Abstract
Background
Cardiac amyloidosis (CA) and coronary artery disease (CAD) can have similar presentations in the acute care setting which can potentially delay the diagnosis of CA.
Methods
We conducted a retrospective analysis of patients referred to our institution for evaluation of cardiac amyloidosis. We obtained demographic and clinical characteristics, laboratory data, and echocardiographic measurements of those patients with confirmed cardiac amyloidosis. The population was divided into two groups based on the presence of CAD. Frequency of heart failure hospitalizations, and one-year overall mortality were compared between both groups.
Results
Between 2018 to 2021, 327 patients with suspected cardiac amyloidosis were referred to our institution. Out of 114 confirmed CA patients, 28 patients (25%) had concomitant CAD and CA. The overall mean age of CA diagnosis was 74.7 (±8.4) years for the CAD group and 69.7 (±9.8) for the non-CAD group (P value 0.002). Notably, a higher percentage of males were observed in the CAD group (92/.9% vs. 60%, p-value 0.002), and a higher prevalence of hypertension (92.9% vs 70%, p-value 0.018) and dyslipidemia (89.3% vs 59%, p-value 0.004) were also found in the CAD group. Overall, there were no significant differences in outcomes.
Conclusion
Larger studies are needed to identify characteristics that will result in a prompt diagnosis of CA in patients with concomitant CAD. Although our study did not appreciate a significant difference between these two groups, outcomes of our study were likely impacted by a small sample size in the CA with CAD cohort.
Introduction
Cardiac amyloidosis (CA) and coronary artery disease (CAD) are two distinct cardiovascular conditions that can present with similar clinical features, particularly in the acute care setting, . Both disorders often manifest with heart failure symptoms, chest pain, and elevations in cardiac biomarkers such as B-type natriuretic peptide (BNP) and troponin, which can complicate the differential diagnosis. The overlap in presentation between CA and CAD can lead to delays in the accurate diagnosis and treatment of cardiac amyloidosis, potentially worsening patient outcomes.
Cardiac amyloidosis is an infiltrative cardiomyopathy caused by the deposition of misfolded amyloid fibrils within the myocardial tissue. , CA can also infiltrate coronary vessels, leading to myocardial ischemia secondary to microcirculatory dysfunction and reduced coronary flow reserve. , Patients with CA tend to be older but have fewer calcified and ostial lesions compared to non-CA heart failure patients. Interestingly, CA can manifest as angina pectoris, even in the presence of normal-appearing epicardial coronary arteries.
A study by Gilstrap et al. used fee for service Medicare beneficiary data to estimate a CA incidence rate of 17 per 100 000 person-years, and prevalence rate of 55 per 100 000 person-years. The two primary types of CA are light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). ATTR amyloidosis is more common and has many variants, ATTR wild type has estimated prevalence of 155 to 191 cases per million persons, and the ATTRv (Val122LLe) is found in 3.4 % of self-identified African Americans. ATTR exhibits age-dependent clinical penetrance with ATTRwt (wild type), regarded as the most common variant and typically found in white male cohorts greater than 60 years of age, as demonstrated in our study. Additionally, specific populations are known to carry higher prevalence of amyloidosis; for instance, an estimated 4-16 % of patients with aortic stenosis have coexisting ATTR amyloidosis. Studies also show a significant overlap between CA and heart failure, with an estimated prevalence of 13.7% of HF patients also having CA. When further stratified based on ejection fraction, the prevalence of CA in patients with heart failure (HF) with preserved ejection fraction (EF) was an estimated 15.1%, while the prevalence of CA in patients with HF with reduced EF, was 11.3%.
Notably, the prevalence of ATTR CA has risen, largely due to multiple factors, including an aging population and advances in diagnostic modalities allowing for increased disease detection. Despite being underrecognized, the use of 99m technetium bone scintigraphy, alongside echocardiography and magnetic resonance imaging, has facilitated increased detection of ATTR by way of non-invasive measures. Diagnosis relies on clinical symptoms, imaging techniques, and histological examination, which can be obtained through directional atherectomy. , ,
The presence of CAD in patients with underlying CA may exacerbate heart failure symptoms, further elevate cardiac biomarkers, and make the diagnosis of CA more challenging. Additionally, patients with both CAD and CA have been shown to have significantly worse outcomes. Babu et al. found that CAD inpatients with amyloidosis had higher in-hospital mortality (1.6% vs. 0.9%), with an odds ratio (OR) of 1.87 (95% CI 1.66–2.11, p <0.001). They also reported increased length of hospitalization rates (6.66 days vs. 4.68 days) and higher total charges ($156,149.76 vs. $119,442.71) for admitted CAD with amyloidosis. The study also showed that CAD inpatients with amyloidosis had a higher rate of major loss of function (56.5% vs. 30.5%).
Early and accurate diagnosis of CA is critical, as the degree of cardiac involvement significantly impacts survival. Recent therapeutic advances in AL and ATTR amyloidosis have improved patient outcomes, emphasizing the importance of early disease detection and timely intervention. , Therapies for AL, derived from multiple myeloma treatment, have drastically improved AL survival in the last decade, with most patients surviving >10-15 years beyond diagnosis. For ATTR, novel disease-modifying therapies have also been found. Tafamidis, a TTR stabilizer, has been shown to reduce all-cause mortality, lower re-hospitalization rates, and improve heart failure symptoms. TTR silencers, such as patisiran and inotersen, have also demonstrated beneficial cardiac effects. , The therapeutic approach to CA with concomitant CAD is complex and requires careful consideration of medication selection and revascularization strategies. , Early recognition of CA in patients presenting with acute coronary syndrome is crucial for appropriate management and improved outcomes. ,
Despite the clinical significance, the prevalence and impact of concomitant CAD in patients with CA have not been well characterized. Understanding the interplay between these two conditions is critical for improving diagnostic accuracy and optimizing patient outcomes.
This study aims to: 1) Determine the overall prevalence of CAD in patients with CA; 2) Identify differences in baseline characteristics and comorbidities in patients with CA with CAD vs. without CAD; 3) Compare outcomes, including heart failure hospitalizations, acute coronary syndrome events, heart transplantation rates, and mortality in patients with coexisting CA and CAD.
Methods
Study design and setting
This study is a retrospective analysis of patients with suspected CA at our center from 2018 through 2021 was performed. Baseline demographics, comorbidities, and outcomes were compared between patients with CAD (Group 1, n = 29) and non-CAD (Group 2, n = 80). Baseline demographic information, comorbidities, and clinical characteristics were obtained from electronic medical records. Clinical data, including cardiac biomarkers (BNP, troponin I), renal function (creatinine, eGFR), medication utilization, and hematologic parameters (hemoglobin, albumin), were collected. Echocardiographic measurements, including left ventricular ejection fraction (LVEF), left ventricular size, left and right atrial size, LV strain and the presence of diastolic dysfunction, were also recorded.
Outcome measures
Primary outcomes included one-year mortality. Secondary outcomes were the frequency of heart failure hospitalizations and heart transplantation events. Follow-up for outcomes began at the time of CA diagnosis, with patients censored at the time of transplant or death.
Statistical analysis
Baseline patient characteristics were compared between the CAD and Non-CAD groups. Analyses were conducted between the CA with CAD compared to CA without CAD groups. Secondary analyses were also conducted between the TTR and AL subgroups for patients with CAD and patients without CAD. Mean values with standard deviations (SD) were used to describe continuous variables and numbers (percentages) were reported for categorical variables. Chi-square tests were used for categorical variables and two independent sample t-test for continuous variables. Follow-up for all outcomes was started at the time of diagnosis. 1 year mortality was analyzed using Kaplan-Meier methodology. Patients were censored at the time of transplant or death. All tests were 2-sided, and p -values <0.05 were considered statistically significant. All analyses were performed using SPSS version 20 (IBM SPSS Statistics).
Results
Out of 327 patients referred to our institution for suspected CA between 2018 and 2021, 114 patients were confirmed to have CA and included in the study.
Among these, 28 patients (24.5%, group 1) had concomitant CAD, while 80 patients (75.5%, group 2) had CA without CAD ( Fig. 1 ). The mean age at diagnosis was significantly higher in the CAD group compared to the non-CAD group (74.7 ± 8.4 years vs. 68.1 ± 9.7 years, p= 0.002) ( Table 1 ). The CAD group also had a significantly higher proportion of male patients (92.9% vs. 60.5%, p =0.002) ( Table 1 ). Comorbidities such as hypertension (92.9% vs. 70.9 p = 0.018) and dyslipidemia (89.3% vs. 59.3%, p = 0.004) ( Table 1 ) were more prevalent in the CAD group. Patients in the non-CAD group were more likely to be initiated on CA treatment compared to those in the CAD group. Among the non-CAD cohort, patients diagnosed with TTR were more likely than AL patients to have diabetes and hypertension ( p value <0.05) ( Table 2 ). The mean LVEF across the groups was 45% ( Table 3 ). Echocardiographic findings revealed that the left atrial volume index (LAVI) was significantly higher in the CAD group compared to the non-CAD group (57 mL/m² vs. 47 mL/m², p = 0.004) ( Table 3 ). However, no significant differences were observed in other echocardiographic parameters, such as LVEF, diastolic dysfunction, or right ventricular function, between the two groups. Table 4 summarizes treatment differences between the 2 groups. There was no significant difference in one-year mortality (50% in the CAD group vs. 42.4% in the non-CAD group, p = 0.741) ( Table 5 , Fig. 2 ), or overall mortality between the two groups (46.4% in the CAD group vs. 52.9% in the non-CAD group, p =0.55) ( Table 5 ).
| Variable | Total (N=114) | No CAD (N=86) | CAD (N=28) | p-value |
|---|---|---|---|---|
| Age at diagnosis | 69.7 (9.8) | 68.1 (9.7) | 74.7 (8.4) | 0.002 |
| Male | 78 (68.4%) | 52 (60.5%) | 26 (92.9%) | 0.002 |
| Race | 0.747 | |||
| White | 58 (51.8%) | 42 (50%) | 16 (57.1%) | |
| Black | 53 (47.3%) | 35 (48.8%) | 13 (42.9%) | |
| Hispanic | 1 (0.9%) | 1 (1.2%) | 0 (0%) | |
| Race | 0.585 | |||
| White (Hispanic=1) | 59 (52.7%) | 43 (51.2%) | 16 (57.1%) | |
| Black | 53 (47.3%) | 41 (48.8%) | 12 (42.9%) | |
| Diabetes | 24 (21.1%) | 20 (23.3%) | 4 (14.3%) | 0.312 |
| Hypertension | 87 (76.3%) | 61 (70.9%) | 26 (92.9%) | 0.018 |
| Dyslipidemia | 76 (66.7%) | 51 (59.3%) | 25 (89.3%) | 0.004 |
| CKD | 70 (61.4%) | 54 (62.8%) | 16 (57.1%) | 0.594 |
| Smoking history | 44 (38.6%) | 34 (39.5%) | 10 (35.7%) | 0.718 |
| Obesity | 18 (15.8%) | 14 (17.4%) | 3 (10.7%) | 0.554 |
| Family history of CAD | 6 (5.3%) | 5 (5.8%) | 1 (3.6%) | 1 |
| Amyloid type | 0.758 | |||
| AL | 42 (36.8%) | 31 (36.1%) | 11 (39.3%) | |
| TTR | 72 (63.2%) | 55 (63.9%) | 17 (60.7%) | |
| NYHA class | 0.350 | |||
| I | 5 (4.4) | 5 (5.8) | 0 | |
| II | 26 (22.8) | 21 (24.4) | 5 (17.9) | |
| III | 76 (66.7) | 56 (65.1) | 20 (71.4) | |
| IV | 7 (6.1) | 4 (4.6) | 3 (10.7) | |
| Troponin I (ng/ml), N | 80 | 59 | 21 | |
| 0.16 [0.07–0.3] | 0.14 [0.07–0.28] | 0.22 [0.11–0.34] | 0.253 | |
| BNP (pg/ml), N | 107 | 80 | 27 | |
| 769 [418–1479] | 798 [434–1568] | 644 [372–1186] | 0.559 | |
| Cr (mg/dl) | 1.3 [1.0–1.8] | 1.2 [ 0.9–1.7] | 1.45 [1.15–2.05] | 0.12 |
| eGFR (ml/min/1.73 m 2 ) | 57.2 [37.0–60.0] | 58.9 [ 41.1–60.0] | 48.9 [31.8–60.0] | 0.094 |
| Hemoglobin (mg/dl) | 12.6 [11.4–13.9] | 12.6 [11.1–13.9] | 12.6 [11.5–13.8] | 0.913 |
| Albumin (g/dl) | 3.4 [2.9–3.7] | 3.3 [2.9–3.7] | 3.5 [3.1–3.8] | 0.227 |
| Therapy.initiation | 0.021 | |||
| No | 28 (24.8) | 26 (30.6) | 2 (7.1) | |
| Yes | 85 (75.2) | 59 (69.4) | 26 (92.9) |
| No CAD (N=86) | CAD (N=28) | |||||
|---|---|---|---|---|---|---|
| AL (N=31) | TTR (N=55) | P-value | AL (N=11) | TTR (N=17) | P-value | |
| Age at diagnosis | 61.2 (8.4) | 71.9 (8.2) | <0.001 | 68.7 (7.1) | 78.6 (6.9) | 0.001 |
| Male | 13 (41.9%) | 39 (70.9%) | 0.008 | 10 (90.9%) | 16 (94.1%) | 1 |
| Race | <0.001 | 0.441 | ||||
| White + 1 Hispanic | 24 (80%) | 19 (35.2%) | 5 (45.5%) | 11 (64.7%) | ||
| Black | 6 (20%) | 35 (64.8%) | 6 (54.5%) | 6 (35.3%) | ||
| Diabetes | 3 (9.7%) | 17 (30.9%) | 0.025 | 0 (0%) | 4 (23.5%) | 0.132 |
| Hypertension | 16 (51.6%) | 45 (81.8%) | 0.003 | 9 (81.8%) | 17 (100%) | 0.145 |
| Dyslipidemia | 14 (45.2%) | 37 (67.3%) | 0.045 | 19 (90.9%) | 15 (88.2%) | 1 |
| CKD | 15 (48.4%) | 39 (70.9%) | 0.038 | 4 (36.4%) | 12 (70.6%) | 0.121 |
| Smoking history | 12 (38.7%) | 22 (40%) | 0.906 | 4 (36.4%) | 6 (35.3%) | 1 |
| Obesity | 3 (9.7%) | 12 (21.8%) | 0.154 | 1 (9.1%) | 2 (11.8%) | 1 |
| Family history of CAD | 2 (6.5%) | 3 (5.5%) | 1 | 1 (9.1%) | 0 (0%) | 0.393 |
| NYHA class | 0.052 | 0.628 | ||||
| I | 7 (22.6%) | 18 (34.0%) | 3 (27.3%) | 3 (17.7%) | ||
| II | 13 (41.9%) | 9 (17.0%) | 4 (36.4%) | 5 (29.4%) | ||
| III | 8 (25.8%) | 23 (43.4%) | 4 (36.4%) | 6 (35.3%) | ||
| IV | 3 (9.7%) | 3 (5.6%) | 0 (0%) | 3 (17.7%) | ||
| Troponin I (ng/ml), N | 21 | 38 | 8 | 13 | ||
| 0.21 [0.07–0.42] | 0.13 [0.07–0.26] | 0.506 | 0.18 [0.12-0.69] | 0.22 [0.10-0.34] | 0.856 | |
| BNP (pg/ml) | 30 | 50 | 10 | 17 | ||
| 796 [464–2051] | 798 {379–1413] | 0.477 | 607 [372–2054] | 747 [447–942] | 0.959 | |
| Cr (mg/dl) | 1.0 [0.8–1.7] | 1.3 [1.0–1.8] | 0.114 | 1.2 [1.0–2.3] | 1.6 [1.2–1.8] | 0.310 |
| eGFR (ml/min/1.73 m 2 ) | 60 [41–60] | 57 [37–60] | 0.581 | 60 [26–60] | 41 [34–57] | 0.327 |
| Hemoglobin (mg/dl) | 12.9 [11.8–13.6] | 12.3 [11.0–14.0] | 0.587 | 12.4 [11.4–13.4] | 12.9 [12.0–13.9] | 0.459 |
| Albumin (g/dl) | 3.1 [2.6–3.6] | 3.4 [3.0–3.7] | 0.107 | 3.3 [2.9–3.5] | 3.6 [3.3–3.8] | 0.157 |
| Therapy.initiation | 0.001 | 1 | ||||
| No | 2 (6.4) | 24 (44.4) | 1 (9.1) | 1 (5.9) | ||
| Yes | 29 (93.6) | 30 (55.6) | 10 (90.9) | 16 (94.1) | ||
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