there is a new effective treatment for some people with heart failure
The right chambers of the heart collect blood that has delivered oxygen and nutrients to the body. Then its muscles pump the liquid through the lungs where the red blood cells are oxygenated. The blood then enters the hollow innards of the left heart. The heart muscles contract and they force the blood through the arteries of the body.
When the heart is damaged or weakened, it fails to fill or contract completely, fluid backs up and people develop symptoms.
Many now believe that Cardiac amyloidosis is responsible
for over 10 percent of the cases of heart failure in older
people. Doctors have long known the condition existed but there was
no way to prevent it so few tested for it. Now there is a medication
that makes a difference. It is made by Pfizer. It’s
expensive, and it works.
The liver makes a protein called TTR –the body uses it to
transport vitamin A and the hormone Thyroxin.
On occasion, as people age the gene for the TTR protein mutates. The altered gene directs the liver to make
TTR protein that is unstable. TTR is a tetramer—a conglomeration of
four monomer proteins. When the TTR protein is unstable it breaks
into four parts. Then the segments mis-fold, TTR becomes insoluble
and it enters the amyloid state:
The “breaking apart” of the protein is the initial step in the development of the abnormal proteins that deposits in the heart and/or nerves.
Over time, amyloid aggregates accumulate in the heart and nerves. At times they cause neuropathy and on other occasions they infiltrate the heart and keep it from pumping normally. Some of the affected become “short of breath or fatigued. Others faint or develop abnormal heart rhythms.
To check for the disease
a doctor needs to order a specialized radioactive isotope scan. According to
experts writing in the New England Journal of Medicine, “The technetium-labeled
bone scintigraph tracing is highly sensitive and specific for the diagnosis of
transthyretin amyloid cardiomyopathy.”
“Although the prevalence
of ATTRwt is uncertain, studies that use an approach to diagnosis that is not
based on biopsy have reported a
prevalence of 13% among patients with heart failure with a preserved ejection
fraction, 16% among patients undergoing transcatheter aortic-valve replacement
for severe aortic stenosis, and 5% among patients with presumed
hypertrophic cardiomyopathy.”
Tafamidis is a new drug that stabilizes the protein, keeps it from breaking apart. In a large study 400 patients were given either Tafamadis or placebo and they were treated for 2 ½ years. At the end of the time the people who took the drug had significantly fewer hospitalization and deaths, and their quality of life declined much less slowly. Tafamidis slows the disease but it doesn’t seem to reverse or cure it.
the Pfizer ad:
“VYNDAMAX® (tafamidis) can help those living with ATTR-CM live longer with fewer heart-related hospital visits”
(There’s another treatment in the wings. Using CRSPR researchers have also been able to destroy the TTR gene. )
There
is also an inherited lethal form of amyloidosis. People who are born with the
abnormal gene make and accumulate a form of amyloid that they are unable to
break down. Over decades their livers amass waste amyloid
protein. (Some, but not all amyloid proteins are cytotoxic and
directly damage cells.) When the liver is full of amyloid, the
protein spills into other parts of the body and causes kidney failure,
uncontrollable diarrhea, and neuropathy.
https://www.nejm.org/doi/full/10.1056/NEJMoa1805689
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Trivia: In the 1800s physicians began examining thin slices of tissue using powerful microscopes. Stains and dyes were used to “enhance contrast in the samples.” One of the colorizers, "Congo" red, is a textile dye that was developed in Germany in 1885. Using it doctors identified fibrils that had an affinity for Congo red and displayed a yellow-green birefringence under polarized light.
https://karger.com/aha/article/143/4/322/15397/The-Pathology-of-Amyloidosis-in-Classification-A
Amyloid deposits are formed from globular, soluble proteins, which undergo misfolding and, subsequently, aggregate into insoluble fibrils, leading to progressive organ damage.
Hereditary ATTR amyloidosis is thought to be caused by mutations in the TTR gene and has an estimated worldwide prevalence of 50,000 individuals, To date, there are more than 120 TTR mutations reported.
From Pfizer; TTR-CM primarily affects the heart. Clumps of amyloid are deposited in the heart tissue and this affects the heart’s ability to pump blood, hearts enlarge, and fluid backs up into the body.
This condition may be inherited from a parent but may also occur in people without a family history of the disease. People with the hereditary form typically experience symptoms in their 50s or 60s. Some people, however, may not have symptoms until their 70s, or even later. https://www.pfizer.com/news/articles/understanding_this_rare_disease_called_attr_amyloidosis#:~:text=ATTR%20amyloidosis%20is%20caused%20by,cause%20them%20to%20function%20abnormally.
TTR, is a 127-amino acid, 56 kDa transport protein primarily expressed by the liver. It’s gene is located on chromosome 18q12.1, and spans 4 exons and 5 introns.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501197/
https://en.wikipedia.org/wiki/Familial_amyloid_cardiomyopathy
a Swiss company recently completed and published the results of a Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid and in Jan 2022 Jan 7 2022--AstraZeneca and the Swiss company--Neurimmune sign exclusive global collaboration and license agreement to develop and commercialize NI006. July 20, 2023 N Engl J Med 2023; 389:239-250
“At doses of at least 10 mg per kilogram, surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The use of NI006 was associated with no apparent drug-related serious adverse events.”
Sept 8 2023 New Engl Journal of Medicine--Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. ATTR deposits accumulate primarily in the cardiac extracellular space. Deposits stiffen the myocardium and cause diastolic dysfunction; as the disease progresses, conduction abnormalities, arrhythmias, and ultimately impaired systolic function occur.
TTRstabilization therapy and supportive care are current options for the management of cardiovascular complications, but heart transplantation remains the only approach available for the restoration of cardiac function. Tafamidis does not prevent disease progression. Additional therapies for TTR gene silencing are in late-stage clinical development. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells.
In a phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS :The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro–B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.)
Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. NEJM Sept 8, 2023
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