Stress and Cardiovascular disease

I found this paper I wrote for 4th year Herbal Medicine - seems to refuse to go on a new page.

Assignment 1

From the information presented in Ullian 1999, Kivimaki et al 2002, your understanding of stress physiology, and a review of the relevant literature, discuss how and to what extent chronic stress may influence cardiovascular morbidity and mortality. Suggest appropriate clinical interventions revolving around herbal medicines and lifestyle modification.

Stress and Cardiovascular Disease

Abstract

Stress has long been believed to adversely affect heart disease, however there has been limited clinical and research evidence to support this. Recent studies have clarified the mechanisms and measurable effects of chronic stress on the cardiovascular system and the consequent effects on cardiovascular morbidity.
Studies have shown stressful working conditions can induce sustained changes in neuroendocrine and autonomic activity, increasing atherogenesis. Jobs with high demands and low control are associated with an increased CHD risk and low control is also associated with high levels of the clotting factor fibrinogen, which predicts cardiovascular disease.
The responses to stress include release of catecholamines and corticosteroids, increases in heart rate, cardiac output and blood pressure, and changes in processes relating to clotting processes (coronary vasoconstriction, platelet aggregation or plaque rupture). In patients with atherosclerosis these changes may trigger clinical events. A 2004 study found the increased risk of myocardial infarction associated with psychosocial stressors to be comparable to that from hypertension and abdominal obesity but less than that from smoking. Psychosocial factors contribute to the development and promotion of CHD by direct atherogenic effects, by contributing to maintenance of unhealthy behaviours and further as a barrier to lifestyle modification strategies.
Herbal adaptogens are “natural bioregulators, which increase the ability of the organism to adapt to environmental factors and to avoid damage from such factors.” Eleutherococcus senticosus appears to alter the levels of neurotransmitters and hormones involved in the stress response, primarily at the hypothalamic-pituitary-adrenal (HPA) axis.
Nervines, sedatives and nervine trophorestoratives, such as Leonurus cardiaca, Hypericum perforatum Valeriana officinalis, Turnera diffusa, Scutellaria lateriflora and Avena sativa are beneficial for symptoms related to stress exposure.
Most herbs which positively influence cardiac function also have beneficial effects on risk factors such as hyperlipidaemia. Allium sativa has numerous actions beneficial to cardiovascular disease, including lipid lowering, inhibition of platelet aggregation, prolongation of bleeding and clotting time and enhancement of fibrinolysis. Crataegus spp have been shown to reduce myocardial demands in clinical studies, and also to have antioxidant, coronary vasodilatory and cardioprotective activity. Salvia miltiorrhiza is indicated for angina due to its vasodilatory, antiplatelet and cardioprotective effects, and was found to exhibit anti-oxidant activity and prevent atherosclerosis in rabbits fed a high cholesterol diet. Forskolin in Coleus forskohlii inhibits platelet activation and degranulation, inhibits mast cell degranulation and histamine release, increases cardiac contractility, relaxes arterial smooth muscle and antagonises PAF by interfering with receptor binding. Terminalia arjuna bark has been used in the treatment of CAD, CCF, angina and hypercholesterolaemia. An open study found a 50% reduction in anginal episodes and a significant reduction in systolic BP in patients with stable angina.
A meta-analysis of more than 20 controlled trials found that those receiving psychosocial treatments showed greater reductions in psychological distress, blood pressure, heart rate and cholesterol than controls. In the half of these studies containing morbidity and mortality data, those not receiving psychosocial treatments showed greater mortality and cardiac recurrence rates during the first 2 years follow up.
Lifestyle interventions based on exercise training and yoga can reduce cardiovascular risk factors.
Stress has long been believed to adversely affect health, and specifically heart disease, however, there has been limited clinical and research evidence to support this. Recent studies have clarified the mechanisms and measurable effects of chronic stress on the cardiovascular system and the consequent effects on cardiovascular morbidity. There are limited studies to date addressing the effects of stress on cardiovascular mortality.
Stress can be defined as the external or environmental factors to which people are exposed and the behavioural or biological response to it. ⁽¹⁾ Selye’s general adaptation syndrome describes how prolonged, uncontrollable physical and/or psychological distress may ultimately result in a state of exhaustion. ⁽²⁾ The impact of stress is, however, moderated by the personality and coping capacity. Until the 1990’s the “type A” coronary-prone personality theory dominated, however studies failed to show associations with coronary heart disease (CHD). Recent work suggests hostility (“type D” personality) is the “toxic” component for cardiac risk. ⁽³⁾ Hostility is also associated with behavioural risk factors including alcohol, smoking and dietary fat intake, so some effects on CHD are behavior mediated.⁽³⁾
Feelings of extreme tiredness and lack of energy are amongst the most common premonitory symptoms of myocardial infarction and sudden cardiac death. It is suggested that this exhaustion is a consequence of prolonged psychological distress. ⁽²⁾
Studies have shown stressful working conditions can induce sustained changes in neuroendocrine and autonomic activity, increasing atherogenesis. Jobs with high demands and low control are associated with an increased CHD risk. ⁽²⁾ The Whitehall II study of British civil servants found that low job control predicts future CHD independently of standard cardiovascular risk factors.⁽³⁾ A Finnish study over 28 years had similar results, with a combination of high work demands and low job control resulting in a 2.2 fold cardiovascular mortality risk. For employees with effort-reward imbalance, including low salary and lack of social approval, the risk ratio was 2.4.⁽⁴⁾ Longitudinal studies show that self-reports of low control at work predict CAD in a dose-response gradient. ⁽⁵⁾ Low control is also associated with high levels of the clotting factor fibrinogen, which predicts cardiovascular disease. ⁽⁵⁾
CHD [or coronary artery disease (CAD) or ischaemic heart disease (IHD)] refers to conditions resulting from atherosclerosis – plaque accumulation in coronary arteries. This is an insidious and complex process with a series of biochemical, immune and inflammatory and haemodynamic processes interacting with various risk factors. ⁽⁵⁾ At least 3 studies have shown that mental stress induced ischaemia predicts subsequent clinical events in patients with CHD. One study also reported that patients with mental stress ischaemia were more likely to die over a 3 year follow-up period. ⁽⁵⁾
Ischaemia in CHD patients is caused by increased cardiac demand or decreased coronary supply. Mental challenge tasks induce ischaemia in 30%-60% of CAD patients.⁽²⁾ During “daily life activities”, ischaemia ( defined as ST-segment depression of 1mm or more for a duration of > 1 minute) was preceded by mental arousal but not physical activity in the evening, suggesting increased cardiac demand is not the only mechanism involved. Anger was the emotional state most strongly associated with ischaemia. ⁽²⁾
The haemodynamic and neuroendocrine responses to stress are characterised by release of catecholamines and corticosteroids, increases in heart rate, cardiac output and blood pressure, and changes in processes relating to clotting processes (coronary vasoconstriction, platelet aggregation or plaque rupture). In patients with atherosclerosis these changes may trigger clinical events. ⁽⁵⁾
Stress induced autonomic activation may also predispose to cardiovascular events by promoting the development of atherosclerosis over time, or by endothelial dysfunction or directly triggering lethal arrhythmias. ⁽⁵⁾
These interactions have been succinctly summarised by Kop (1999).

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From 2. Kop WJ . Chronic and Acute Psychological Risk Factors for Clinical Manifestations of Coronary Artery Disease.1999. Psychosomatic Medicine 61:476-487



Acute mental stress has been demonstrated to induce prolonged endothelial dysfunction via activation of endothelin-A receptors, reducing the endothelium-dependent, nitric oxide (NO)-mediated vasodilation by half. The authors assert that this supports the concept of an atherogenic effect of mental stress, and “a new therapeutic strategy in the prevention of atherosclerotic vascular disease and its complications.” ⁽⁶⁾ Corticosteroids can cause hypertension by enhancing renal sodium reabsorption, and by augmenting vascular tone via potentiation of the actions of vasoconstrictor hormones (noradrenaline, angiotensin II) and by direct actions on vascular smooth muscle cells. ⁽⁷⁾
Increasingly the inflammatory nature of coronary disease resulting from endothelial dysfunction is being described. Both biomechanical factors associated with pulsatile blood flow and biochemical factors, such as cytokines and growth factors, appear to promote inflammatory inducers of atherosclerosis (e.g. vascular cell adhesion molecules).⁽⁸⁾ Sympathetic nervous system hyper reactivity (AKA cardiovascular reactivity) is a dispositional tendency to exhibit exaggerated heart rate and blood pressure responses to stimuli experienced as engaging, challenging or aversive. ⁽⁸⁾ The previously noted “hostile“ individuals ( displaying negative orientations toward interpersonal relationships and such traits as anger, cynicism and distrust) have been shown to have higher blood pressure and heart rate responses to mental tasks and higher blood pressure during daily life activities. They also exhibit hypercortisolaemia and high levels of circulating catecholamines, and decreased mononuclear leukocyte beta-adrenergic receptor function.⁽⁸⁾ Studies utilising serial carotid Doppler measurements have demonstrated progression of carotid atherosclerosis was more rapid among individuals manifesting more pronounced heart rate and blood pressure responses to physiological challenge.⁽⁸⁾ Finally, hostile CAD patients have a higher rate of restenosis following angioplasty and manifest more ischaemia during stress testing. ⁽⁸⁾
A Lancet case control study in 2004 ⁽⁹⁾ found the increased risk of myocardial infarction associated with psychosocial stressors to be comparable to that from hypertension and abdominal obesity but less than that from smoking. The article concludes
“the importance of psychosocial factors is much more important than commonly recognised, and might contribute to a substantial proportion of acute myocardial infarction” ⁽⁹⁾

Clinical Interventions:

Clinical therapeutic interventions should address the response to chronic stress, the deleterious effects upon the cardiovascular system, and other risk factors. As the risk factors for CHD work synergistically, reduction in all risk factors is desirable. Stress management should facilitate the reduction in use of alcohol, smoking and poor dietary habits. ⁽⁵⁾
Herbal adaptogens are specifically utilised in the management of chronic and maladaptive stress responses. Adaptogens have been defined as
“natural bioregulators, which increase the ability of the organism to adapt to environmental factors and to avoid damage from such factors.” ⁽¹⁰⁾
Withania somnifera radix has been described as being “ ideally suited to the treatment of patients who are overactive but debilitated, for whom Korean Ginseng would tend to cause overstimulation” ⁽¹¹⁾ In animal studies it reduced plasma cortisol and adrenal weight, and prevented many of the biochemical changes of cold stress and immobilisation stress.⁽¹²⁾ W. somnifera is considered to be adaptogenic, anti-arrhythmic, hypotensive, sedative and a nervine tonic.⁽¹³⁾ It was also found to reduce serum cholesterol and ESR in a randomised, double-blind, placebo controlled trial in healthy men aged 50-59. Another trial in six patients with hypercholesterolaemia showed significantly reduced TC, TGs, LDL and VLDL compared with baseline. ⁽¹¹⁾ Dosage: Radix FE 1:2 2 - 4mls tds.⁽¹²⁾
Eleutherococcus senticosus appears to alter the levels of neurotransmitters and hormones involved in the stress response, primarily at the hypothalamic-pituitary-adrenal (HPA) axis. It degrades the enzyme (catechol-o-methyl transferase) and increases the levels of noradrenaline and serotonin in the brain and adrenaline in the adrenal glands. ⁽¹⁰⁾ The Commission E has a contraindication for use in hypertension, however the glycosides in E. senticosus have been found to lower blood pressure. ⁽¹⁴⁾ Pharmacologic research has found E. senticosus can increase repair in damaged heart muscle, increased the number of mitochondria in cardiac muscle and increased the conversion of fat into glycogen for energy. Clinical studies have been of variable standard, but one randomised, comparative trial found a reduction in total cholesterol, LDL and triglycerides. ⁽¹¹⁾ E senticosus has also been shown to bind to receptors for oestrogen, progestin (sic), mineralocorticoids and glucocorticoids. ⁽¹⁰⁾ Dosage: Radix FE 1:2 1 – 4mls bd. ⁽¹²⁾
Herbs to help with symptoms related to stress: Nervines, anxiolytics, sedatives and nervine trophorestoratives.
Leonurus cardiaca. Commission E notes the paucity of recent research for L. Cardiaca, while supporting its use for nervous cardiac disorders.⁽¹⁴⁾ Traditionally L. cardiaca has been used for heart disease, cardiac debility, tachycardia and effort syndrome, in addition to hysteria, nervous conditions and mild hyperthyroidism.⁽¹¹⁾ It is considered to be cardiotonic, hypotensive, antiarrhythmic, nervine tonic, antithyroid, antispasmodic and an emmenogogue. ⁽¹¹⁾ Ursolic acid has cardioactive, antiviral, tumour-inhibiting and cyotoxic effects, while leonurine produces CNS depressant and hypotensive effects when administered intravenously ⁽¹¹⁾ in animals.⁽¹⁴⁾ Dosage: FE 1:2 2.0 – 3.5mls daily. ⁽¹¹⁾
Hypericum perforatum is useful for anxiety and depression; however its interactions with orthodox medicines including digoxin and warfarin limit its usefulness in CHD management. Dosage: Standard or High hypericin FE 1:2 1 – 2mls tds. ⁽¹¹⁾
Valeriana officinalis is anxiolytic, mildly sedative, hypnotic and antispasmodic. It is traditionally used for treatment of anxiety, nervous tension, restlessness and insomnia. ⁽¹¹⁾ One randomised, controlled, double-blind study using a combination of V. officinalis and H. perforatum found beneficial effects comparable to amitriptyline 75-150mg/day in depression over a 6 week treatment period. A double-blind, multicentre trial of combination V. officinalis (containing 0.9 – 1.8 dried root/day) and H. perforatum (containing 0.45-0.9 mg TH/day) showed a comparable reduction in fear and depressive mood to amitriptyline 75-125mg. ⁽¹¹⁾ Dosage: FE 1:2 0.7 – 2mls tds. ⁽¹¹⁾
Turnera diffusa is a nervine trophorestorative used in managing nervousness, anxiety, depression and sexual inadequacy. There are no clinical or pharmacological studies supporting these actions. ⁽¹¹⁾ Dosage: FE 1:2 1 -2mls tds.⁽¹¹⁾
Scutellaria lateriflora is a nervine tonic, mild sedative and antispasmodic traditionally used for nervous excitability, functional cardiac disorders due to nervous causes and “disorders arising from physical or mental overwork”.⁽¹¹⁾ Dosage: FE 1:2 2 - 4.5mls daily.⁽¹¹⁾
Avena sativa is a nervous system trophorestorative used for nervous exhaustion, debility and depression. The seeds have also been attributed with cardiotonic properties.⁽¹¹⁾ In a randomised, placebo controlled trial green oats reduced tobacco use in habitual smokers compared with controls. ⁽¹¹⁾ Dosage: Seed FE 1:1 1 – 2mls tds. Green (straw) FE 1:2 1 – 2mls tds.⁽¹¹⁾
Herbs specifically to address cardiovascular dysfunction:
Most herbs which positively influence cardiac function also have beneficial effects on risk factors such as hyperlipidaemia. Allium sativa has numerous actions beneficial to cardiovascular disease, including lipid lowering, inhibition of platelet aggregation, prolongation of bleeding and clotting time and enhancement of fibrinolysis. ⁽¹⁴⁾ 2 meta-analyses n the 1990’s found reductions in total cholesterol of 9% (using the equivalent of ½ - 1 clove /day) and 12%.⁽¹²⁾ More recent studies have had mixed results, with some also showing reductions in triglycerides and modest reductions in systolic and diastolic BP. ⁽¹²⁾ A double-blind, placebo controlled study found that 800mg of garlic powder/day for 4 weeks caused a significant reduction in platelet aggregation and circulating platelet aggregates.⁽¹²⁾ Spontaneous platelet aggregation was reduced by 56.3%.⁽¹⁴⁾ This effect is likely due to ajoene modification of the platelet membrane structure. ⁽¹²⁾ Another randomised, double-blind placebo controlled 4 year trial assessed the effects of 900mg dried garlic tablets on atherosclerosis. Plaque volume in carotid and femoral arteries measured by serial ultrasound decreased by an average 2.6% in the garlic group compared with an average increase of 15.6% in the placebo group. The authors conclude this suggests a possibly curative rather than merely preventative effect of garlic in atherosclerosis. ⁽¹⁴⁾ The Commission E supports garlic as a support to dietary measures in hyperlipidaemia, and ESCOP (1997) has added indications based on clinical studies for “ prophylaxis of atherosclerosis. Treatment of elevated blood lipid levels insufficiently influenced by diet. Improvement in blood flow in arterial vascular disease.” ⁽¹⁴⁾ Dosage: Fresh bulb 4g/day. Dried powder 600-900mg/day. FE 1:1 4mls/day. ⁽¹⁴⁾
Crataegus spp have been shown to reduce myocardial demands in clinical studies, and also have antioxidant, coronary vasodilatory and cardioprotective activity. The leaves have a more potent antihypertensive effect. ⁽¹²⁾ Crataegus extract and its isolated flavonoids have been shown to inhibit thromboxane A₂ in vitro, thus acting as platelet aggregation inhibitors,⁽¹⁵⁾ but also to stimulate platelet aggregation by enhancing prostacyclin synthesis.⁽¹⁶⁾ Crataegus inhibits the Na+ K+ ATPase in human myocardial cells, increasing intracellular calcium and thus force of contraction. ⁽¹⁶⁾ Unlike most cardioactive medications, Crataegus has been shown, in animal studies, to prolong the myocardial refractory phase, by prolonging the action potential and delaying sodium channel recovery, ⁽¹⁶⁾ which potentially reduces the risk of arrhythmias. ⁽¹⁵⁾ In most animal models standardised Crataegus extracts reduce ischaemia-induced arrhythmias. ⁽¹⁶⁾ Flavonoids, including vitexin and acetyl-vitexin-2”-O-rhamnoside, inhibit phosphodiesterase (PDE) activity in animal and in vitro studies, resulting in vasodilation, increased coronary flow, reduced vascular resistance and increased cardiac contractility and heart rate. Vasodilation may also be due to PDE inhibition of endothelium-derived nitric oxide. ⁽¹⁶⁾ Dosage: [Mixed parts] FE 1:2 0.5 – 2.5mls tds.⁽¹⁷⁾
Salvia miltiorrhiza is indicated for angina due to its vasodilatory, antiplatelet and cardioprotective effects.⁽¹²⁾ It also has anti-arrhythmic, anti-fibrinolytic, antifibrotic, hypotensive and renal tonic actions, ⁽¹³⁾ and is hypocholesterolaemic and hypoglycaemic. ⁽¹⁸⁾ A water-soluble extract of S. miltiorrhiza was found to exhibit anti-oxidant activity and prevent atherosclerosis in rabbits fed a high cholesterol diet. ⁽¹⁹⁾ S. miltiorrhiza inhibited triol- (an oxysterol) induced aortic endothelial cell apoptosis in a concentration-dependent manner. Oxysterols are responsible for the vascular cell apoptosis induced by oxidised LDL involved in atherogenesis. ⁽¹⁹⁾ Dosage: FE 1:2 1.25 -2.5mls tds. ⁽¹⁷⁾
Coleus forskohlii is an Ayurvedic herb traditionally used for cardiovascular disease, containing the diterpene forskolin. Forskolin activates cyclase, increasing cAMP in cells and producing most of the therapeutic actions.⁽²⁰⁾ Raised cAMP - inhibits platelet activation and degranulation; inhibits mast cell degranulation and histamine release; increases cardiac contractility, relaxes arterial smooth muscle and bronchial smooth muscle; increases insulin and thyroid hormone release and increases lipolysis. Forskolin antagonises PAF by interfering with receptor binding. ⁽²⁰⁾ Dosage: FE 1:1 2 – 4.5mls tds.⁽¹⁷⁾
Terminalia arjuna bark has been used in the treatment of CAD, CCF, angina and hypercholesterolaemia. An open study found a 50% reduction in anginal episodes and a significant reduction in systolic BP in patients with stable angina, but no effect in patients with unstable angina after 3 months treatment. Both groups showed improved left ventricular (LV) ejection fraction.⁽¹⁵⁾ In patients with severe refractory cardiac failure (NYHA Class 1V) treated with T. Arjuna while continuing standard drug treatment, there was improvement in symptoms (dyspnoea, fatigue, oedema) and echocardiographic improvement in stroke volume and LV ejection fraction. After 4 months treatment with T.Arjuna, 9 patients had improved to NYHA Class 11, and 3 to Class 111. ⁽¹⁵⁾ Animal studies show a significant, dose-dependent reduction in TC and LDL compared with controls, although the high dose (100mg/kg and 500mg/kg) makes such results unlikely in humans taking relatively smaller doses.⁽¹⁵⁾ Dosage: FE 1:2 0.75 – 2.25mls tds.⁽¹⁷⁾
Dietary interventions are essential for risk factor modification. Modest salt restriction has been shown to reduce BP in double-blind studies. High potassium and magnesium salt reduces BP, and fish oil 6g/day had a mild BP lowering effect.⁽¹²⁾ A diet rich in fruit and vegetables and low fat dairy products and lactovegetarian diet both reduce BP in trials.⁽¹²⁾ Reducing saturated fats and alcohol and increasing consumption of oily fish, fibre, legumes oats and rice can be beneficial for hyperlipidaemia.⁽¹²⁾ Supplemental Omega 3 (such as maxEPA) 3000-4000mg/day, magnesium 300-600mg/day and calcium 500-1000mg/day, Natural Vit E (mixed tocopherols) 250-500 iu/day (if not on low dose aspirin) Co-enzyme Q10, 10-50mg/day ( especially if taking statin drugs) and chromium picolinate= 50mg elemental chromium tds. Green tea for its antioxidant effects and Tilia tea for sedative and hypotensive effects. ⁽²¹⁾

Psychosocial factors contribute both directly and indirectly to the development and promotion of CHD. Apart from direct atherogenic effects they also contribute to maintenance of unhealthy behaviours e.g. smoking and poor diet and further as a barrier to lifestyle modification strategies.⁽⁸⁾ Amelioration of behavioral risk factors may also promote psychosocial wellbeing – exercise improves functional capacity and may improve symptoms of depression.⁽⁸⁾ Animal studies have shown that while exposure to chronic stress impairs endothelium-mediated dilation of atherosclerotic iliac arteries in monkeys fed a high fat diet, its removal tends to reverse this process. This may explain the mechanism by which behavioural interventions reduce the incidence of cardiac events. ⁽⁸⁾

A meta-analysis of more than 20 controlled trials utilising a variety of endpoints evaluating the impact of psychosocial treatments among cardiac patients found that those receiving psychosocial treatments showed greater reductions in psychological distress, blood pressure, heart rate and cholesterol than controls.⁽⁵⁾ In the half of these studies containing morbidity and mortality data, those not receiving psychosocial treatments showed greater mortality and cardiac recurrence rates during the first 2 years follow up. More recent studies have given both positive and negative results. ⁽⁵⁾
An uncontrolled study of a yoga based 10 day lifestyle intervention on biochemical risk factors for cardiovascular disease and diabetes in 98 subjects showed beneficial metabolic effects. Fasting blood glucose, TC, LDL, VLDL and TGs were significantly lower, and HDL significantly higher on completion of the 10 day course. Changes were more marked in those with hyperglycaemia or hypercholesterolaemia. ⁽²²⁾
Regular exercise training reduces cardiovascular disease risk. Studies support the hypothesis that exercise improves vascular endothelial function, probably by improved nitric oxide bioavailability from increased synthesis and reduced oxidative stress- mediated destruction. ⁽²³⁾

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