If any infectious agent is involved in Atherogenisis, the Herpes virus, Cytomegalovirus appears the front runner in most disease I believe. A Herpes virus was implicated in Marek’s Lymphoma of chickens.These chickens developed atheroma like lesions with this infection. Cholesterol crystals and esters were found adjacent to the lesions. The chickens could be ‘immunised’against the lymphoma and atheroma like lesions. Almost since organ transplants commenced, Cytomegalovirus infection has been associated with the organ rejection. In the transplant rejected heart, the virus fragments are found in ‘atheroma’ like lesions of the coronary arteries. Cardiac transplant patients can experience angina from these lesions, but Cytomegalovirus also plays a part in the rejection process, possible by its ability to lie dormant and effect artery and myocardial inflammation. Lesions have been found in the coronary arteries of childrem infected with Measles and Coxsackie virus, described as ‘atheroma’ like lesions.These infants, children were not smokers, had no hypertension or were obese.Same with the extensive studies of the young with fatty streak and fibrous plaques, they had none of the conventional risk factors.
Early in the 1970’s most of us in medicine had been drowned in the dogma of the Lipid Hypothesis from the US, but were aware in our own practice, that you did not have to have the conventional risk factors to sustain a heart attack or symptoms of partial obstruction.It was very difficult to shift serum cholesterol levels with diet alone. Keys a stalwart of the Lipid Hypothesis knew that from his own nutrition studies. It was estimated at that time that 50% of patients with symptomatic AVD did not have conventional risk factors. What else was contributing?Most of us in NZ were aware of Ian Prior’s Tokelau Study, where this Island cohort consumed 35-50% of their daily calories from the ‘coconut meat’, consisting of saturated fats largley, with none of our degenerative diseases.They emigrated to NZ, stopped the fat consumption and contracted OWOB, CHD, DM, and hypertension!!Except for Gary Taubes, the Americans ignored the study. They ignored the Lyon Heart study for 12 years, with its demonstration of marked mortality advantage by diet!! They ignored Doll’s and Yudkin’s skillful argument against Key’s medically simplistic concept of saturated fat and cholesterol causing atheroma, CHD.
The US then ignored Key’s confession that he was wrong linking saturated fat to CHD and that his 7 Countries data on review, indicated sucrose sugar and processed CHO were the culprits. The issue was then taken over by interested pressure groups, politics, agriculture, commerce, lawyers via the McGovern Committee and the US was advised officially, to avoid animal fat and cholesterol!! Medicine was allowed to advise, but no decision maker had graduated in medicine!! This Monty Python skit is very similar to the acceptance of WOMD by the US and UK on the basis of very elementary evidence of an unfinished PhD student’s thesis.That arguably led to a massive mortality in the ME.The US decision on nutrition has led to arguably a larger morbidity and mortality catastrophe in the affluent world.Fortunately Chowardry from the UK and Krauss from the US, have finally put us on the right track and ‘officially’ (I think) put the Lipid Hypothesis in the cemetry. It will take a while; official bodies are reluctantly cleansing themselves slowly.
While this confusion washed over ‘Western Medicine’, no study had shown that anyone who consumed saturated fat and cholesterol contracted CHD!Population studies with defective reported nutrition at best squeezed small association numbers.No cause and effect! No one since the 1970’s looked at processed CHO and sugar or more recently corn fructose. Why? Studies of carnivore Inuit in North America and Scandinavia showed no evidence of atheroma. Vetinarians knew the carnivores they were working with did not contract atheroma!! Every ‘health’ body on earth were advising to avoid ‘fats’, then bad fats, there are good fats apparently. But in the vast volumes of studies, no one had demonstrated how the atheroma lesion arose, commenced!!Having two steaks, three sausages, four bacon slithers, three eggs, with four cream laden coffees for breakfast, as some of my cattle grazier patients did, with angiographically absent CHD, was enlightening. In the same area the Indigenous Australian was dying 20 years earlier with mainly CHD, that is highly unlikely to have seen a breakfast like that in a life time.Debates with some Australian cardiology colleagues was very un-enlightening.The Indigenous cardiac patients I treated in Central Queensland were not consuming much animal fat or cholesterol.I had our hospital dietitian confirm that. This dilemma for me biologically and and professionally was the genisis of our Central Queensland Indigenous Cardiac Risk Factor Study.
Meanwhile a thoughtful group of researchers continued the investigation for an initiating agent, and infectious agent, to attempt to link solid data together.The spectrum of virus and bacterial agents had been reduced to Cytomegalovirus, HSV1 and HSV2, Coxsackie virus B4, Helicobactor Pylori and Chlamydia pneumonia.There is considerable reputable evidence from these studies suggesting they were present when studied, but may only be ‘associated’, on lookers, innocent bystanders, not provable initiators, participators.The infective agent intact is never found, just identifiable fragments, either in the atheroma lesion, adjacent in artery tissue, removed from the coronary arteries, and the Aorta. The Herpes viruses with CMV often had cholesterol crystals and Cholesterol ester crystals adjacent to the virus fragments. CMV has been found to synthesis cholesterol crystals in endothelial and vessel smooth muscle cells in situ.(in lab)Antibodies to these agents were found in those with proven CHD. Unproven patients were more likely to have CHD if there was evidence of inflammation with a raised CRP or just very high CMV titres that we found amongst the Indigenous Australians we studied. We measured the CRP but because there was considerable attendant other infections and peridontal disease, we could not interpret its significance. Patients with CMV antibodies had thickened internal media of the carotid arteries, a non invasive indicator of atheroma. Patients with proven CHD had a poorer prognosis if they had high CMV titres and elevated CRP. The incidence of restenosis after angioplasty is significantly higher in those who are CMV positive. Stents of various kinds have helped alleviate this issue.CMV DNA and other fragments are found at artery bifurcations, where atheroma and early lesions are found predominantly.
We have no satisfactory evidence as yet that any infectious agent is involved in any stage of the evolution of atheroma lesions in homosapiens. I believe Fabricant satisfied Koch’s postulates with the Herpes virus, Marek’s virus, in the chicken.Infecting the host with the virus, producing very similar atheroma lesions and adjacent cholesterol crystals, then re-infecting the host after vaccination, that prevented the lesions arising, is a tidy piece of patho-biology.BUT, it was in a chicken!!
In our Indigenous study of 803 adults and 72 children, CMV IgG antibody >15Au/ml was 97% and 96% seropositive and above 250Au/ml 66% and 61% seropositive. So this cohort of adults and children under 15 years were almost universally infected and near two thirds had very high titres.Elevated CRP was very common, but too difficult to interpret because of other infective agents. At this stage it is not clear that other sources of inflammation could act as a template with CMV for atheroma. My professional experience of periodontal and dental disease with myocardial infarction is suggestive and there have been published data supporting this association. Other inflammatory pathologies such as Rheumatoid Arthritis and Inflammatory Bowel Disease, have increased CHD.
Review of other CMV seropositivity studies, had a pattern of earlier and more marked positivity in the lower socio-economic areas and nations. Australian data saw levels start to increase from 40% at 15 years and steadily with age up to 80-90%. One could argue this seropositivity shadowed atheroma lesions numerically and clinically, but this was not part of my hypothesis.
There was considerable interest and study numbers published by the early 1970’s, investigating the presence of CMV antibodies and antigens with atheroma lesions and arteries of those with atheroma, that persuaded me to assess the same in a cohort of Indigenous Australians, who died 20 years prematurely of CHD. I will present all the data from this study in a future blog.The concept was supported and reviewed by cardiology colleagues who I had worked for at Auckland Medical School. Prof John Neutze, Prof. Sir John Scott and Prof Norman Sharpe. My thesis was that it was possible that CMV could be the ‘injury factor’by infecting the artery endothelium and medium, giving rise to fatty streak and fibrous plaque lesions, potentially in utero as the fetus, infant child and through life. Seropositivity in the mother, infant indicated CMV infection was common in both and a potential initiator of lesions. My thesis was that with time, life nutrition and life practices would determine whether and how these lesions evolved. Remember the Nigerian children with the early lesions, who lived in a population of adults who did not experience symptomatic CHD!
We presented the results of the study to arguably the most prestigious Cardiology publication on the planet, Circulation.The editors and reviewers there all said the concept and results were’ interesting’ and made suggestions how by having a control group, we would make the thesis and results more credible.This would have required near $150-200,000 in funds which was impossible for us. We were a voluntary group and Tom Lynch offered the laboratory work at his expense.Different aspects of the study were presented at Physician meetings, GP meetings, Cardiology meetings in Western Australia, Northern Territory, Qld., NSW and NZ. I included the study results in my publication, Stone Agers in the Wrong Lane.
Two important features in the results confounded conventional thinking at the time.The concept of infection playing a part and that in this population ‘riddled’ with CHD, that their mean total cholesterol and LDL were within normal limits. Three hundred and seventy six adults had raised TG’s and depressed HDL, that satisfied what we describe today as Atherogenic Dyslipidemia, arguably the basis of mature atheroma lesions, that produces small dense LDL. We had an explanation and I treated the 376 with fibrate medication. Atherogenic Dyslipidemia had limited support in cardiology as a culprit entity when we collated our results in 1996, but it is nowaccepted. Part of the treatmen program is removal of processed CHO and sugar.
I reviewed a large number of Indigenous Australian diabetic studies of the past and found their lipid results were consistent with Atherogenic Dyslipidemia, that had not had any accepted cardiological credence at that time!!In our Indigenous Australian Study I would say with smoking, it was a major contributor to the prevelance and prematurity of their CHD. It was at this time the German PROCAM Study was published, suggesting the TG/HDL ratio was an important contributor to CHD.