- Summary
-
- Once upon a time, by the turn of the last century, flying
in the face of over a hundred years of research and clinical observation
to the contrary, medicine abandoned the link between infection and atherosclerotic
heart disease; not because it was ever proven wrong, but because it did
not fit in with the trends of a medical establishment convinced that chronic
disease such as heart disease must be multifactorial, degenerative and
non-infectious.
-
- Yet it was the very inability of 'established' risk factors
such as hypercholesterolemia, hypertension and smoking to fully explain
the incidence and trends in cardiovascular disease that resulted in historically
repeated calls to search out an infectious cause, a search that began more
than a century ago.
-
- Today, half of US heart attack victims have acceptable
cholesterol levels and 25% or more have none of the "risk factors"
associated with heart disease, including smoking, high blood pressure or
obesity, most of which are not inconsistent with being caused by infection
[7,56].
-
- Even the traditionalist's 2003 assault in JAMA (Journal
of the American Medical Association) to 'debunk' what they call the "50%
risk factor myth" [20] fell woefully short under scrutiny. In one
group 30% died of heart disease with a cholesterol of at least 240 mg/dl,
a condition which also existed in 21% who did not die during the same period.
And the overlap was obvious throughout the so-called risk categories. Under
such scrutiny, lead author Greenland conceded that if obesity, inactivity
and elevated cholesterol in the elderly are included, just about everyone
has a risk factor and he likened the dilemma of people who do or do not
wind up with heart disease akin to the susceptibility of people who are
exposed and at one time contract tuberculosis, but do not presently have
active disease.
-
- In Infections and Atherosclerosis: New Clues from an
old Hypothesis? Nieto stressed the need to extend the possible role of
infectious agents beyond the three infections which have in recent years
been the focus of research: Cytomegalovirus (CMV), Chlamydia pneumonia,
and Helicobactor pylori [39].
-
- Mycobacterial disease shares interesting connections
to heart disease. Not only is tuberculosis the only microorganism to depend
on cholesterol for its pathogenesis but CDC maps for cardiovascular disease
bear a striking match to those of State and regional TB case rates. Why
should this be?
-
- Ellis, Hektoen, Osler, McCallum, Swartz, Livingston and
Alexander- Jackson all saw clinical and laboratory evidence of a causative
relationship between the TB, its related mycobacteria and heart disease.
And Xu showed that proteins of mycobacterial origin actually led to experimental
atherosclerosis in laboratory animals. Furthermore present day markers
suggested as indicators for heart disease susceptibility such as C-Reactive
Protein (CRP), interleukin-6 and homocysteine are all similarly elevated
in tuberculosis.
-
- Although more than 120 years have passed since its discovery,
Mycobacterium tuberculosis is still the leading cause of death globally
due to a single infectious agent (Dye et al. 1999). This high mortality
rate exists in spite of the fact that for over 50 years tuberculosis has
been a preventable, diagnosable, and treatable disease.
-
- It therefore behooves us to explore the historical, clinical,
and pathological link between heart disease, typical, and atypical tuberculosis.
-
-
- Introduction
-
- Attached at the hip, the American Heart Association (AHA),
first to push towards medical heart specialization, was actually an offshoot
of The National Tuberculosis Association, without whose money and help
it would never have survived. In one of its first Bulletins, the AHA (American
Heart Association) came up with a long list of the similarities between
tuberculosis and heart disease [2], a view supported by Ellis in The New
England Journal of Medicine half a century later [15]. In a 'name that
disease' Ellis fleshes-out a medical condition who's mortality rate was
200 to 300 per 100,000, was widespread, and by whom many in their prime
were struck down. Treatment was only partially effective. Doctors recommended
diet and exercise. Special hospitals were built for it. In a tough decision,
Ellis's readers only recognized the disease as TB when he said it struck
75 years ago, the white plague of the 20th century, for the mortality rate
for ischemic heart disease (IHD) at the time of Ellis's writing was also
200 to 300 persons per 100,000.
-
- Yet it was not until after WWII that the subject was
pursued in earnest, and by two women, one of them the first female medical
resident in New York. Sometime in 1965, Rutger's investigators Virginia
Livingston, M.D. and Eleanor Alexander-Jackson PhD, fueled by Fleet and
Kerr Grants, working with sterile, post catastrophic heart attack coronary
artery specimens, established low-grade tubercular infection, staining
'acid-fast' (not decolorized with acid-alcohol) in all ischemic heart disease
specimens [32].
-
- Even in stained slides of the heart muscle itself, Livingston
documented small, acid-fast globoidal tubercular bodies which soon appeared
to enter into a gradual state of digestion (Ibid).
-
- In 1986, Hektoen, studying how tuberculosis attacked
blood vessels of the cardiovascular system, saw the blood born microbes
implanting themselves in cardiovascular walls. Eventually these microbes
would penetrate all layers of the arterial wall, including its muscular
coat. The offshoot led, often, to the degeneration of whole arterial segments.[23].
Since tubercular attack came from the inside of the vascular wall outwards,
Hektoen often spotted the initial attack as involving the intimal or adventitial
layers.
-
- Even William Osler, arguably the greatest physician since
Hippocrates, and to this day an icon for accurate clinical judgment, made
clear that arteriosclerosis was frequently associated with tuberculosis
[42].
-
- MacCallum's investigation [34] recognized that of all
the infectious causes of heart disease, only one, tuberculosis, caused
arteriosclerosis. At autopsy, he cited 101 cases of advanced tuberculosis.
Of these cases, there were 49 cases in children in the first decade of
life - none of which showed arterial changes. Even in the second, third
and fourth decades there were only 11 autopsies who died of TB with moderate
cardiovascular sclerosis; while 13 showed nothing. But by the fifth, sixth,
seventh and eighth decades, true to current coronary timetables, there
were only 2 autopsies with normal arteries and 26 with TB arteriosclerosis
(Ibid).
-
- By 1972, pathologist Phillip Schwartz, once a student
of Loffler, became aware that the 'lardaceous', waxy degeneration misnamed
by Virchow as starch-like "amyloid" (starch was called amylum),
showed that amyloid (starch-like) degeneration occurred more frequently
in elderly cardiovascular systems than hardening and atheromatous lesions
of their arteries. But along with this, he noticed that such amyloid degeneration,
upon autopsy, usually revealed signs of lingering pulmonary and lymph node
tuberculosis [59].
-
- Classic thought regarding atherosclerosis never was terribly
convincing. It supposedly begins with the appearance of cholesterol and
fat-laden macrophages (white blood cells) called "foam cells".
The fact that some of these macrophages died, just added to the debris.
Macrophages died, tradition dictated, because they could not eliminate
cholesterol the way they got rid of bacteria. They simply stuffed themselves
compulsively with more and more cholesterol, converting into the large
'foam cells' that filled the plaques of advanced atherosclerosis. Macrophages,
then, said orthodoxy, literally ate themselves to death at our cardiac
blood vessels expense.
-
- But there were obvious flaws to such thinking. First,
unlike with other microbes, human macrophages were not that good at eliminating
germs like tuberculosis, which in turn kills many of them. Second cholesterol
by itself, normally the most abundant steroid in man, was on the rise in
Japanese blood during the very decade (19801989) when the incidence
of coronary heart disease was on its way down [40]. In the meantime, in
the US, half the people who had a heart attack had acceptable cholesterol
levels, including its HDL and LDL fractions.
-
- Although cholesterol thus seemed an imperfect criterion
for determining coronary heart disease, its intimate interaction with TB
and the mycobacteria presented extremely interesting coincidental findings.
Not only were virulent tuberculosis and the mycobacteria the only pathogens
that actually relied upon cholesterol to enter the body's white blood cells
or macrophages [17], but, it was the Mycobacteria that in addition were
able to produce [31], esterify [29], take up, modify, accumulate [4], and
promote the deposition of and release [26] of cholesterol.
-
- Orthodox thought then pronounced that smooth muscle cells
of the cardiovascular system somehow responded to fat proliferation under
the influence of certain platelet factors, which are otherwise supposed
to function exclusively in clotting, to eventually cause inflammation.
But, to many, it seemed fuzzy logic that inflammation should occur from
fat proliferation to begin with. Livingston and Alexander- Jackson's meticulous
work clarified this, finding in all specimens, an infectious agent behind
that inflammation and fat propagation [32]. But unfortunately, they worked
as "outsiders" at a time when women doctors and scientists weren't
fully accepted.
-
- Others Notice
-
- A 1973 watershed study by Benditt and Benditt reported
that cells found in artherogenic plague had a monoclonal origin, that is,
they were derived from a single cell population [6]. Confirmatory studies
[43,44] prompted the revival and legitimization of a search for an infectious
cause. But by concluding that such monoclonal origins were caused by "Chemical
mutagens or viruses or both" Benditt and Benditt's agenda blindsided
a third major possibility- tuberculosis and the mycobacteria, each capable
of churning out its own monoclonal enzymes, once systemic [13,45].
-
- It was in no small part as a result of Benditt's study,
much of the world's scientific and medical community focused on an extremely
limited role for tuberculosis and the mycobacteria in heart disease, and
at the same time seemed to purposefully marginalize studies that kept seeping
into the Index Medicus. For example, in the same year Livingston pursued
her heart work at Rutgers, the Russians, unhindered by the American brand
of politicized medicine, began proving the link between tuberculosis, atherosclerosis
and heart disease [8,25,27,28].
-
- Which Infection?
-
- Since a 1988 report of raised antibodies against Chlamydia
pneumoniae in patients with heart disease appeared, it was hoped that the
microbe might be behind atherosclerosis [21,41,50]. Hurting this hypothesis
was the low incidence of atherosclerosis in the tropics despite chlamydia's
high frequency there [52].
-
- Also Loehe and Bittman concluded that although Chlamydia,
on occasions, might be present, it was not a causative factor [33] because
there was no correlation between the severity or extent of atherosclerosis
and the involvement of chlamydial infection at the same site. This report
was in concert with Thomas [57] and Gibbs [19]. Combined, these studies
seemed to ask: What if Chlamydia pneumoniae was just a passenger bacteria,
a friendly bystander? And when, in 1995, MC Sutter's editorial Lessons
For Atherosclerotic Research From Tuberculosis And Peptic Ulcer, warned
we might be overlooking the role of a microorganism in atherosclerosis,
he did not have chlamydia specifically in mind [53]. Nevertheless, statistics
showed that people who used a lot of antibiotics had less heart attacks,
and so by 2000 the CDC found that 14% of the cardiologists in Alaska and
West Virginia treated heart patients with antibiotics for angina, heart
attacks, angioplasty or after by-pass surgery.
-
- And certain antibiotics did seem to work, but the question
was their efficacy based upon their anti-Chlamydial activity? Azithromycin,
for example has a documented, if moderate activity against certain mycobacteria
as well.
-
- Something More conclusive
-
- As the millennium approached, something much more irrefutable
was happening. Xu had previously been found that injecting rabbits with
normal cholesterol with protein from TB resulted in atherosclerotic changes
[61]. Now George and Shoenfeld were implicating these very same proteins
in not only the origin of the atherosclerosis in cardiovascular blood vessels
but of fatty streak formation there as well [18]. In the meantime, Mukherjee
and De Benedictis showed that an increase in antibodies against such tubercular
proteins somehow already in the body was actually associated with re-stenosis
or future closure of coronary vessels [37]. By 2000, it became obvious
to Afek that mice injected with high doses of such tuberculoproteins developed
significantly larger areas of atherosclerosis despite the fact that their
diet was devoid of high fat content [1]. Revisiting this subject, Xu, also
using the same tubercular protein (HSP-65), proved the same thing in New
Zealand white rabbits [62]. In Xu's study, such rabbits with normal serum
cholesterol injected with the TB preparation led to the formation of all
the classic features of arteriosclerosis in humans - the inflammatory cell
accumulation and the smooth cell proliferation (Ibid) that Livingston and
Alexander-Jackson had decades ago attributed to tuberculosis.
-
- In fact, the only finding missing from Xu's study using
normal cholesterolemic animals were "foam cells": tissue macrophages
in which tuberculosis not only lived but thrived in, capable of ingesting
material that dissolved during tissue preparation, especially lipids. However,
this missing piece of the puzzle was soon remedied when in addition to
tuberculous proteins his animals were given a cholesterol rich diet, at
which point Xu saw all the lesions found in classic human heart disease,
including foam cells. Obviously, tuberculoproteins were overwhelming the
systems macrophages, not allowing them to get rid of ingested fat.
-
- When Man Thinks - Heaven Laughs
-
- There was also incriminating epidemiologic evidence.
The higher incidence of coronary heart disease in young males had a remarkable
parallel in bacterial diseases such as TB [52]. And the association between
low socioeconomic status and coronary disease found common ground with
the incidence of tuberculosis.
-
- The Centers for Disease Control and Prevention (CDC)
maps for the total cardiovascular disease and death rates across the country
[10] bore a conspicuous similarity to state and regional incidence for
CDC TB case rates maps in the United States [9]. In addition, the statins,
among the most popular drugs in America (Lipitor, Lescol), though inhibitors
of Coenzyme-A compound (HMG-CoA or 3-hydroxy-3-methylglutaryl CoA reductase)
and as such lowered serum cholesterol levels, did much more.
-
- Specifically, when macrophages were depleted of cholesterol
by such pharmacological treatment, mycobacteria such as tuberculosis could
not enter the macrophage TB liked to house in, thrive in and depend upon
[17]. Furthermore, this block of macrophage uptake with cholesterol depletion
was specific only for tuberculosis and the mycobacteria and no other pathogen.
In other words, cholesterol played a crucial role in tuberculosis's establishment
of intracellular infection leading both to the long term survival of the
germ and the death of 1.9 million people a year.
-
- The large British heart protection study took many by
surprise when they learned that even lowering "normal" cholesterol
levels lowered heart disease risk [12]. This led again to speculation that
there must be some other risk factor involved besides cholesterol itself.
Lead- author Collins countered that the reason for his study's finding
was that even what we call "normal" cholesterol values are too
high, but it is just as easily posited that the lower the blood cholesterol
the less likely there is to be chronic mycobacterial infection which would
also be of benefit derived from lower than normal cholesterol levels.
-
- It is hardly a coincidence that studies have shown that
statins, which indirectly decrease mycobacterial disease, also lower C-reactive
protein (CRP). C-reactive protein is an age-old, non-specific protein,
first identified in 1930, and then found in the serum of various persons
with certain inflammatory and degenerative diseases [48]. Recently an elevated
CRP has been touted as an excellent marker for the approximately 25 million
US patients that have none of the risk factors associated with heart disease,
yet are at risk for a heart attack. However CRP and elevated sedimentation
rate have long been excellent markers of active tuberculosis [22], CRP
being present at all times when erythrocyte sedimentation rate (ESR) is
elevated but returning to normal faster than ESR as tuberculosis, once
treated, becomes inactive. Indeed CRP is a sensitive indicator of the activity
of tuberculosis [5].
-
- Researchers have even tried to neatly tie in excessive
weight and its fat cells to indirectly increasing C-reactive protein (CRP)
by dumping interleukin-6 (IL-6) into the blood, which, in turn supposedly
promotes an inflammatory response, key to signaling the liver, and perhaps
the arterial walls themselves, to churn out more CRP. But again, and significantly,
higher levels of interleukin-6 are consistently found in either the lung
secretions [58] or serum [54] where TB resides. Russell noted sustained
release of IL-6 repeatedly issued from human macrophages infected with
TB [49], a defense strategy the microbe uses to possibly create anergic
conditions (conditions with lowered immunity) that prevent macrophages
from killing them.
-
- Others look towards elevated serum levels of homocysteine,
an amino acid also linked as an index of potential heart disease, as the
marker of the future even though a homocysteine marker metaanalysis appeared
in JAMA, concluding that elevated homocysteine was at most a modest independent
predictor of Ischemic Heart Disease (IHD) in healthy populations [24].
Nevertheless homocysteine, it is claimed by some, although not deposited
in blood vessel walls like cholesterol, can damage the inside lining of
these vessels and make platelets more likely to clot, the scenario which
supposedly leads to stroke or heart attacks.
-
- Homocysteine is formed from another amino acid in our
diets, methionine. But methionine is also the protein that M. tuberculosis
brings systemically into its host to initiate its own protein synthesis
[11]. Although Homocysteine can be turned back into methionine and its
level lowered in the blood, this requires two essential cofactors: vitamin
B12 and "folate" or folic acid, both of which can be lowered
in tubercular infection, leading to elevated homocysteine levels [35,46].
-
- Nieto's extensive review concludes that the introduction
of antibiotic therapies in the 1940s and 1950s could have contributed to
the decline of heart disease and heart attacks in the last few decades
[39]. Although the tetracyclines appeared in the 1950s it was only after
the introduction of the macrolides, in particular erythromycin in the 1960s
that the cardiovascular disease mortality curve began to sink. Though it
was hypothesized that such decline was the effect of tetracycline and the
macrolides against Chlamydia pneumonae, many of the atypical mycobacteria
were also sensitive to erythromycin and the tetracycline doxycycline [36].
Also, the antibiotic time-curve Nieto cites excludes the actual introduction
of anti-tubercular antibiotics.
-
- Although erythromycin is very effective against C. pneumoniae,
the microorganism may persist in the respiratory tract despite adequate
blood levels of the antibiotic [51]. There can be no doubt that the availability
of antibiotics lowered the morbidity and mortality of cardiovascular disease.
Netter mentions that tuberculosis, once often associated with cor pulmonale
was less so linked in recent years, probably because of the widespread
use of antibiotics and antimicrobial agents [38].
-
- Conclusion - Runs Silent, Runs Deep
-
- When Nieto stressed the need to extend the possible role
of infectious agents beyond the 3 infections which have in recent years
been the focus of research: namely, Cytomegalovirus (CMV) C. pneumonia
and Helicobactor pylori [39], was he picking Sir William Osler's brain
regarding that arteriosclerosis was frequently associated with tuberculosis?
[42]. Still many ridicule the possibility that microbes might be the agents
of arteriosclerosis. These were the same minds that in another, far gone
era, would have jeered the possibility that syphilis in its late stages
had a special preference for the arteries and could cause devastation of
major cardiovascular vessels. Eventually though, these minds were proven
wrong. But the lessons of syphilis are far-gone or are they?
-
- When by 1982, keynote speaker and then Harvard infectious
disease guru Louis Weinstein addressed the annual session of the American
College of Physicians he mentioned: "We thought initially that the
disease (tuberculosis) was disappearing, but we are now seeing up to 27
different syndromes and extapulmonary forms, etc. It is today's great mimic,
a greater mimic than syphilis ever was"[60].
-
- In Atherosclerosis and Tuberculosis: Are They Both Chronic
Diseases?, after going over the many similarities between tuberculosis
and Chlamydia pneumoniae, Anestad focuses on Norwegian 20th century statistics
in which two things become obvious. First, that until 1945 tuberculosis
was easily the leading cause of infectious death in Norway, surpassing
cardiovascular death at the time. Second, that as the diagnosed cases of
tuberculosis fell from his statistics, cardiovascular disease increased
dramatically until 1975, when its stats too somewhat tapered [3]. At first
glance, these statistics seem unrelated even though they are on the same
bar graph. But are they? Or are we just looking at another example of Weinstein's
reference to occult TB finding an expanded niche in the cardiovascular
system in one of its quests to become "a greater mimic than syphilis
ever was"?
-
- In Tuberculosis In Disguise, Rab and Rahman document
cases of congestive heart failure and IHD (Ischemic Heart Disease) with
chest pain, raised erythocyte sedimentation rate, leukocytosis and inverted
T-waves across the chest leads otherwise indistinguishable from the real
thing, which turned out to be miliary (systemic) tuberculosis [47]. Rab
and Rahman again warned "confusion may occur because tuberculosis
can mimic so many other conditions".
-
- Certainly with tuberculosis and for some time now, we
have a human population affected that dwarfs syphilis in its prime. At
least a staggering 1.7 million around the globe die of tuberculosis each
year, while another 1.9 billion are infected with M. tuberculosis and are
at risk for active disease[14].The World Health Organization (WHO) estimates
that 1/3 of the planet has contracted TB.
-
- It would take such a disease to adequately explain the
scope of cardiovascular disease, which affects about 61 million people,
or almost one-forth of the population in the US alone. Almost 6 million
US hospitalizations each year are due to cardiovascular disease. (www.cdc.gov/nccdphp/aag/aag_cvd.htm)
-
- The linkage of tuberculosis to acute myocardial infarction
and resulting heart attacks is nothing new [16,30,55]; yet serious clinical
trials have never been undertaken. And one is left wondering whether the
present flurry of trials designed to simply label the markers in the blood
that TB and the mycobacteria throw our way is ever really going to quell
the near epidemic cardiovascular disease that is presently in our midst.
-
-
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