Heart disease and atherosclerotic heart disease are generally treated as the same thing and the terms used interchangeably.
Atherosclerotic heart disease (ASHD), also called coronary artery disease and arteriosclerotic heart disease, is heart disease caused by decrease of blood supply due to narrowing of the coronary arteries. It's most dramatic manifestation is sudden death from acute myocardial infarction. ASHD is certainly a major cause of death and morbidity; but it is not the only major cause of heart disease in aged persons.
Morbidity and death from heart failure is very common in the animal world; but atherosclerosis is uncommon. Atherosclerosis appears to only affect herbivores who eat an atherogenic diet. Dogs, cats, tigers and lions can be saturated with fat and cholesterol in their diet; but do not develop atherosclerotic plaques; yet they still can develop heart failure if live to old age. Carnivores have claws and sharp teeth. Humans resemble herbivores; but they like to eat like carnivores.
In the sections that follow, will review studies done on two animals, dogs and mice, that do not have atherosclerosis; but develop age-associated heart disease, similar to age-associated heart failure in humans.
Galen, a Greek physician and philosopher, who lived about 2000 years ago, put forth the idea that aging was not a disease; because everybody got aging and therefore aging was natural. Current dogma fully accepts this notion. Furthermore, traditional dogma states that people who die of natural causes, must die from a specific disease and since aging is not recognized as a disease, nobody can die from aging. In my opinion, this 2000 year old theory is long overdue to be relegated to the dustbin of history.
Another idea is that if something is a disease; then there might be a magic bullet to cure the disease; but if something is a natural process, then there can be no magic bullet.
In the following section, we will review a dog study and two mouse studies in which rapamycin did indeed act like a magic bullet. Short term (10-12 weeks) of rapamycin reversed age-related heart changes; the same pathology seen in humans in heart failure.
The point of this discussion, is that while atherosclerosis, hypertension, and diabetes can all cause heart disease; these is also intrinsic heart disease due to aging.
The focus of this section is intrinsic heart disease caused by aging, hereafter called age-associated cardiomyopathy, a disease not found in traditional textbooks of medicine.
Silvan Urfer, Matt Kaeberlein, 2017, Seattle, Washington.
"In this study, 24 middle-aged healthy dogs received either a placebo or a non-immunosuppressive dose of rapamycin for 10 weeks. All dog received... echocardiography before and after the trial. Our results showed no clinical side-effects in the rapamycin-treated group compared to dogs receiving the placebo. Echocardiography suggested improvement in both diastolic and systolic age-related measures of heart function (E/A ratio, fractional shortening, and ejection fraction) in the rapamycin-treated dogs."
"Age is the single greates risk factor for nearly every major cause of morbidity an mortlity inhumans and their companion animals...Rapamycin is the drug that has shown the most robust and reproducible increase in lifespan and healthspan in laboratory mice.
"Treatment with rapamycin increases lifespan in evolutionarily divergent laboratory-organism including yeast, nematodes, fruit flies and mice. In addition to increasinglifespan, treatment with rapamycin has also been shown to improve a variety of age-associated conditions in mice, including cancer incidence, improving cognitive function, reversing cardiac and immune declines, restoring stem cell function and improving muscle function in aged animals."
We carried out a double-blinded clinical trial to assess dosing, safety and effects of rapamycin treatment for 10 weeks in healthy middle-aged companion dogs. Rapamycin treatment was either 0.05 or 0.1 mg/kg delivered orally 3 times per week.
All dogs were at least 6 years old and weighed 40 pounds. Dogs were very varied group with 12 mixed breed. They varied from 6.8 year old Doberman (lifespan 10-13 years to 10.4 year old Great Dane (life span 8-10 years) to oldest dog, mixed breed, 12.7 years.
8 dogs in control group, 5 in low rapamycin group, 11 in high rapamycin group.
Ejection Fraction (EF) Percent of the end-diastolic left ventricular blood volume that is ejected from the left ventricle during systol.
Fractonal Shortening (FS) Percent by which the left ventricular interior diameter is reduced at peak systole as compared to that of end-diastole.
E/ARatio: Ratio of early-to-late-diastolic velocity of blood flowing from the left atrium into the left ventricle.
Side effects: All clinical pathology blood tests remained normal.
Increased activity 70% (7/10) high rapamycin group and 40% (2/5) low rapamycin group.
"Both the low and high dose rapamycin treatment group showed a trend toward improved fractional sshortening (FS) ejection fraction (EF) and E/A."
"Rapamycin significantly improved both FS as a measure of systolic function and the E/S ratio as a measure of diastolic function in rapamycin-treated dogs when compared to placebo.
Supplemental data showed high dose more effect than low dose.
Over 11 weeks, high rapamycin group showed marked improvement in all 3 measures, placebo group showed a marked deterioration in all 3 meaures and low dose rapamycin generally remained unchanged.
Effect on cardiac function
"Both systolic and diastolic function are know to deteriorate with age in dogs as well as in humans. Among these age-associated changes are reduced stroke volume and cardiac output as signs of systolic (through not necessarily accompaniedby a reduced EF), and a reduced E/A as a sign of diastolic dysfunction."
"There is evidence that rapamycin improves age-related deterioration of cardiac function in laboratory mice. Our study provides the first evidence that rapamycin may partially reverse age-related heart dysfunction in dogs by improving measures of both diastolic and systolic functions...All three outcomes (EF, FS and E/A ratio) showed trends toward improved function following rapamycin treatment and two of them (FS and E/A ratio) reached statistical significance.
"It appears that FS improvement was most prominent in rapamycin-treated dogs with lowever baseline values, while dogs that had higher values at baseline did not improve as much in response to rapamycin." This may suggest that degree of decline already present in each individual will determine degree of improvement. (greater initial decline, greater improvement).
Possible effects of rapamycin on behavior
Seventy percent (7/10) high dose rapamycin, owners reported dogs displayed increased activity and energy as did 40% (2/5) on lose dose.
25% (4/15) reported dogs behavior changed in a way they interpreted as more affectionate.
Conclusion: "Our resultsthus indicate that pharmacological inhibition of mTOR in older dogs likely has effects on heart function that are consistent with a reversal of age-related functional changes"
"to summarize, this initial study of rapamycin in healthy, middle-aged dogs showed that low-dose rapamycin treatment is safe over a period of 10 weeks and appears to recapitulate some of the beneficial effects that have been described for mTOR inhibition in mice... The absence of significant side effects here is consistent with findings from studies of marmosets in captivity
Flynn, 2013, Buck Institute, Calif.
Results and Discussion:
"One of aging's molecular hallmarks is the presence of a sterile inflammation and cytokine production."
[ASG: Cytokines are a broad and loose category of small molecules that are important in cell signaling. They are produced by a broad range of cells. Cytokines have an effect on behavior of cell around them. They have great importance in health and disease. For discussion chronic inflammation and age-related disease see: Inflammatory Networks uring Cellular Senescense: Causes and Consequences. Freund, 2010]
"Sterile inflammation is defined as the presence of an immune response as a result of cellular damage from noninfectious sources."
"We sought to test whether rapamycin treatment reduces inflammation systemically in the sera and within aged heart tissue."
In sera (blood) evaluated 32 cytokines. 4 were significantly reduced from baseline with rapamycin treatment.
"To further investigate potential inflammation within the heart at the protein level, tested for 145 cytokines in cardiac tissue. 45 were significantly different between treated and control groups. ALL 45 were reduced in rapamycin treated group.
These data suggest that rapamycin treatment in the aged heart results in a suppression of the pro-inflammatory signaling which arises with age. Overall, our data suggest that ... the anti-inflammatory effects of rapamycin are more potent within cardiac tissue than systemically in the sera."
Discussion: "We determined that rapamycin was shown to significantly reduce the presence of specific inflammatory cytokines within the blood and more dramatically within the cardiac tissue. "One potential mechanism for the beneficial effects of rapamycin i mice may be the suppression of age-related inflammation...The release of pro-inflammatory cytokines from cardic cells has been demonstrated to promote fibrotic changes and hypertrophy, and therefore, a reduction in pro-inflammatory cytokines may prevent tissue damage both locally in the heart and systemically."
To determine the potential beneficial effects of rapamycin on cardiovascular function with 3 months rapamycin treatment in avanced age (>20 months of age), hearts evaluated with ultrasound imaging.
Control mice Rapa Mice
% ejection fraction 67-61 down 7.2% 63-69 up 8.5%
Weight heart 113 gm ---171 gm Up 51% 133 gm ---- 139 gm up 5%
The demonstrated a reversal of age-related cardiac dysfunction.
The rapamycin fed mice had significantly less cardiac hypertrophy over 3 months in advanced age.
"To further investigate the improvement in heart function, we carried out speckled-tracjing strain analysis of the echocardiogram data." [ a very sensitive test of cardiac function.
Results: Control mice showed slight decrease in whole wall function and in systolic and early diastolic strain rate in circumferential view.
Rapamycin treated mice showed significant improvement in both whole wall function and systolic and diastolic views.
Discussion: "Our results strikingly showed a functional improvement in ejection fraction and multiple other functional metrics with a reduction in hypertrophy of the heart over baseline levels prior to rapamycin treatment. These data showed a reversal of the typical progressive age-relate decline seen in C57BL/6J mice."
"Additionally, we observed improvement in the global peal strain and peak strain rates, a sensitive measure of myocardial systolic and diastolic function...Here we observed significant improvement in the circumferential orientation, which appear directly related to the net improvement in ejection fraction.
"Importantly, these same measures are used clinically and significantly decline with age or hypertrophy in patients. This result demonstrates for the first timerapamycin's ability to prevent loss of heartfunction in the context of the aging mouse."
"Because of the striking functional improvement in the heart compared with th other tissues examined, we performed detailed analysisof the molecular changes within cardiac tissue that arise due to rapamycin treatment in late life...We determined 700 genes differentially expressed in response to rapamycin treatment, with the majority, 521 downregulated..."The majority of upregulated genes upon rapamycin treatment are related to pathways involved in metabolic function and energy metabolism, consistent with related studie showing rapamycin enhances mitochondrial function."
The downregulated genes in categories related to immune function and inflammation. The data suggest that with age , there is increase in inflammatory processes known to be associated with aging. "Rapamycin attentuates the enhance cardiac inflammatory response."
One upregulated gene was PXR "whose signaling represses the inflamatory response through inhibition of the NF-KB pathway."
[ASG: NF-KB is major regular inflammation and and one of usual suspects in most age-related disease.]
The data showed anti-inflammatory effects. "However, reduced inflammation alone does not provide mechanistic explanation for the improved contractile function we observed via echocardiogram. To further investigate, examined a number of other classical markers within the heart tissue.
Cardiac hormone ANP was lowered after 3 months rapamycin treatment. Reduced ANP may prevent or dampen hypertrophic signaling.
analysis of expressed genes showed upregulation of heart disease-related protein RAD. Increased RAD "capable of both inhibiting hypertrophy and enhancing cardiomyocyte function by modulating calcium channels. RAD is suppressed in left ventricle of patients with end-stage heart failure and is linked to heart hypertrophy. "These data provide a potential linkage between rapamycin treatment and suppression of hypertrophy via enhanced levels of RAD and potentially explain the improved diastolic function observed."
Discussion: "the analysis of the remaining cardiac-related differentially expressed genes identified RAD as a potential modulator of cardiac function in the aged heart, which is a key protein in calcium signaling and has been linked to cardiac hypertrophy and heart failure. "We determined that RAD is indeed significantly upregulated with rapamycin treatment, which couldbe mechanistically linked with antihypertrophic and improvement in cardiac contractility. RAD functions in the cardiomyocyte related to calcium channels.
"Overall, these data support the hypothesis that rapamycin treatment improves excitation-contraction coupling in cells while simultaneously reducing endogenous stress signaling in the heart, resulting in preserved if not improved cardiac function with aging."
Dai, Rabinovitch, 2014, University of Washington, Seattle, Wa.
This is two part study regarding age-associated cardiomyopathy in aged mice.
One part of study is about reversal cardiac dysfunction with short-term caloric restriction or oral rapamycin. The second part of study is about changes in global cardiac proteome with same treatment. Cardiac proteome is all proteins in heart.
The study only included female mice. One control group was 4 month old mice fed regular diet. The other control group was 26 month old mice fed regular diet.
The study group was 26 month old mice kept on 40% caloric restriction for 10 weeks. The other study group was fed oral rapamycin for 10 weeks in same dose used in Harrison anti-aging mice study in 2009.
The first part of study was cardiac function in aged mice after 10 weeks on control diet, caloric restriction or rapamycin.
"At baseline, the aged heart phenotypein mice recapitulates the age-related changes of the human heart, including left ventricular hypertrophy and impairment of myocardial performance and diastolic dysfunction, as measured by echocardiography.
Left ventricular mass: Old mice fed with ad libitum control diet had an approximately twofold increase in left ventricular mass index compared to young controls indicating left ventricular hypertrophy. In both CR and rapamycin treated mice, echocardiogram showed reversal of age-dependent ventricular hypertrophy.
Fractional shortening (FS) did not significantly change with age or with treatment. (young, old and treated mice had same results)
Myocardial performance index (MPI) significantly worsened (increased) in old mice at baseline. CR or Rapamycin significantly improved the MPI in old heart when compared to control mice.
Diastolic function (E/A) significanly declined in old heart. While old mice have progressive decline of E/A after 10 weeks, treatent with CR or rapamycin significantly increased E/A. Treatment with rapamycin restored E/A to young mice level.
Discussion: "This study demonstrates that short-term, 10 week treatment with CR or rapamycin, initiated at old age, reverses many of the pre-existing functional deficits of cardiac aging, rather than just slowing down the aging process." TREATMENT WITH EITHER CR OF RAPAMYCIN FOR 10 WEEKS EFFECTIVELY REVERSES THE PREEXISTING CARDIAC HYPERTROPHY AND DIASTOLIC DYSFUNCTION.