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Transthyretin cardiac amyloidosis

Noninvasive diagnostic techniques have broadened the understanding of affected populations, and novel therapies that reduce morbidity and mortality in ATTR-CA are rapidly emerging.

On the basis of positive technician 99M Pyro phosphate scans the prevalence of cardiac amyloidosis may as highest 10 to 15% in those younger than 70 years and up to 30% and older adults with heart failure.

Cardiac deposition is, in many patients, the most serious complication of ATTR. 

Wild type ATTR cardiomyopathy is attributed to altered proteostasis with aging.

In the inherited form of ATTR amyloidosis TT R gene variants cause anmino acid substitutions promoting amyloidogenesis.

Systemic amyloidosis due to accumulation of misfolded transthyretin protein (TTR) causes cardiomyopathy in approximately 50 to 150,000 people in the US.

Transthyretin is also known as pre-albumin, is a circulating protein, synthesized by the liver, that transports thyroid hormone, and the retinol (vitamin A) binding protein 4 complex.

TTR typically exists as a homotetramer, but can dissociate into its constituent subunits that subsequently misfold and aggregate into amyloids fibrils.

With ATTR cardiomyopathy ATTR deposits occur between cardiac myocytes in the interstitial space contributing to impaired diastolic function, progressive ventricular wall, thickening, and impaired longitudinal systolic function.

Myocellular injury manifests as troponin release and abnormal plasma troponin concentration, develops because of myocyte damage and necrosis, and is associated with misfolded protein accumulation and/or microvascular dysfunction.

Cardiomyopathy due to ATTR can cause heart failure, arrhythmia, and death.

ATTR cardiomyopathy develops over years or even decades.

Wild type ATTR is the most common type of ATTR amyloidosis with approximately 75% of the cases and typically manifest as cardiomyopathy, and a fewer 10% of patients have concurrent polyneuropathy.

Wild type amyloidosis transthyretin (ATTR) protein cardiomyopathy is more common in males.

More than 130 gene variants in TTR have been identified.

A common inherited pathological TTR variant exists                                                              in more than 1.5 million people in the US.

Val1421 genetic variant occurs in 3 to 4% of persons in the US who identify as African-American or Black.

Autopsy findings demonstrate the 25% of heart from decedents older than 80 years, without known heart failure,  have wild type ATTR amyloid deposits and the prevalence of amyloid deposits was higher among older males with heart failure.

ATTR amyloidosis due to a genetic variant is more common in people who are older.

Genetic variants are inherited as an autosomal dominant manner.

TTR  is a four-exon gene residing on chromosome 18.

Most of the 130 gene variants in TTR promote transthyretin protein folding and result in ATTR amyloidosis.

Gene variants represent single nucleotide changes in the TTR gene resulting  in amino acid substitutions, the stabilization of TTR, and protein folding.

The Val30Met variant, causing a substitution of methionine for valine at position 30, and is the most common encountered variant outside of the US and effects one in every 500 individuals.

People with this variant typically developed ATTR poly neuropathy before age 50, and ATTR cardiomyopathy after age 50.

Echocardiography enables visualization of increased ventricular wall thickness, increased septal thickness, valvular thickening, valvular insufficiency atrial enlargement and appearance of granular sparkling.

 

Echocardiography findings are not sensitive nor specific enough to be diagnostic but is highly suggestive when present.

 

Amyloid deposits in the heart occur in the ventricular interstitium.

 

Amyloid deposits lead to thickening of the ventricular walls and interventricular septum without an increase in the intracardiac volume. 

Early detection of cardiac abnormalities is important as the prophylactic implantation of pacemakers was found to prevent 25% of major cardiac events in TTR-FAP patients followed up over an average of 4 years. 

 

Doppler echocardiography diastolic evaluation reveals impaired ventricular relaxation early in the course of disease, which progresses to short deceleration. 

 

The cardiac ejection fraction is preserved until late in disease. 

 

 

Bone scintigraphy using technetium-provides very high diagnostic accuracy in the noninvasive assessment of cardiac ATTR. 

 

 

Electrocardiography is a low-voltage QRS complex in the limb leads, resulting from replacement of normal cardiac tissue by nonconducting amyloid material. 

 

The loss of anterior forces suggests anteroseptal infarction that is not confirmed at autopsy. 

 

Various arrhythmias may be seen and can be life threatening. 

A study aimed at clarifying the natural history of 1034 individuals with either hereditary (ATTRh) or wild-type (ATTRwt) CA referred to the United Kingdom National Amyloid Center (UK-NAC) between 2000 and 2017.

All diagnoses of ATTR-CA were based on validated diagnostic criteria.

ATTRh-CA has a comparatively worse prognosis than ATTRwt.

In contrast to light chain amyloidosis (AL), symptomatic cardiac involvement in ATTR does not necessarily portend a poor prognosis. Median survival in cardiac AL is about 6 months, but is several years in older patients with cardiac ATTR, even in those with a TTR variant.

ATTR-CA was associated with progressive declines in functional capacity and quality of life.

This observation unfortunately parallels diagnostic delays for light-chain amyloidosis.

Myocardial amyloid infiltration occurs before clinically manifestations of changes in ejection fraction, cardiac biomarkers, and renal function.

Most patients with ATTR-CA likely have a long latency period before declines in functional capacity occur.

Therapeutic window is hypothesized to be before significant organ dysfunction has occurred.

Biomarkers include: cardiac troponin T, amino-terminal pro-B-type natriuretic peptide, and glomerular filtration rate.

Comparing the outcomes of patients with the most common heritable form of cardiac amyloid (V122I ATTRh) versus those with ATTRwt, in general, have shown a worse prognosis with the former.

TTR V122I originated in West Africa, has spread throughout that area and the Americas, and is carried by 3.9% of African Americans. 

One of the most common genetic causes of hereditary Transthyretin amyloidosis is a valine to isoleucine amino acid substitution a position 122 (V1221) in the TT or a coding sequence that is primarily found in individuals of African ancestry.

TTR Val1221le Mutation is a significant risk factors for heart failure among people age 60 years or older of African dissent living in the US with the population frequency of approximately 3% for the disease allele.

Among individuals of African or Hispanic/Latino ancestry the TTRV122I, genetic variant is significantly associated with heart failure.

ATTI variant122 is in approximately 3.4% of African-Americans or approximately 1.5 million people in the US.

This variant originated in the western coast of Africa is associated with the development of ATTR cardiomyopathy later in life, typically after age 60.

For both wild type and variant disease, the main age of diagnosis, is between 74 and 90 years, while women tend to  present approximately three years older than men.

The median time from onset of heart failure symptoms to the diagnosis of Transthyretin amyloid cardiac myopathy is approximately three years.

As a result cardiac amyloidosis is more prevalent among African Americans than among people of other races in the United States. 

The median time from symptom onset to diagnosis is shorter (25 months) in ATTRh than in ATTRwt (39 months), which, when coupled with the more rapid increase in amino-terminal pro-B-type natriuretic peptide and decrements in quality of life, provides substantive evidence that the V122I genotype is more aggressive than ATTRwt.

It is anticipated genetic testing can play in identifying allele carriers who are at risk for ATTRh-CA, facilitating therapies at a time earlier in the course of their disease.

There remains a progressive decline in quality of life mirrored by a progressive decline in exertional capacity.

A study of 24 men with wt-ATTR cardiomyopathy demonstrated that consumption of green tea extract for 1 year may potentially inhibit amyloid fibril formation in the heart. 

Diuretics are the mainstay of therapy for amyloid-related CHF.

 

Diuretic agents must be used with caution with TTR due to the restrictive effect of the disease, ventricular compliance is poor and end-diastolic volumes are low. 

As patients often require a higher filling pressure to distend the stiffened heart, and diuretic therapy reduces preload, further reducing stroke volume and systolic blood pressure. 

Two gene-silencing therapies reduce circulating transthyretin (TTR), and halt or slow the progression of ATTRh polyneuropathy: inotersen, an antisense oligonucleotide; and patisiran, a small interfering RNA.

These treatments may have favorable cardiac effects in ATTRh-CA and ATTRwt-CA as well.

In a trial period of 12 months, Patisiran resulted in preserved functional capacity in patients with transthyretin cardiac amyloidosis (Maurer MS).

In addition other treatments stabilize the TTR tetrameric structure preventing tetramer dissociation, which is the rate-limiting step in TTR amyloid fibril formation.

Tafamidis is a small molecule engineered to bind to the thyroxine binding pocket of TTR and stabilizes the TTR tetramer.

Tafamidis reduced mortality and cardiovascular hospitalizations in both ATTRwt-CA and ATTRh-CA along with a slowing of the decline in functional capacity and quality of life.

Both types of therapies work by inhibiting amyloid fibril formation and may therefore be more efficacious if administered earlier in the course of the disease when there is less cardiac dysfunction from amyloid deposits.

Normal-sequence ATTR forms cardiac amyloidosis predominantly in men above 60 years of age, a disorder termed senile cardiac amyloidosis.

 

Senile cardiac amyloidosis is often associated with microscopic deposits in many other organs.

 

The clinical manifestations of severe senile cardiac amyloidosis  are similar to those observed in familial ATTR and in cardiac amyloidosis of the immunoglobulin light chain type (AL).

In  patients  with transthyretin amyloid cardiomyopathy,  acoramidis rresulted in significantly better outcomes of mortality, morbidity, and function than placebo.

 

 

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