Syncope is defined as the transient loss of conscience due to cerebral hypoperfusion, characterized by a rapid onset, short duration, and spontaneous complete recovery. It comes with loss of postural tone, leading to falls and sometimes traumas, accompanied by amnesia about the event.⁸ The symptoms presented immediately before syncope are called prodromes. They represent the beginning of all processes of fainting, when the arterial pressure and consequently cerebral perfusion, begins to drop.

The pathophysiological mechanism of syncope is explained by global cerebral hypoperfusion; thus, for the occurrence of syncope, arterial pressure should drop abruptly or progressively for some reason. There are three main mechanisms that can result in syncope, namely, reflex, orthostatic hypotension (OH), and cardiac syncope. All these mechanisms are related to impairment of two hemodynamic parameters: vascular peripheral resistance and/or cardiac output⁹ (Figure 1).

Figure 1 CO: cardiac output; VPR: vascular peripheral resistance. Figure generated with assistance of Microsoft Bing.

The duration of prodromes is correlated to the nature of the event; the shorter the prodrome, the greater the chance of a sudden drop of arterial pressure, such as paroxysmal arrythmias, severe dysautonomia, abrupt loss of blood, traumatic cardiac tamponade, massive pulmonary embolism, etc. Therefore, the length of the prodromes (10 seconds) is a clue to the main causal component (fast versus slow installation). When prodromes last less than 10 seconds they are considered suspect for arrythmias as a first good hypothesis. Despite this, severe dysautonomia or gradual drops in blood pressure (BP) in a standing position not recognized by the patient can also lead to short prodromes.¹⁰ As all these issues can occur together in patients with amyloidosis, it is highly difficult to point out only one cause for syncope without investigating all the possible components involved in syncope in this disease (Central Illustration).

Reflex syncope, also known as vasovagal syncope, is the most common cause of syncope in all ages. The mechanism is related to sympathetic withdrawal and vagal overstimulation secondary to a specific trigger, which leads to sudden drop of heart rate (HR) and/or arterial pressure. The most common trigger is orthostatic stress that involves a lowering in venous return to the heart, which frequently occurs in hot places and when people persist a lot of time standing up. It can be potentiated by hypovolemia or hypotensive drugs and venous pooling in the lower limbs (due to the presence of varicose veins or sarcopenia). In this specific situation the lower blood volume that reaches the heart provokes stimulation of mechanoreceptors in the ventricular wall through vigorous contraction of an “empty” heart, which can trigger vagal response. There are other triggers such as emotional (fear, pain, phobia) and situational ones (micturition, gastrointestinal stimulation like swallowing and defecation, cough, sneezing, post-exercise, and less common ones like laughing and brass instrument playing). Prodromes are compatible with autonomic activation (pallor, sweating and/or nausea).

This syncope mechanism can also be present in patients affected by amyloidosis, since patients are frequently on diuretics and have hypertrophied left ventricle with a small cavity.

Syncope provoked by OH is common in amyloidosis and seems to be multifactorial. The definition of OH is a drop of more than 20 mmHg in systolic arterial pressure (SAP) or more than 10 mmHg in diastolic arterial pressure (DAP) when a patient adopts an orthostatic position, compared with supine arterial pressure measures. When the patient has supine hypertension (> 150/90 mmHg), the drop should be more than 30 mmHg in SAP and 15 mmHg in DAP. If the patient cannot adopt orthostatic position, the diagnosis of OH is made if there is a drop of more than 15 mmHg in SAP or 7 mmHg in DAP in the sitting position¹¹ (Table 1).

Table 1

OH with supine normal AP	Drop > 20 mmHg in SAP or > 10 mmHg in DAP in standing position
OH with supine AP > 150/90 mmHg	Drop > 30 mmHg in SAP or > 15 mmHg in DAP in standing position
OH when patient cannot stand up	Drop > 15 mmHg in SAP or > 7 mmHg in DAP in the sitting position

Classically, OH can result from exacerbated venous pooling and may be triggered by prolonged bed rest, deconditioning, post-exercise, and after carbohydrate-rich meals. Other significant causes include polypharmacy, volume depletion, primary autonomic failure (found in pure autonomic failure), multiple system atrophy, Parkinson’s disease, and dementia with Lewy bodies. Also, there are secondary autonomic failure causes, due, for instance, to diabetes, amyloidosis, spinal cord injuries, autoimmune autonomic neuropathy, paraneoplastic autonomic neuropathy, and kidney failure. The typical OH prodromes include dizziness, light-headedness, fatigue, weakness, visual and hearing disturbances, low back pain, neck and shoulder pain (coat-hanger pain), or precordial pain.

OH is subdivided based on the time of occurrence, as follows: a) Initial OH takes place within 15 seconds of orthostasis, with a drop of 40 mmHg in SAP or 20 mmHg in DAP. It appears to result from a transient mismatch between cardiac output and total peripheral resistance; b) Classical OH occurs between 15 seconds and 3 minutes of orthostatism due to impaired increase in total peripheral resistance and HR in autonomic failure, leading to blood pooling, or it can be secondary to severe volume depletion; and c) Delayed OH occurs after 3 minutes of orthostatism, where the progressive fall in venous return and low cardiac output seems to be the best explanation, almost always caused by autonomic neuropathies and classified as neurogenic OH (nOH).^9,11,12 Changes in HR on standing help determine if OH is neurogenic. In patients with nOH, reduced sympathetic innervation leads to a much smaller HR increase than expected for the BP fall magnitude. Thus, a blunted HR increase during hypotension indicates a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg upon standing or head-up tilt is diagnostic for nOH, while a ratio ≥ 0.5 suggests a non-neurogenic cause.¹³ A tilt table test could be necessary to diagnose nOH since the BP fall can occur several minutes after orthostasis, mainly in early disease (Figure 2). Other non-invasive autonomic tests like HR variability, Valsalva test, respiratory test, or quotient 30:15 with orthostasis may be valuable in evaluating dysautonomia.¹⁴

Figure 2

Cardiac syncope results from heart malfunction, either due to pump deficit or rhythm disorders. Prodromes are often short or non-existent, sometimes preceded by palpitations. Patients with cardiac syncope face increased risks of death from any cause, non-fatal myocardial infarction, coronary heart disease death, and fatal or non-fatal stroke compared to controls. Various prognostic markers and risk calculators, including OESIL Score, San Francisco Score, EGYS Score, and Rose Score, help stratify sudden death risk in syncope patients.^15-18

The two initial exams for cardiac syncope are ECG and echocardiogram. They are crucial for risk stratification. Red flags for cardiac syncope and similarly for CA include abnormal ECG and/or echocardiogram.

In amyloidosis, multiple mechanisms are possible (Figure 1), and not infrequently, more than one of them contributes to manifestation of syncope. However cardiac syncope should always be looked for.

CA initially manifests as HFpEF with reduced left ventricular end-diastolic volume and impaired diastolic functioning resulting in diminished stroke volume and cardiac output. Dilatation of both atria develops due to raised left ventricular filling pressures. The interstitial amyloid deposition leads to restrictive cardiomyopathy. Consequently, arrhythmias are common in CA, with atrial fibrillation (AF) being the most common, although complex ventricular arrhythmias (VA) are also observed. Atrioventricular (AV) conduction system disease and sinus disease have also been described.^6,19-24 All these rhythm disturbances can cause syncope as they can contribute to an additional decrease in cardiac output.²

Common symptom constellations of AL include HFpEF, nephrotic range proteinuria, organomegaly due to amyloid deposition (hepatomegaly, macroglossia, enlarged salivary glands, etc.), peripheral and autonomous neuropathy, and constitutional symptoms (weight loss, fatigue).²⁵ In AL, infiltration of cardiac structures, which is a consequence of plasma cell dyscrasia, can damage the tissues in two ways: first, amyloid deposits in the extracellular space of the myocardium and coronary blood vessels, which results in cardiomyocyte necrosis and interstitial fibrosis; second, it is thought that oxidative stress due to circulating light chain toxicity is directly myotoxic, which is unique to AL and may be responsible for the rapid progression to cardiomyopathy in patients with AL.²⁶ In addition to diastolic dysfunction, caused by cellular and interstitial damage, AL can also manifest with rhythm disturbance due to amyloid deposits in the conduction system (with sinoatrial and/or AV fibrosis).^2,7,21 Faraj et al. reported a case of accelerated junctional rhythm as initial arrhythmic presentation of AL, followed by complete heart block (CHB) and syncope,²⁷ which highlights the possible occurrence of substitution rhythms.

ATTR is a condition where TTR, a physiological protein synthesized by the liver, misfolds into insoluble β-pleated sheets and deposits as amyloids in the extracellular space of the myocardium. TTR is always present in serum, its physiological role being the transportation of retinol and thyroxine. The inherent propensity of TTR to fold and aggregate into insoluble amyloid fibers can be increased by a single-point mutation, as in hereditary TTR amyloidosis (h-ATTR). Wild-type TTR amyloidosis (wt-ATTR) is similar to h-ATTR, except that it is non-hereditary (sporadic), and the precursor protein is structurally normal TTR. It was also known as “senile systemic amyloidosis” and is still an underdiagnosed disease, accounting for a significant number (13%) of HFpEF cases.²⁸

The h-ATTR phenotype varies based on the causative genetic mutation, tending to be either cardiac-predominant or neuropathy-predominant, determined by the amino acid substitution site on the TTR gene. For example, those with the Val30Met TTR mutation commonly have heart conduction issues requiring pacemaker (PM) implantation. Other variants like Val122Ile and Thr60Ala commonly affect the cardiovascular system, but less frequently primarily impact the conduction system. Importantly, those with wt-ATTR have a greater probability of rhythm disturbances (typically AF) than those with h-ATTR.

A valuable red flag for suspecting ATTR is a history of hypertension that resolves over time and intolerance of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, or beta-blockers, which not infrequently leads to pre-syncope, syncope, and worsening fatigue on exertion.

The typical pattern of h-ATTR amyloid neuropathy is an ascending symmetrical length-dependent sensorimotor axonal polyneuropathy. Interestingly, patients with the Val122Ile mutation have more severe neurological symptoms and walking disability than those with wt-ATTR. As in AL, h-ATTR is also associated with autonomic neuropathy, primarily presenting with gastrointestinal symptoms. The numerous diagnostic red flags, like bilateral carpal tunnel syndrome, tendon rupture, and lumbar spinal stenosis, are all associated with h-ATTR. In wt-ATTR, the heart is usually the most clinically affected organ. However, signs of HF may be preceded by lumbar spinal stenosis or bilateral carpal tunnel syndrome by 10 to 15 years.^29-31

Literature data show that syncope is uncommon in ATTR (8%) and more frequent in AL (20%).³² When it occurs during exertion, it represents the inability to increase cardiac output, which leads to high mortality. In addition, sensitivity to intravascular fluid depletion combined with autonomic neuropathy, depressed myocardial reserve, atrial dysfunction, and rigidity, and the presence of arrhythmias contribute to the occurrence of syncope. All these possibilities make syncope a multifactorial presentation in CA.³³

nOH is a prominent and disabling manifestation of autonomic dysfunction in patients with h-ATTR, affecting an estimated 40% to 60% of patients and reducing their quality of life. As mentioned above, OH in patients with h-ATTR can be a consequence of HF due to amyloid cardiomyopathy or volume depletion due to diarrhea or drug effects. When none of these circumstances are apparent, OH is usually neurogenic, caused by impaired norepinephrine release from sympathetic postganglionic neurons due to neuronal amyloid fibril deposition. It is frequent, early, and severe in patients with the early-onset Val30Met mutation disease, but appears to be less severe in Val30Met cases with late-onset disease.^34,35 OH is also present in up to 100% of patients with the Ala97Ser mutation, with 71% of them having frequent syncope, particularly in the late stages of the disease. Conversely, OH appears to be infrequent in patients with TTR mutations with a high prevalence in Scandinavian countries (Ala45Ser, Tyr69His, Leu111Met variants) and in patients with the Val122Ile mutation, which is the most common TTR mutation in African Americans.^36-38 In a recent study involving > 3000 subjects enrolled in the multinational, longitudinal, observational Transthyretin Amyloidosis Outcomes Survey (THAOS), 58.7% had symptomatic OH. Moreover, the severity of the fall in BP when standing appeared to worsen at annual follow-ups, reflecting the progressive nature of autonomic failure. More pronounced orthostatic BP reductions were associated with increasing age, worse polyneuropathy disability stage, and diarrhea.

Autopsy studies in patients with h-ATTR and severe OH showed amyloid-related degeneration of the peripheral autonomic nervous system, namely, anterior, and posterior roots of the spinal cord, sympathetic ganglia, postganglionic sympathetic nerves, and the vagus nerve. Neuronal density in the intermediolateral column of the spinal cord was reduced, and there was degeneration of sympathetic postganglionic cholinergic fibers. Plasma levels of norepinephrine, the main sympathetic neurotransmitter, are severely reduced and fail to increase when standing in patients with h-ATTR.³⁹ Moreover, administration of norepinephrine elicits noteworthy increases in HR and BP, indicating sympathetic denervation oversensitivity.

The mechanisms of nOH in h-ATTR are similar to those of peripheral neurodegenerative synucleinopathies, like Parkinson’s disease, dementia with Lewy bodies, and pure autonomic failure, in which dysfunction of the sympathetic nerves is mediated by accumulation of another misfolded protein, α-synuclein, highlighting the high affinity that both misfolded TTR and α-synuclein have for the autonomic nervous system. Furthermore, studies with 123I-metaiodobenzyiguanidine (MIBG) cardiac neuroimaging showed reduced cardiac sympathetic innervation, which can be present before any abnormal echocardiographic sign.⁴⁰ Moreover, cardiac sympathetic denervation predicts worse prognosis.¹³

The initial steps of syncope treatment in CA involve recognizing red flags for disease diagnosis, confirming the event as syncope, accessing the risk of death, excluding rhythm disturbances, and ensuring cautious prescription to avoid harm.

Drugs that reduce intravascular volume (diuretics), induce vasodilatation (sildenafil, nitrates, vasodilators), block the pressure drop through a physiological compensation mechanism (beta-blockers), or block norepinephrine release/activity at the neurovascular junction (α-blockers, centrally acting α2-agonists, tricyclic antidepressants) worsen nOH and symptoms. Anemia also can worsen nOH and should be investigated and treated with erythropoietin (25 to 50 units/kg, subcutaneous, 3 times a week) and iron supplements. It is fundamental to make sure that there is no blood loss as a cause of hypovolemia.¹³ Additionally, anemia is a high-risk feature in syncope patients at initial emergency department evaluation, suggesting gastrointestinal bleeding.⁸

Commonly prescribed HF drugs have been proven to be unhelpful in CA. Angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, and beta-blockers decrease mortality in most patients with HF. However, in patients with amyloidosis-induced HF, these drugs are detrimental. Angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers promote hypotension due to the added effect of autonomic dysfunction and can only be tolerated in low doses in patients with predominant cardiac phenotype. Similarly, beta-blockers have been shown to provoke bradycardia in these patients. Calcium channel blockers are ineffective due to the strong binding of the drug to amyloid fibrils, leading to worsening HF, hypotension, and syncope. Strong binding to amyloid fibrils can also occur with the use of digoxin, leading to digitalis toxicity, which includes yellow-tinted vision, cholinergic agonism, and arrhythmias.²

When OH is the cause of syncope, patients must be aware of the diuretic effects of alcohol and avoid sugary beverages (e.g., bottled juices and soda) because of the hypotensive effects of high-glycemic index carbohydrate ingestion. Fluid intake should be 2 to 2.5 L/day. Patients should be encouraged to increase salt intake by adding 1 to 2 teaspoons to a healthy diet. In patients with nOH, drinking 0.5 L of water produces a marked increase in BP, and this can be used as a rescue measure since the pressor effect is quick (peaks in around 30 minutes), although short-lived.¹³

On the other hand, cardiomyopathy and HF are present in many patients, complicating the management of nOH, as treatment of HF typically involves reducing the cardiac preload with diuretics, causing intravascular volume depletion, which worsens nOH. Similarly, diarrhea, a manifestation of gastrointestinal involvement in h-ATTR, causes volume depletion and aggravates nOH. The challenge is to avoid both hypovolemia and hypervolemia in patients with mixed phenotypes of cardiomyopathy and neuropathy.

Daytime hypertensive episodes are of lesser importance, while sleep-time hypertension should be treated if BP consistently exceeds 160/90 mmHg in uncomplicated cases (symptomatic OH without concomitant target-organ damage), preferably below 140/90 mmHg in patients with a history of cerebrocardiovascular disease, diabetes, or renal failure. A reverse dipping pattern with OH is particularly detrimental, indicating more than a doubled risk of incident cardiovascular disease. Thus, reducing nighttime BP and restoring normal sleep-time dipping are crucial, preferably with short-acting drugs like losartan, captopril, or hydralazine, which are easily monitored with repeated 24-hour ambulatory BP monitoring and patient diaries.⁸ In severe cases, discontinuing antihypertensive treatment may be the only solution if the patient remains symptomatic despite treatment modification. Other educational methods include avoiding immobilization, prolonged recumbence, and physical deconditioning; gradually rising from supine and sitting positions, especially in the morning, after meals, and after urination/defecation; adapting to small and frequent meals; learning physical counterpressure maneuvers (e.g., leg crossing, muscle tensing, squatting) in the standing position and at the onset of prodromal symptoms; and sleeping with a head elevation of 10 to 30 degrees.¹² It is also critical to treat sarcopenia and do strength exercises for the legs and abdomen (Figure 3).

Figure 3 CA: cardiac amyloidosis; HF: heart failure.

Even with proper non-pharmacologic methods, many patients still need pharmacologic treatment for symptomatic nOH. Two common strategies are expanding intravascular volume with fludrocortisone and increasing peripheral vascular resistance with midodrine or droxidopa. Selection depends on each patient’s features, needs, peripheral sympathetic denervation, and heart disease degree.¹³

In reflex syncope, besides avoiding triggers, treating hypovolemia, stopping polypharmacy, and increasing salt and water intake, pharmacologic treatment may be necessary. The same drugs, midodrine and droxidopa (for low BP phenotype), are used if non-pharmacological approaches fail. PM implantation is recommended for dominant cardioinhibition, especially in older patients with CA. In the same group with short or non-existent prodromes, loop recorder implantation is advised due to the likely occurrence of arrhythmias.⁸

Cardiac syncope in CA, when caused by rhythm disturbance, will need a specific approach for each finding as will be addressed next.

Pharmacologic treatment of ATTR begins with drugs that avoid amyloid deposition, acting as TTR stabilizers (diflunisal and tafamidis) and RNA interference agents (patisiran and inotersen) in both hereditary and wild type.^41-45 There are 2 drugs approved and tested in large randomized trials for cardiac TTR phenotype: tafamidis and patisiran.^42,45

The AL type is preferentially treated with stem cell transplants, chemotherapy, and proteasome inhibitors. The goal of treatment for AL is to reduce the production of light chains, remove light chain amyloid deposits, and inhibit amyloid fibril formation. The current standard of care for patients with AL is chemotherapy using cyclophosphamide, bortezomib, and dexamethasone (CyBorD). In the ANDROMEDA study (phase 3), daratumumab, (DARA-SC), a drug used in the treatment of multiple myeloma, was studied in conjunction with CyBorD. It demonstrated robust hematologic and organ responses. In patients with cardiac involvement of amyloidosis, the median time to respond was 114 days.⁴⁶