabetes with statin therapy and provided evidence of a dose-dependent association. Furthermore, the meta-analysis predicted an 11.3% enhanced risk of rhabdomyolysis with utilization of high-dose statin therapy. However, clinical studies and large-scale randomized controlled trials demonstrated differences between individual statins, with pravastatin tending to reduce risk of new onset of diabetes while atorvastatin, rosuvastatin and simvastatin together significantly increasing such risk.61 Objective re-evaluation of trials on the use of statins in secondary stroke prevention,62 such as the SPARCL trial,63 has presented evidence for the avoidance of statin therapy poststroke in order to avoid intracerebral hemorrhage. Moreover, a meta-analysis of 11 randomized controlled trials involving 65,229 participants, conducted to investigate the relationship between statins and all-cause mortality in highrisk primary prevention, did not find any evidence for the benefit of statin therapy on all-cause mortality prevention.64 The finding in a Cochrane Systemic Review by Taylor et al.65 is alarming. They reviewed the current concept of the use of statins in primary prevention and found evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease. Only limited evidence showed that primary prevention with statins may be cost-effective and improve patients’ quality of life. The authors cautioned about prescribing statins for primary prevention among people at low cardiovascular risk.

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Parkinson’s disease and ataxia-like syndrome are increasing in nature in a subcategory of old patients. Cholesterol is a critical component of neuronal cell membranes and synapses, and plays an important role in their proper functioning. A strong association between lower cholesterol and Parkinson’s disease risk has been reported, such that each mmol/L increase in total cholesterol was accompanied by a 23% decrease in the risk of developing Parkinson’s disease. The risk reduction was significant in women but not in men.66 Cholesterol concentrations are the main determinant of co-enzyme Q10, an important antioxidant and mitochondrial electron receptor.67 Co-enzyme Q10 is neuroprotective, and in a study involving patients with early Parkinson’s disease, administration of high-dosage (1200 mg/day) co-enzyme Q10 significantly slowed the progression of disability, with a halting of their statins.68 Furthermore, evidence exists for an association between the use of statin therapy in patients postkidney transplant and enhanced risk of development of squamous cell carcinoma.69 One systematic review found moderate evidence that statin therapy increased the risk of non-melanoma skin cancers (median risk ratio 1.6, range 1.2–2.2).69 For unknown reasons, since these publications, squamous cell carcinoma has been excluded in all reports from subsequent statin trials.70 Rosenberg and Allard,71 in a government report to the Canadian authority, realized that expectations for the use of statin have not been met. Instead, they have found a pattern of overestimation of benefit and underestimation of harm. Statins, if used, should only be administered on a shortterm basis. This acute benefit is borne from the clinical trial results which demonstrate that despite crossovers between treatment arms or compliance rates, which were as low as 25% in some cases after nine months, once a patient has an initial treatment, their benefit remains even if they stopped taking the statin. What’s more is that from the ASCOT trial, we can see that the greatest survival benefit came from non-cardiovascular deaths, seemingly because of the antiinflammatory effects which reduced deaths from respiratory and infectious causes.72 If statin therapy is used judiciously in the appropriate patient cohort, and stopped before adverse effects develop, they may have a limited role to play, but only in the short term. Cardiovascular disease prevention and regenerative programs We must gaze at refined sugar as a drug and dwell as far away as possible from its consumption. It is more

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treacherous than smoking and hypercholeosteremia combined. Cardiovascular disease prevention and rejuvenating diets must converge on three core pillars: a diminution of calories by 30%, a growth in green leafy vegetables intake by 60% and a cutback on refined sugar intake by 90% as recommended by nutritionist global research. Insulin resistance and hyperglycemia are culprits in the development of vascular diseases in two-thirds of the population. However, this can be reversed through cardiovascular disease prevention and regenerative programs. Positive manipulation of functional metabolic vascular nutrigenomics can be realized by L-arginine and co-enzyme Q10 supplementation. This would permit modulation of a diverse class of medical disorders in a physiological manner. We must promote cardiovascular disease prevention and anti-aging programs, which consist of achievable lifestyle adjustments with caloric restriction, 12 hours fasting from 18:00 to 06:00, 30 minutes daily endurance exercise plus the aforementioned nutrigenomics. The first stage of cardiovascular primary disease prevention and antiaging programs is prohibiting self-harming poisoning; for example, ingestion of aspartame in soft drinks has a negative effect on the brain and long-term disastrous consequences for satiety, postprandial glucose and insulin levels.73 The second stage is recovery and involves replenishing our depleted resources by metabolic vascular nutrigenomics. These are methods and techniques that we must master in our present and future practice. The cardiovascular community must expand on its history of revolution and redeem ourselves from the effortless fashion of prescription of cardiovascular drugs or ingenuous vascular intervention. As vascular surgeons, we have not only borne witness to, but have also been active participants in, the revolutionary developments that have occurred in our field of specialization over the last few years. Cutting-edge technologies have led to dramatic improvements in life-expectancy and quality of life. However, naive and indiscriminate acceptance of novel mainstream therapies is not always advisable and prudence is required in unearthing harmful, covert side-effects. At the same time an open-minded and pioneering attitude is necessary when exploring new frontiers to improve patients’ health. We have objectively reviewed contemporary vascular research and have sifted out industrial bias to unearth a fresh perspective on how we can promote cardiovascular longevity with attainable lifestyle adjustments. Our own cardiovascular primary disease prevention and regeneration program has enhanced clinical efficacy and quality of life and is complementary to our conventional endovascular practice.

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Declarations

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Conflicts of interest: Neither author has any conflict of interest. The authors declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work. Contributorship: Both authors contributed to the literature review, format and writing of the article.

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