WHAT YOU NEED TO KNOW ABOUT STIFF HEART SYNDROME (CARDIAC AMYLOIDOSIS)

Medically Reviewed by Dr. Sony Sherpa (MBBS) - August 13, 2024

It is well-documented that protein metabolism declines throughout the aging process, and this has several consequences for overall health. Of these, stiffening of the heart is a common condition, yet one of the least diagnosed. Varying degrees of cardiac amyloidosis are likely to form part of the aging process and may predispose some individuals to heart failure.

The article below places stiff heart syndrome in the spotlight, addressing what it is, common symptoms, causes, and mechanisms, as well as how to best prevent and treat the condition.

What is Cardiac Amyloidosis?

Cardiac Amyloidosis is a leading cause of infiltrative cardiomyopathy and is more commonly referred to as stiff heart syndrome.

Cardiomyopathy refers to a group of diseases in which the heart battles to pump blood throughout the body. Also known as restrictive cardiomyopathy, infiltrative cardiomyopathy is indicative of an overly stiff, inflexible heart muscle, which distinguishes it from the more common dilated and hypertrophic cardiomyopathies.[1] It presents with a non-dilated left or right ventricle with diastolic dysfunction due to the deposition of abnormal substances into the heart tissue. Other than cardiac amyloidosis, cardiac sarcoidosis, and Hemochromatosis are other conditions that may cause restrictive or infiltrative cardiomyopathy.[2]

In cardiac amyloidosis, hardened protein deposits called amyloid are found embedded in the heart muscle, causing it to harden and become dysfunctional. Stiff heart syndrome is a common cause of both heart failure and mortality. There are several types of amyloid diseases that may cause cardiac amyloidosis.

Prevalence. The frequency of cardiac amyloidosis depends on the cause. Age-related stiff heart syndrome is estimated to affect 10-15% of patients older than 65 years who have heart failure with preserved ejection fraction.

Cardiac Amyloidosis Life Expectancy. Those with untreated cardiac amyloidosis attributed to senile systemic amyloidosis often live 5-7 years after being diagnosed. If diagnosed with another type of amyloidosis, life expectancy could be as short as 9-24 months (AL amyloidosis) or as long as 10+ years.

Symptoms

Cardiac amyloidosis symptoms typically represent those of cardiomyopathy and those pertaining to comorbidities. These include:

• Shortness of breath during exertion
• Chest pain
• Heart palpitations
• Low blood pressure
• Syncope (short loss of consciousness due to quick changes in cerebral blood flow)
• “Pins and needles” or tingling sensations
• Digestive complaints, such as malabsorption, dysmotility, and gastrointestinal bleeding
• Body pain
• Musculoskeletal stiffness
• Urinary difficulties

End-stage cardiac amyloidosis symptoms resemble those of heart failure and may include[3]:

• Shortness of breath (even when sitting or lying down)
• Edema in the feet, ankles, or legs
• Irregular heartbeat
• Chest pain
• Wheezing and other breathing difficulties
• A cough that does not go away with white, pink, or blood-spotted mucus
• Nausea
• Reduced ability to concentrate
• Weakness and fatigue

Causes

Amyloid builds up in tissues and organs, resulting in amyloidosis. Amyloid consists of aggregated amyloid fibrils, which are insoluble malformed proteins that the body struggles to break down and remove.

In cardiac amyloidosis, the heart muscle becomes overrun with amyloid deposits that interfere with coronary blood flow, cardiac contractility, and electrical conduction. Smaller blood vessels in and around the heart may also be affected, promoting micro-ischemia and the risk of a heart attack. Most causes of cardiac amyloidosis are systemic, meaning amyloid proteins are derived from elsewhere in the body.

There are several types of amyloidosis that can cause stiff heart syndrome, with wild-type transthyretin and atrial amyloidosis being the top two:

Isolated Atrial Amyloidosis. This type is caused by atrial natriuretic peptide (ANP) that deposits amyloid into the atria. It is considered to be the only local amyloidosis to cause cardiac amyloidosis and is often seen in early presentations of stiff heart syndrome. As ANP deposits are small, they usually do not add to the symptoms of stiff heart syndrome unless present alongside another heart condition that affects the atria. Nevertheless, research suggests that it may precipitate full-blown cardiac amyloidosis by reducing the heart’s ability to inhibit amyloid formation, as discussed briefly below:

• ANP Anti-Amyloid Properties. The atrial natriuretic peptide is released locally from the heart tissue and serves to dilate the heart and blood vessels, as well as regulate blood sodium and lower hypertension. Studies reveal that functional ANP may also inhibit amyloid deposition of other proteins and slow the progression of other cardiomyopathies due to its antifibrotic and antihypertrophic effects.[4]
• ANP Amyloid Formation and Heart Disease. The production and degradation of ANP are usually highly regulated by cardiomyocytes. The aging process, hormonal decline, and cardiovascular inflammation all appear to contribute to faulty protein degradation and the formation of ANP amyloid. This process indirectly contributes towards a wide variety of heart conditions by increasing the risk for atherosclerosis, thrombosis, and stiff heart syndrome. It may also precipitate kidney disease in patients with heart disease.[5]

Wild-Type Transthyretin Amyloidosis. This most frequently causes cardiac amyloidosis. The associated amyloid protein is transthyretin (TTR), also known as prealbumin. As it is an age-related disease, it is also known as senile systemic amyloidosis. As seen in ANP amyloidosis, TTR is likely deployed to regulate the heart’s functions yet turns faulty over the course of the lifetime, as described below:

• TTR in Cardiac Amyloidosis. Transthyretin is primarily produced by the liver and mainly functions as a transporter protein for retinol and thyroid hormone thyroxine. Similar to ANP, TTR is prone to misfolding through the aging process, likely due to improper degradation or utilization as well as age-related gene mutations and cell senescence.[6] Misfolded TTR fibrils are shown to accumulate in between heart cells and eventually clump together to form amyloid. While more research is required to draw firm conclusions, studies have revealed that healthy TTR may be involved in peripheral nerve repair[7] and that patients with low TTR are at a higher risk for cardiac mortality and hospitalization[8]. This suggests that TTR may be involved in cardiac regeneration and may accumulate more rapidly in the heart tissues prone to cardiovascular inflammation and damage. By contrast, TTR amyloid is known to interfere with both heart conductance and regeneration[9].

Less frequent causes of cardiac amyloidosis include:

• AL Amyloidosis. AL amyloidosis is the most aggressive and the common type of amyloidosis. Also known as primary amyloidosis, this type involves the deposition of antibody fragments known as amyloid light chains. These are produced by cancerous or faulty plasma cells in the bone marrow. Patients with myeloma may develop primary amyloidosis more frequently than other individuals.
• AA Amyloidosis. AA Amyloidosis is the least common type and rarely contributes to stiff heart syndrome. Known as secondary AA amyloidosis, amyloid consists of misfolded serum amyloid A proteins that are released in response to inflammation. Patients with inflammatory conditions or chronic infectious illnesses are at a higher risk for acquiring AA amyloidosis.
• Familial Amyloidosis. An uncommon cause for stiff heart syndrome, familial amyloidosis occurs due to a genetically inherited defect in the genes coding for transthyretin production, causing it to be malformed and prone to amyloid deposition. Familial amyloidosis shares a degree of genetic overlap with the wild type.

Risk Factors

Cardiac amyloidosis risk factors usually pertain to aging and cardiovascular inflammation. A few examples include the following:

Aging and Gender. The biggest risk factor for cardiac amyloidosis is aging. The condition most commonly affects men over the age of 60. Women may be more susceptible to contracting isolated atrial amyloidosis.[10]

Chronic Lifestyle Diseases. Diseases that form part of the metabolic syndrome, including obesity, hypercholesterolemia and dyslipidemia, diabetes, non-alcoholic fatty liver disease, hypertension, and cardiovascular disease, can all increase the risk of stiff heart syndrome. Other diseases that may contribute include hyperthyroidism, blood clotting disorders, and systemic autoimmune diseases.

High Blood Pressure. ANP amyloidosis and hypertension are both risk factors for chronically high blood pressure and can hasten the onset of cardiac amyloidosis and heart failure. Stress, dehydration, and excess fat, salt, or sugar consumption may all heighten blood pressure and serve as indirect risk factors for amyloidosis.

Chemoradiation Therapy. Certain chemo drugs and radiation therapy can cause heart damage and inflammation. Patients receiving treatment for myeloma may be at risk for developing primary AL amyloidosis that can lead to stiff heart syndrome.[11]

Complications

Common complications of cardiac amyloidosis include:

• Heart failure with preserved ejection fraction
• Kidney disease or failure
• Liver disease
• Carpal tunnel syndrome

Cardiac amyloidosis may present with other comorbidities indicative of systemic amyloidosis that cause impairments or diseases of the kidneys, nervous system, immune system, and digestive tract.

Diagnosis

A cardiac amyloidosis diagnosis is frequently overlooked. A physician will take the patient’s case history and will likely suspect a cardiovascular condition. Many other cardiovascular conditions can resemble stiff heart syndrome, and the patient may even be diagnosed with comorbid cardiovascular disease or misdiagnosed with another cardiomyopathy.[12]

In order to rule out other conditions, cardiac testing and imaging are very important. A series of tests are often deployed in a logical progression to ascertain the correct condition:

• Electrocardiogram (ECG). This test records electrical impulses of the heartbeat and provides a quick understanding of overall heart function, including if there are potential blockages or faulty conductance. Findings of a reduced cardiac (QRS) voltage and uneven left ventricular hypertrophy usually suggest cardiac amyloid. Signs of an atrioventricular block with less severe symptom presentations are more common in AL cardiac amyloidosis, while those with left bundle branch block coupled with more severe symptoms and arrhythmias are likely to have TTR amyloidosis. While noted to be the case, it is not possible to distinguish cardiac amyloidosis from other cardiovascular conditions using an ECG alone.
• Echocardiography. The way that blood flows through the heart can be shown graphically during an echocardiogram, which is a form of ultrasound test. This often clearly highlights amyloid deposits as white structures contrasting the darker structures that display other heart tissues. The severity of amyloidosis can be assessed alongside the wall thickness, heart chamber enlargement, and diastolic dysfunction. This can be used to rule out several other heart conditions and almost confirm amyloidosis. AL amyloidosis tends to be more symmetrical than TTR amyloidosis, which often presents with a higher degree of cardiac enlargement.
• Cardiac Magnetic Resonance Imaging. In the last couple of years, physicians have begun to turn towards cardiac MRIs to confirm cardiac amyloidosis as a diagnosis distinct from other conditions, especially hypertensive heart disease, and sarcoidosis. It may be a good idea to include it in the testing panel as it can pick up a lot more detail and even detect early ANP cardiac amyloidosis. An amyloid structure can be detected and confirmed since it is of a different density compared to the rest of the heart tissue and its extracellular location. These readings and others can differentiate amyloidosis from other fibrotic diseases.
• Biopsy or Radionuclide Imaging. An endomyocardial biopsy is the golden standard diagnostic tool after amyloidosis has been confirmed via prior testing. A small piece of heart tissue is retrieved by fine-needle aspiration and analyzed to ascertain whether the condition is caused by AL amyloidosis or another type. Radionuclide imaging (or nuclear spectrometry) is an alternative test that makes use of a radiotracer that can distinguish TTR amyloidosis from the AL type. 
• Genetic Testing. If TTR is suspected, it may require a genetic test to ultimately confirm whether it is familial or age-related, as well as what genetic variants are involved. More than 120 variants have been found that continue to spur research into novel precision treatment options.

Prevention and Treatment

Treatment for stiff heart syndrome depends on symptom severity and disease stage. There are currently no known cures, and treatment is mainly targeted at slowing down amyloid aggregation, lowering heart failure risk, treating comorbid conditions such as hypertension, and helping to minimize symptom severity.

• Leading a Heart Healthy Lifestyle. It is a well-known fact that hypertension and heart disease risk can be substantially lowered through regular exercise and consuming a heart-healthy diet. The same advice applies to preventing cardiac amyloidosis. Additionally, increasing fresh (raw) whole food intake can help to reduce the formation of amyloid, as cooked food (high in AGEs) is known to enhance the risk.
• Cardiovascular Disease Management. Various medications are prescribed in order to control symptoms of cardiac amyloidosis, the main treatment of which would be diuretics to manage hypertension. Medication that attempts to stabilize the heartbeat is debatable for patients with stiff heart syndrome due to being ineffective and giving rise to unwarranted side effects. Amiodarone may be indicated, while drugs with inotropic or chronotropic effects ought to be avoided as these may be toxic or propel the patient toward heart failure.[13] Beta-blockers, calcium channels, and ACE inhibitors are not recommended for similar reasons.[14]
• Anticoagulants proved to be modestly useful for slowing down disease progression in those with cardiac amyloidosis. However, they may not be able to prevent thrombosis.
• Myeloma Treatment in AL Cardiac Amyloidosis. Chemo and radiation therapy regimens may need to be carefully selected by an oncologist for those with myeloma and amyloidosis. Lesser doses are advisable alongside the most heart-friendly chemotherapeutics.
• Stem Cell Therapy. Those with AL Amyloidosis treated with stem cell therapy have been shown to double their survival rates by 2-4 times, living longer than 4 years[15]. This may have dual benefits for treating myeloma and stiff heart syndrome and may additionally improve transplantation outcomes.
• Surgery. If the outlook is bleak, surgery may be advisable. There are various types of heart surgeries available for patients with cardiac conditions, including coronary bypass surgery and assistive device implantation (especially for atrioventricular blockages). Patients with heart failure may be eligible for heart transplantation or a total heart replacement. Heart transplantation may be optimal for those with AL amyloidosis as it can improve their chances of surviving and the results of chemoradiation therapy. Older patients with TTR stiff heart syndrome may be eligible, yet it may not be required due to having a better average survival rate without surgery.
• TTR Protein Stabilizers. A prominent approach emerging from current research would be the use of TTR protein stabilizers to treat cardiac amyloidosis. The NSAIDs tafamidis and diflunisal have proven to reduce the misfolding of TTR and lower amyloid disease progression. Patients with early-stage amyloidosis treated with these agents exhibited better outcomes with doubled survival rates at 1 and 5 years.[16] Other studies suggest it may reduce time spent in the hospital for those with TTR cardiomyopathy.
• Gene Silencing Agents. Patisiran, vutrisiran, and inotersen are all medications that can silence the TTR protein genes in TTR amyloidosis. They have so far been approved for use in the treatment of familial amyloidosis neuropathy and may prove promising for stiff heart syndrome as well.
• Amyloid Removal. Treatments are currently under development that focus on enhancing the removal of amyloid protein deposits. Several agents, such as monoclonal antibody therapy, doxycycline, and bile acid administration, may be able to lower the level of cardiac amyloid, as shown in preliminary research.[17] Antioxidant-rich plant extracts may also be of benefit. 600ml of green tea extract (ECGC) was shown to lower heart mass by an average of 6% over 12 months in 25 men with senile amyloidosis.[18] This was attributable to its ability to disrupt amyloid deposits and enhance removal.

Conclusion

Cardiac amyloidosis is a relatively underdiagnosed cardiomyopathy that is becoming increasingly recognized for its role in the aging process. Patients often present with mild to severe symptoms of heart disease that eventually precipitate heart failure if left untreated. Men tend to acquire stiff heart syndrome more on average than women, and women tend to acquire a more subtle form known as isolated atrial amyloidosis. The most common form pertains to wild-type amyloidosis, in which the aging process causes amyloid deposits of faulty transthyretin protein in the myocardium. Treatment demands supporting heart health, treating underlying heart disease, and making use of anticoagulants. Those with cardiac amyloidosis are often not prescribed conventional heart medications as they prove to be more toxic and less effective. Novel treatment options are now available that help to remove amyloid plaques and correct contributing genetic defects.

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Sources:

• [1] https://www.mayoclinic.org/diseases-conditions/cardiomyopathy/symptoms-causes/syc-20370709
• [2] https://www.ahajournals.org/doi/10.1161/circresaha.117.310982
• [3] https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142
• [4] https://www.ncbi.nlm.nih.gov/books/NBK562257/
• [5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144199/
• [6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724183/
• [7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606379/
• [8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078736/
• [9] https://pubmed.ncbi.nlm.nih.gov/34018852/
• [10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217946/
• [11] https://www.mayoclinic.org/diseases-conditions/cardiomyopathy/symptoms-causes/syc-20370709
• [12] https://www.ncbi.nlm.nih.gov/books/NBK580521/
• [13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087817/
• [14] https://www.ahajournals.org/doi/full/10.1161/circulationaha.111.069195
• [15] https://pubmed.ncbi.nlm.nih.gov/31795821/
• [16] https://www.ahajournals.org/doi/full/10.1161/CIRCHEARTFAILURE.117.004769
• [17] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832446/
• [18] https://pubmed.ncbi.nlm.nih.gov/26673202/

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