Abnormal Cardiovascular Responses During Orthostatic Hypotension in Cardiac Amyloidosis Revealed by Semi-Sitting/Standing Stress Echocardiography

Abstract

Background

Mechanisms of orthostatic hypotension (OH) in cardiac amyloidosis (CA) patients remain largely unclarified.

Case Summary

We performed semi-sitting/standing stress echocardiography in 6 healthy volunteers, 5 patients with CA but without OH [CA/OH(−)], and 4 with CA and OH [CA/OH(+)]. Semi-sitting/standing stress echocardiography revealed broad abnormal responses during semi-sitting/standing in CA/OH(+) patients, including reduced increase in heart rate, reduction in blood pressure, lack of reduction in left ventricular end-systolic dimension (contractile reserve), severely reduced stroke volume/cardiac output, paradoxical reduction in systemic vascular resistance, and paradoxical dilation of inferior vena cava dimension, compared to the group oh healthy volun.

Discussion

These findings may suggest a combined and broad abnormal compensations of all chronotropy, left ventricle, arteries, and veins during semi-sitting/standing, leading to severe OH with CA.

Take-Home Messages

Broad cardiovascular abnormalities were observed in 4 patients with CA and OH. Semi-sitting/standing stress echocardiography may hold potential for exploring the underlying pathophysiological mechanisms.

Visual Summary

Visual Summary.

Images of the Study Patient With Cardiac Amyloidosis and Orthostatic Hypotension and Healthy Volunteer

The top images are in the supine position and bottom images are in the semi-sitting position. Ao = aorta; BP = blood pressure; COi = cardiac output index; HR = heart rate; IVC = inferior vena cava; LA = left atrium; LV = left ventricle; LVDs = left ventricular end-systolic dimension; SVi = stroke volume index; SVRi = systemic vascular resistance index.

Orthostatic hypotension (OH) is frequently observed in patients with cardiac amyloidosis (CA), affecting their quality of life.¹ Autonomic neuropathy with impaired chronotropy is involved in the mechanism.² However, the actual responses of the left ventricle (LV), arteries, and veins during the hypotension remain unclarified.

For the evaluation and diagnosis of OH, an orthostatic challenge is recommended by the guideline.³ This challenge consists of 2 methods: the head-up tilt test, which uses an electronic tilt table, and a simple active standing. The pathophysiology is evaluated based on symptoms, heart rate (HR), and blood pressure (BP). A reduction in systolic BP of more than 20 mm Hg or diastolic BP of more than 10 mm Hg from baseline, or a decrease in systolic BP to <90 mm Hg, serve as the standard diagnostic criteria. Mizumaki et al⁴ further used echocardiography to evaluate the roles of the left ventricle in the pathophysiology of syncope, documenting an excessive reduction in both left ventricular end-diastolic and end-systolic dimensions (LVDd and LVDs) with unchanged systolic contraction (percent fractional shortening) during the head-up tilt test in patients with neurally mediated syncope. To explore broad cardiovascular responses—including HR, BP, LV dimensions, stroke volume (SV)/cardiac output (CO), systemic vascular resistance (SVR), and inferior vena cava dimension—we performed a standard and comprehensive echocardiography during semi-sitting induced hypotension in a patient with CA and severe OH. Furthermore, we conducted semi-sitting/standing stress echocardiography in 6 healthy volunteers, 5 patients with CA but without OH [CA/OH(−)], and 3 additional patients with CA and OH [CA/OH(+)].

History of Presentation

A 91-year-old man with a history of complete atrioventricular block and pacemaker implantation presented with a recent onset of frequent lightheadedness upon standing. He was transported to our hospital by ambulance following an episode of complete syncope. Upon admission, his BP was 67/37 mm Hg and HR was 50 beats/min. Physical examination revealed pulmonary crackles and severe lower extremity edema. A chest x-ray demonstrated cardiomegaly with pulmonary congestion.

Investigations

Transthoracic echocardiography showed slightly increased LVDd (48 mm) and LV end-diastolic volume (100 mL), increase in LVDs (30 mm) and LV end-systolic volume (56 mL) with reduced ejection fraction (44%). Both the interventricular septum and the posterior wall were thickened (14 mm). The LV outflow tract SV tended to be reduced (53 mL/beat, 31 mL/beat/m²) and the CO was clearly reduced (3.1 L/min, 1.8 L/min/m²). The serum and urine free light chain κ/λ ratio was 0.03, and immunofixation electrophoresis revealed the presence of lambda-type M-protein. A skin biopsy demonstrated Congo red positivity. Consequently, he was diagnosed with light chain (AL) amyloidosis associated with monoclonal gammopathy and was classified as Mayo stage III.⁵

Management

Considering his advanced age and high Mayo stage, the patient was managed with palliative symptom control rather than systemic chemotherapy. Heart failure treatment with diuretics and neurohormonal inhibitors was initiated. In response to the severe OH, his preexisting antihypertensive drugs were withdrawn, and the use of compression stockings was initiated.

Outcome and Follow-Up

Although his heart failure symptoms subsequently improved, the persistent hypotension and lightheadedness remained. Because the patient was unable to maintain a standing position, we conducted an orthostatic challenge test using a semi-sitting position to assess the concomitant hemodynamic and cardiovascular responses during the postural changes, This was performed in accordance with the guideline-recommended method: 1) baseline examination, 2) 3 minutes of postural change, and 3) repeated examination during the postural change.³ During this challenge, we performed a comprehensive, standard 2-dimensional and Doppler echocardiographic evaluation to capture hemodynamic and structural changes (semi-sitting stress echocardiography) (Figure 1). Hemodynamic and echocardiographic changes are presented in Figure 2 and Supplemental Table 1 (CA/OH(+); study patient in red font). During the orthostatic challenge, his BP dropped severely (from 130/88[102] to 71/35[47] mm Hg], while his HR failed to show a compensatory increase (from 59 to 63 beats/min). Regarding the echocardiographic parameters, the LVDd reduced (from 48 to 38 mm), while LVDs remained unchanged (from 30 to 30 mm), resulting in a reduction in percent fractional shortening (from 38% to 21%). Both the SV index (SVi) was reduced (from 31 to 24 mL/beat/m²) and CO index (COi) was clearly reduced (from 1.9 to 1.5 L/min/m²). Consequently, the SVR index (SVRi) also demonstrated a reduction (from 1,497 to 585 dyne/s/cm⁵/m²). Furthermore, the response of the inferior vena cava maximal dimension showed enlargement (from 8 to 24 mm).

Figure 1.

Images of the Semi-Sitting/Standing Stress Echocardiography

Standard echocardiography with measurement of blood pressure is initially performed in the left lateral supine position. The same procedure will follow after 3 minutes of semi-sitting or standing.

Figure 2.

Images of the Study Patient With Cardiac Amyloidosis and Orthostatic Hypotension

The top images are in the supine position and bottom images are in the semi-sitting position. (A1 and A2): Blood pressure (BP) severely decreased from supine to semi-sitting (from 130/88[102] to 71/35[47] mm Hg]). The increase in heart rate (HR) was only slight. Left ventricular end-systolic dimension (LVDs) in the parasternal long-axis view did not change by semi-sitting. (B1 and B2): The left ventricular outflow tract stroke volume index (SVi) was reduced by semi-sitting. The cardiac output index (COi) was reduced by semi-sitting, however, its reduction rate (−21%) was less than that of the mean BP (−54%). Consequently, the systemic vascular resistance index (SVRi) decreased considerably (from 1,497 to 585 dyne/s/cm⁵/m²). (C1 and C2): The maximum diameter of the inferior vena cava (IVC) clearly increased by semi-sitting (from 8 to 24 mm). Ao = aorta; LA = left atrium; LV = left ventricle.

To evaluate the multiple cardiovascular responses of the patient, we performed semi-sitting/standing stress echocardiography in 6 healthy volunteers, 5 patients with CA/OH(−) and 3 additional patients with CA/OH(+) (Figure 3, Table 1). Results are summarized as follows:

• •Compared to the healthy volunteers, the increase in HR during semi-sitting/standing tended to be attenuated or even reduced in CA/OH(−) and CA/OH(+) patients.
• •BP was generally preserved in both the healthy volunteers and CA/OH(−) patients, whereas it was significantly decreased in the CA/OH(+) patients by definition.
• •The baseline LVDd seemed slightly decreased in both CA/OH(−) and CA/OH(+) patients, and its reduction during semi-sitting/standing remained comparable among the 3 groups.
• •The baseline LVDs tended to be slightly increased in CA/OH(+) patients. While the healthy volunteers demonstrated reduction in LVDs during the semi-sitting/standing (reflecting contractile reserve), this reserve was not clear in both CA/OH(−) and CA/OH(+) patients.
• •The baseline percent fractional shortening of the LV ended to be reduced in both CA/OH(−) and CA/OH(+) patients. The shortening remained unchanged during semi-sitting/standing in the healthy volunteers, whereas it similarly decreased in both the CA/OH(−) and CA/OH(+) patients.
• •The baseline SVi tended to be reduced in CA/OH(−) patients, and was further diminished in the CA/OH(+) patients. Reduction during semi-sitting/standing was not necessarily greatest in CA/OH(+) patients, but consequent SVi during semi-sitting/standing was minimal in the patients.
• •The baseline COi was preserved in the CA/OH(−) patients, and tended to be reduced only in the CA/OH(+) patients. The reduction during semi-sitting/standing tended to be greater in both CA/OH(−) and CA/OH(+) patients, and consequent COi during semi-sitting/standing was minimal in the CA/OH(+) patients.
• •The baseline SVRi tended to be elevated in both the CA/OH(−) and CA/OH(+) patients. During semi-sitting/standing, SVRi was slightly or considerably increased in healthy volunteers and CA/OH(−) patients; however, it was paradoxically reduced in all CA/OH(+) patients.
• •The baseline inferior vena cava dimension seemed comparable between the 3 groups. It tended to decrease during semi-sitting/standing in healthy volunteers. In contrast, the dimension showed a paradoxical dilation in both the CA/OH(−) and CA/OH(+) patients, with this tendency being most prominent in the CA/OH(+) patients.

Figure 3.

Images of a Healthy Volunteer

The top images are in the supine position and bottom images are in the semi-sitting position. (A1 and A2): Maximum blood pressure (BP) did not change, however, minimum and mean pressure tended to increase. Heart rate (HR) increased. Left ventricular end-systolic dimension (LVDs) was reduced by semi-sitting. (B1 and B2): The left ventricular outflow tract stroke volume index (SVi) was reduced, however, the cardiac output index (COi) remained unchanged with increase in HR during semi-sitting. Consequently, systemic vascular resistance index (SVRi) slightly increased. (C1 and C2): The maximum diameter of the inferior vena cava (IVC) was reduced by semi-sitting.

Table 1.

Demographics and Cardiovascular Responses During Semi-Sitting/Standing Stress Echocardiography

	Healthy Volunteers (n = 6)	CA/OH(−) Patients (n = 5)	CA/OH(+) Patients (n = 4)
Amyloid type	—	ATTR-wt in 5	AL in 1, ATTR-wt in 3
Stress type	Semi-sitting in 2, standing in 4	Semi-sitting in 1, standing in 4	Semi-sitting in 4
HR, beats/min	Increased (+24%) (63 ± 10 → 78 ± 7)	Reduced (−7%) (71 ± 19 → 66 ± 8)	Increased (+18%) (60 ± 12 → 71 ± 16)
Mean BP, mm Hg	Preserved (92 ± 8 → 97 ± 6)	Preserved (91 ± 14 → 93 ± 7)	Reduced (−32%) (88 ± 10 → 60 ± 9)
LVDd, mm	Reduced (−13%) (45 ± 3 → 39 ± 4)	Reduced (−8%) (40 ± 8 → 37 ± 6)	Reduced (−14%) (43 ± 4 → 37 ± 1)
LVDs, mm	Reduced (−14%) (28 ± 2 → 24 ± 2)	Unchanged (28 ± 8 → 29 ± 8)	Unchanged (30 ± 3 → 30 ± 3)
%FS	Unchanged (36 ± 3 → 38 ± 10)	Reduced (−21%) (29 ± 9 → 23 ± 10)	Reduced (−28%) (29 ± 10 → 21 ± 7)
SVi, mL/m2	Reduced (−24%) (38 ± 9 → 29 ± 8)	Reduced (−15%) (34 ± 6 → 29 ± 7)	Reduced (−26%) (27 ± 7 → 20 ± 6)
COi, L/min/m2	Slightly reduced (−4%) (2.3 ± 0.4 → 2.2 ± 0.4)	Reduced (−21%) (2.4 ± 0.6 → 1.9 ± 0.6)	Reduced (−13%) (1.6 ± 0.2 → 1.4 ± 0.2)
SVRi, dyne/sec/cm5/m2	Slightly increased (1,012 ± 314 → 1,094 ± 285)	Increased (+28%) (1,253 ± 379 → 1,609 ± 584)	Reduced (−28%) (1,337 ± 155 → 960 ± 303)
IVC, mm	Reduced (−19%) (16 ± 3 → 13 ± 2)	Dilatation (+50%) (12 ± 5 → 18 ± 4)	Dilatation (+60%) (15 ± 7 → 24 ± 3)

%FS = percent fractional shortening; AL = light chain amyloidosis; ATTRwt = wild-type transthyretin amyloidosis; BP = blood pressure; CA/OH(−) = cardiac amyloidosis and no orthostatic hypotension; CA/OH(+) = cardiac amyloidosis and orthostatic hypotension; COi = cardiac output index; HR = heart rate; IVC = inferior vena cava; LVDd = left ventricular end-diastolic dimension; LVDs = left ventricular end-systolic dimension; SVi = stroke volume index; SVRi = systemic vascular resistance index.

Discussion

This AL cardiac amyloidosis case report with data from additional patients and healthy volunteers demonstrated multiple abnormal responses of the cardiovascular system during OH. The abnormal responses during semi-sitting/standing observed in our 91-year-old male patient with AL CA and severe OH, including attenuated increase in HR, reduction in BP, lack of reduction in LVDs, reduction in LV percent fractional shortening, severely reduced SVi/COi, paradoxical reduction in SVRi and paradoxical dilation of the inferior vena cava, were approximately common in all of the 4 CA/OH(+) patients. Attenuated increase in HR, lack of reduction in LVDs, reduction in LV percent fractional shortening, and paradoxical dilation of inferior vena cava during semi-sitting/standing were also observed in the CA/OH(−) patients. Paradoxical reduction in SVRi may be specific in CA/OH(+) patients. To our knowledge, this is the first report to document actual abnormal responses of LV, arteries, and veins during semi-sitting/standing in CA patients with or without severe OH.

Although this report documented novel and abnormal responses of the cardiovascular system in patients with CA during OH, multiple new questions follow. The abnormal responses documented in the present study need to be confirmed in a larger number of patients with CA. The LV responses to postural changes such as standing or semi-sitting in CA/OH(−) or CA/OH(+) patients differs from neurally mediated syncope patients with OH.⁴ In the present study, the reduction rate in LVDd in CA/OH(−) patents (−8%) and CA/OH(+) patients (−14%) was comparable to that of the healthy volunteers in our study (−13%) and that of the healthy subjects in the study by Mizumaki et al⁴ (−14%). In contrast, LVDs showed no further reduction in both CA/OH(−) and CA/OH(+) patients in the present study, while it was further reduced in neurally mediated syncope patients (−28%). Consequently, percent fractional shortening of the LV was reduced during semi-sitting/standing in CA/OH(−) and CA/OH(+) patients, while neurally mediated syncope patients showed a preserved shortening during the head-up tilt test.⁴ Therefore, hypotension during standing commonly develops in both patients with CA/OH(+) and neurally mediated syncope, however, cardiovascular system responses to postural changes seem different between the 2 entities. With a better understanding of the pathophysiology involved in the OH in CA, beneficial interventions may be innovated.

In addition, semi-sitting/standing stress echocardiography may have the potential for exploring previously unrecognized pathophysiology during postural changes. While the traditional orthostatic challenge test mainly evaluates symptoms, HR, and BP, semi-sitting/standing stress echocardiography—with its comprehensive hemodynamic and structural assessments—can further explore broad responses of cardiovascular system, including LV contractile reserve, SV/CO, SVR of resistance arteries, and the inferior vena cava. Orthopnea and postural changes in the location of pericardial fluid are important targets to explore the mechanism or characteristics. In addition, size reductions in the LV, left atrium, right ventricle, and right atrium during semi-sitting/standing, observed in the present report, seem important for pericardial disease with tamponade or constriction. This also seems highly important for mitral valve regurgitation, prolapse, its systolic anterior motion, tricuspid regurgitation, or others, since atrioventricular valves with connections to ventricular papillary muscles are considerably influenced by ventricular size.

Conclusions

Although confirmation in a larger number of patients is needed, broad abnormal responses of chronotropy, the LV, arteries, and veins during semi-sitting/standing were observed in 4 patients with cardiac amyloidosis and orthostatic hypotension. Among these findings, the paradoxical reduction in systemic vascular resistance may warrant the utmost attention. Semi-sitting or standing stress echocardiography holds significant potential for exploring broad abnormal responses of the cardiovascular system during postural changes, including orthostatic hypotension in patients with cardiac amyloidosis.

Funding Support and Author Disclosures

Funding was received by the Japan Society of the Promotion of Science KAKENHI, Tokyo, Japan, grant number 25K15972 (to Dr Iwataki). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Message

• •Multifaceted abnormal responses of broad cardiovascular system, including paradoxical reduction in systemic vascular resistance index, were observed in 4 patients with cardiac amyloidosis and orthostatic hypotension; furthermore, semi-sitting/standing stress echocardiography offers a potential method in understanding the associated pathophysiological mechanisms.