The role of chronic psychosocial stress in pathophysiology of cardiovascular diseases has been presented as a first hypothesis. The second hypothesis is derived in which same pathophysiologic processes are implicated in the development of several diseases as a result of micro vascular circulation involvement.
Once chronic psychosocial stress sets in chronic inflammation which is global in reach, the question arises why is the inflammation not present in every tissue with same severity. This has been observed in macro vascular diseases that, some arterial segments are more susceptible than others and some organs are more susceptible than others in case of micro vascular diseases. This may be explained by the fact that some tissues may have very high concentration of receptors ie brain tissue s, hypothalamus, hippocampus and amygdala and prefrontal cortex have very high concentration of corticosteroid receptors, similarly renal parenchyma has dense sympathetic innervation.
The stress response may be of variable severity depending on the level of stress an individual is exposed to and / or magnitude of appraisal.
Low level chronic stress generates mild stress response, low grade inflammation causing mild allostatic load as seen in ageing. Therefore in ageing low level chronic inflammation as a result of ox LDL particles causes slow piece meal tissue damage (Figure 3).
This results in increased incidence of hypertension, diabetes, chronic kidney disease, Alzheimer’s disease, osteoporosis, osteoarthritis, coronary artery disease, atrial fibrillation, congestive heart failure
from non-ischemic cardiomyopathy, cataracts and so on.
The chronic moderate level of psychosocial stress generates stress response of higher intensity resulting in accelerated systemic inflammation. There is increased delivery of lipoproteins including LDL across the inflamed, permeable endothelial cells to the macro and micro vascular circulation, which causes more rapid progression of atherosclerosis and tissue damage in the organs affected. This results in more rapid progression of the diseases; hence there is progression of atherosclerosis in macro circulation and more tissue damage in micro vascular territories, resulting in progressive loss of function, more requirement of insulin in diabetes, more thyroxin replacement in thyroid disease and so on.
At this point if there is a change in the level of stress to higher intensity, a more robust stress response will be generated, resulting in amplification of HPA and SAM axes, which will result in rapidly progressive inflammation. This will in case of atherosclerosis in coronary arteries result in rapid expansion of soft plaque extending towards intima, rupture, increased procoagulant state, platelet activation, clinically causing acute coronary syndrome, which may progress to acute myocardial infarction. The adaptive immunity will take several days to begin its effect.
In case of organs sub served by microcirculation i.e. pancreas, thyroid gland, kidney and brain tissues this may result in accelerated damage and loss of function.
Once adaptive immune response begins, the healing process starts, inflammation begins to resolve and fibrosis develops until the next episode of stress related relapse. In case of macro vascular disease due to focal disease and total occlusion, there will be loss of tissue in segmental manner such as myocardial infarction in territory of epicardial artery, stroke or peripheral arterial occlusion but in micro vascular disease there can be extensive diffuse loss of tissue, resulting in serious consequences.
The study quoted in section of stress, published in American Journal of Psychiatry.
Emphasizes that individuals who are already suffering from major depression, which is a disease due to systemic inflammation from chronic stress, associated with elevated markers of inflammation (i.e. IL-6 performed in this case). Acute stress has resulted in mounting another stress response and amplifying the activation of HPA and SAM axes, triggering further inflammation (Figure 4).
Cardiovascular disease which is a common comorbid condition with clinical depression or without clinical depression will demonstrate a similar acute response on preexisting moderate atherosclerotic process which might have been clinically quiescent or stable. This may transform into acute coronary syndrome.
Most of the macro vascular diseases and micro vascular diseases lend themselves to diagnosis once clinically manifested and may be detected by routine testing as screening measures. Hence diabetes can be diagnosed by blood sugar assays, CKD by albuminuria and e GFR estimation, Thyroid disorders by thyroid function tests, Fatty liver by liver function test abnormalities and ultrasound, retinopathy and cataracts by eye exam, COPD by pulmonary function tests, Pulmonary hypertension by echocardiogram, systemic hypertension by clinical examination, coronary artery disease by stress testing, CAC and coronary angiography, and carotid disease by carotid ultrasound.
If these tests are abnormal it indicates that disease process is already present and we are dealing with secondary prevention. The interventions initiated as a result have been focused largely on symptomatic management as seen in articles on COPD and diabetes presented in earlier sections and disease process continues to progress until it reaches end stage with complete tissue damage. The same is the case in osteoarthritis an thyroid disorders. This eventually results in the need for replacement therapy, i.e. Thyroxin in thyroid disorder, dialysis /renal transplant in CKD, insulin in diabetes, Heart transplant in non-ischemic cardiomyopathy, liver transplant in advance liver disease from fatty liver and total hip and knee replacement in end stage osteoarthritis, and aortic valve replacement in aortic stenosis.
It is of more serious consequences in central nervous system diseases especially small vessel diseases such as Alzheimer disease, multiple sclerosis, Parkinson’s disease, chronic anxiety disorders, depression and schizophrenia. These conditions do not lend themselves to objective laboratory evaluations, until they present clinically which result in less satisfactory outcomes as cortical necrosis may have already ensued.
It is important to outline ways to ensure primary prevention of all these diseases resulting from psychosocial stress.
As far as risk factors are concerned, most of the conventional risk factors are, indeed manifestation of various organs involvement presenting at different time frames in an individual i.e. diabetes and hypertension.
Hyperlipidemia / Dyslipidemia
: LDL –C is the key player in the process of inflammation as seen in atherosclerosis. Although elevated serum levels signify increased risk of CVD the benefits of LDL lowering have been demonstrated in any range in Jupiter Trial for primary prevention and HPS (Heart Protection Study) for secondary prevention [48
]. It is the influx of LDL particles on continuous basis across the endothelium into arterial wall which results in ox LDL formation and inflammation, irrespective of LDL levels in circulation.
Out of emerging risk factors CAC and CIMT are disease markers as these demonstrate the presence of disease process, which predicts future events and their presence can raise the concern for this process to be also present in other organs sub served by microcirculation. ABI reflects the severity of stenosis, as it predicts future events if < 1.1 or > 1.4 but does not have the ability to demonstrate a transition in increased biologic activity of the atherosclerotic process.
hs-CRP if elevated, reflects one of the steps in the inflammation process if no other etiologies are contributing to its elevation such as infection or cancer, provided there is no significant liver disease which will disqualify it from predicting the disease activity. It is a disease marker rather than a risk factor. It can predict the severity of inflammatory process by its rising levels, which may fall with resolution of inflammation. As seen CRP is not specific to cardiovascular diseases / macro vascular diseases but demonstrates this behavior in all the tissues undergoing inflammation as a result of psychosocial stress, ie pancreas in diabetes, renal parenchyma in CKD and thyroid inflammation in thyroid and in psychiatric diseases.
The definite modifiable risk factors are ageing, smoking, atherogenic diet / hyperlipidemia and physical inactivity.
Ageing has been discussed already. It has low grade inflammation, which accentuates the inflammation caused by chronic psychosocial stress.
As far as diet as a risk factor is concerned, atherogenic diet with high saturated fat is a risk factor for these vascular diseases. Body is continuously mobilizing free fatty acids due to chronic stress related systemic inflammation and dietary saturated fat keeps adding the fuel for ox LDL production in the arterial walls. Restricting dietary saturated fat decreases this burden and hence contributes in decreasing the inflammation.
Decreased physical activity is a risk factor for CVDs. Promoting physical activity decreases the risk, most importantly by increase in fat metabolism with activity and exercise thereby decreasing LDL-C availability for conversion to ox LDL.
Cigarette smoking is a risk factor for CVDs. Nicotine is a strong activator of the HPA axis. Low grade inflammation and increased inflammatory markers such as interleukin-6 and CRP are associated with cigarette smoking . As reviewed in earlier section the pathophysiology is similar in individuals with cigarette smoking on vasculature i.e. inflammation and atherosclerosis as seen in typical CVDs associated with dyslipidemias. Thus cigarette smoking accentuates the effects of inflammation by dyslipidemias in similar ways as ageing process.