Impact of amyloidosis on the outcomes of patients with coronary artery disease: A nationwide analysis

Introduction

Amyloidosis is a rare group of multisystem diseases characterized by an abnormal deposition of misfolded proteins in the extracellular compartments of multiple organs in the body.¹ Deposition of amyloid fibrils alters the tissue architecture and disrupts the intracellular signaling pathways, compromising the function of the afflicted organs and leading to organ failure.^1,2 The prevalence rate of amyloidosis in the US is estimated to be 8–17 per 100,000 person-years among Medicare beneficiaries.³ Even though the prevalence of amyloidosis has increased significantly over the past years due to increased awareness of the condition and the advancement of diagnostic modalities, most cases of amyloidosis remain undiagnosed.^1,4

Although amyloidosis has a heterogenous clinical manifestation, the cardiovascular system is the most common organ system affected by amyloidosis, as the heart is involved in approximately 75% of cases of light chain amyloidosis (AL), the most commonly diagnosed type of cardiac amyloidosis.^2,5 Besides AL, the transthyretin subtype of amyloidosis (ATTR) also contributes to significant numbers of cardiac amyloidosis cases observed in clinical settings. Recent studies have implied that the prevalence of ATTR cardiac amyloidosis might not reflect the actual number in the population, as it is often underdiagnosed.^1,3,5,6 ATTR is further classified into two major phenotypes: ATTRv, which is characterized by inherent mutation of the transthyretin gene, and ATTRwt, which is mainly associated with age-related alterations.^3,5,7 ATTRv is highly prevalent among the black male population, while most subtypes of amyloidosis affect both sexes equally.³

Multiple studies have documented robust evidence of the association of cardiac amyloidosis with HFpEF (heart failure with preserved ejection fraction), conduction abnormalities, and aortic stenosis.^8,9 However, a concrete link between cardiac amyloidosis and coronary artery disease (CAD), the leading cause of cardiovascular death in adults in the USA, has not been completely explored and elucidated in studies.^10–12

Cardiac amyloidosis and CAD may share a common ground in chest pain manifestation as the deposition of amyloid in the lumen of epicardial coronary arteries is analogous to atherosclerotic changes in CAD.^13–15 On the other hand, cardiac amyloidosis is also thought to accelerate preexisting CAD by precipitating endothelial dysfunction.^16,17 A cohort study revealed that the prevalence of significant epicardial CAD in HFpEF patients with cardiac amyloidosis was slightly less compared to non-amyloidotic HFpEF patients.¹³ However, two other studies found that individuals with heart failure and concurrent cardiac amyloidosis had more calcified lesions of the coronary vessels.^14,17 A study by Hassan et al. also supported the notion that CAD is more prevalent in ATTR cardiac amyloidosis; however, they also found that ATTR was not associated with subsequent death or hospitalization among obstructive epicardial CAD patients.¹⁸

In our study, we delineate the differences in demographic characteristics and hospitalization outcomes in patients with coronary artery disease by comorbid cardiac amyloidosis and explore the risk factors for in-hospital mortality due to cardiac amyloidosis in coronary artery disease (CAD) inpatients. The lack of studies pertaining to these two diseases, coupled with the conflicting result findings from the existing studies, drives the authors to scrutinize and gain more insights to bridge the gap of associations between the two entities.

Methods

Results

Amyloidosis was seen in 7.3% of the inpatients admitted with a primary diagnosis of CAD and were majorly constituted by elder age (mean age, 66.88 years), male (64.2%), and white (70.9%). There was statistically no significant difference in demographics in these inpatients by comorbid amyloidosis. There was a significantly higher prevalence of comorbid diabetes, hypertension, arrhythmia, lipid disorders, obesity, and alcohol and tobacco abuse in CAD inpatients with comorbid amyloidosis compared to those without amyloidosis.

A higher proportion of CAD inpatients with comorbid amyloidosis had a major loss of function (56.5%), and higher in-hospital mortality (1.6%). There existed a significant mean difference in the LOS and total charges, thereby increasing it by two-day and 36,707$, respectively, during CAD-related hospitalization, as shown in Table 1.

We found that certain factors that may increase the risk of in-hospital mortality in CAD inpatients. Rising age increases the risk of mortality by 5% (OR 1.05, P <0.001), and median household income below the 50^th percentile increases the risk by 1.5 times (OR 1.50, P <0.001). Sex and race did not have any significant impact on mortality risk. While studying comorbidities, we found that arrhythmia (OR 2.28, P <0.001), alcohol abuse (OR 1.81, P <0.001), and diabetes (OR 1.25, P <0.001) increased the risk of mortality in CAD inpatients. After controlling the regression model with potential confounders, we found that comorbid amyloidosis increases the risk of in-hospital mortality by 87% (OR 1.87, P <0.001), as shown in Table 2.

Discussion

The aim of this study was to determine the relationship between CA and CAD, along with the implications of their concomitant occurrence with hospitalization outcomes. The results of this study revealed a significant reciprocal association between CAD and CA to several indicators that determine the hospitalization outcomes of the patients, such as in-hospital mortality, length of stay, economic burden, and major loss of functions.

From an epidemiological point of view, our study found that there were no significant demographic factors among patients with concurrent CAD and CA that were associated with hospitalization outcomes. These findings were in contrast with the outcomes of a study conducted by Ream et al., which showed that hospitalized individuals with ATTR-CA subtype were more likely to be older males (72.03% were males, and the overall mean age was 77.6 ± 11.17; p<0.0001) with CAD (30.51%; p value = 0.0002), while hospitalized patients with AL-CA subtype were associated with non-Hispanic White patients (63.71% of AL-CA patients were white; p-value = 0.0006).¹⁹ A retrospective cross-sectional study by Al Hadidi et al. that analyzed in-patient AL amyloidosis from the NIS database, also revealed that non-Hispanic White patients and Hispanic patients with AL-CA were associated with a higher risk of mortality compared to non-Hispanic Black patients (6.6% and 6.2% versus 4.9%, p <0.01).²⁰ Since the primary focus of our study is on CA in concurrence with CAD, our result findings might generate new insights into the association and relationship between the two disease entities, which could lie beyond demographic characteristics. These findings might also result from the overt frequency discrepancy between White and non-White patient populations in our study.

The presence of significant loss of functions of CAD patients concurrent with CA in this study might be explained by the fact that CA augments the progression of CAD, leading to increased morbidity by amplifying the degrees of microvascular dysfunction of the coronary vessels.^21,22 Progressive deposition of the amyloid substances in the wall of coronary vessels enhances luminal stenosis in pre-existing CAD, while the accumulation of amyloid deposits in the interstitial compartment compresses the surrounding vessels, impairing diastolic dysfunction, which could exert further deterioration of physical capacity.^22,23 This pathogenesis was also reinforced by a post-mortem study which identified amyloid deposits in the coronary arteries of 97% of individuals with AL (primary) amyloidosis, affecting the right coronary artery (RCA) with obstruction slightly more than the other branch of coronary arteries.²⁴ A study by Bulut et al. complemented the association of CAD and cardiac involvement by discovering the propensity of CFR (coronary flow reserve) decrement in 32 individuals with AA (secondary) amyloidosis with chronic inflammatory diseases (CID) compared to 73 non-amyloid CID and healthy controls (1.8 (1.5–2.1) vs. 2.1 (2–2.4) and 3 (2.8–3.2), p <0.001. CFR decrement, which is an indication of microvascular dysfunction of the coronary vessels, insinuates exercise capacity decline and cardiac performance diminution.^25,26 Additionally, another clinical trial by Rossi et al. also mentioned that individuals with cardiac amyloidosis and cardiac amyloidosis had a significant increase in 6-MWT (6-minute walking test) when complicated with aortic stenosis, implying a marked decline in the degrees of functional capacity, and therefore supports our findings.¹ A clinical trial conducted by Nitsche et al. found that among patients who were referred for TAVR with DPD bone scintigraphy disseminated from Perugini grading, 6 MWT values in meters were 194 (82-286) for DPD0, 260 (191-369) for DPD1, 95 (50-225) for DPD 2/3 with a p-value of 0.034.²⁷

Arrhythmia was also found to be a significant factor affecting the clinical outcomes of CA with CAD patients in this study. Deposition of amyloid substance within cardiac tissues, along with cellular injuries that arise from inflammatory reactions precipitated by the amyloid fibrils, has the potency to disrupt the normal electrophysiology of the heart conduction system, generating arrhythmia.²⁷ Multiple conducted studies have shown that atrial arrhythmias are along the most common comorbidities noted in patients with ATTR-CA, especially atrial fibrillation, which occur in as many as 71% of patients of ATTR-CA.²⁸ Not only is AF a common cause of decompensation leading to acute heart failure in ATTR-CA, leading to increased hospitalization and death in some cases; AF also increases the risk of embolic stroke, which puts the patients at ongoing risk for further loss of functions.^28,29 Apart from CA, CAD by itself is an independent risk factor for AF which advances the degree of focal ectopic activity.³⁰ Sometimes, the incidence of AF varies in different races for cancer patients.³¹ It has not been established whether the presence of CAD in CA could further augment the degree of AF complications such as embolic stroke and acute heart failure, which prompts the need for further investigation.

Many studies have linked cardiac amyloidosis to increased length of stay and readmission rate, which aggravate the economic burden.^32,33 A descriptive cohort study by Quoak et al. showed that CA patients had a mean LOS of 8.3 (11.1) days, 16.7% of patients were readmitted in 30 days, with 11.2% in-hospital mortality, and mean readmission cost of USD$18,536.³³ A national readmission database study by Arora et al. showed that hospitalizations for HF in amyloidosis were associated with longer LOS with a least-square mean difference of 1.46, 95% CI: 1.12–1.8; a higher 30-day readmission rate (OR:1.17; 95% CI: 1.05–1.31), and higher inpatient mortality (6%) compared to HF without amyloidosis.³² These findings were in line with our study. Acute heart failure, which is precipitated by restrictive cardiomyopathy and AF in CA, elevates the degree of severity, impacting hospitalization requirements and adding to procedural management complexity, which ultimately leads to an increased economic burden.²⁹ Heart failure readmissions and further interventions like left ventricular assist devices, if needed, add to the healthcare cost.^34,35 In theorem, coronary revascularization complications, which include pulmonary edema and cardiogenic shock, could occur more frequently in CA. A study showed that in STEMI patients with CA comorbidity, the presence of CA portends a greater risk of cardiogenic shock (12.7%) compared to STEMI patients without CA (7.3%).³⁶ The risk of intra-procedural coronary perforation as one of the possible complications due to stent mismatch could also lead to cardiac tamponade, which leads to more stent placement and the use of intravascular ultrasound, entailing an increased cost.³⁷ Standard management of cardiogenic shock would often require the utilization of an Impella device to relieve coronary perfusion in HF.³⁸ As the Impella device is currently widely used despite the rising cost, the prospect of an economic burden, if such complication occurred, could be extrapolated to be immense.

A national readmission database study (NRD) by Uddin et al. showed that another complication that is prominent in CA with STEMI is AKI requiring dialysis which occurred in 5.3% of cases in one study, compared to 4% incidence in STEMI patients without CA. ICU admissions were also more frequent with CA with STEMI (25.2%) compared to CA without STEMI 15.3%.³⁶ These findings could give rise to an increase in LOS and cost burden in CA. Apart from the complications from the complexity of the procedural conducts in the management of CA patients with CAD, the high cost of Tafamidis, which has been associated with the improvement of clinical outcomes of individuals with ATTR-CA, also adds to the increased economic burden trend with the mean cost of $225,000 per year.^39,40 As Tafamidis was deemed the most expensive cardiovascular drug in the US, coupled with the fact that non-Hispanic Black patients constitute most of the ATTR-CA patient population, the economic disadvantage of this population could lead to the inability of patients to afford co-pays, limiting the general use of Tafamidis for patients with ATTR-CA.^19,40 However, since our study did not show any significant difference in demographic factors, our study might provide another insight that racial disparity might not be the only factor that contributes to the lack of general use of Tafamidis.

Ultimately, this study also showed an increase in the mortality of CAD patients with CA by 87% (OR 1.87, P <0.001). In terms of the mechanism of death, cardiovascular events with circulatory failure due to cardiogenic shock and acute heart failure remain the most common cause of death in CA, which account for two-thirds of death causalities in both ATTR-CA and AL-CA.⁴¹ Although cascades of pathways have been postulated to elucidate the association between amyloidosis and CAD, conducted studies showed conflicting results pertaining to the increased mortality of CAD patients with cardiac amyloidosis. A recent study by Oladiran et al., in which CAD was found to be the second most common cardiac comorbidity in hospitalized patients with cardiac amyloidosis (23.5%), showed that the presence of cardiac manifestations generated by cardiac comorbidities such as non-ischemic cardiomyopathy, CAD, conduction abnormalities, HF, ischemic heart disease, arrhythmia, and pulmonary hypertension, cumulatively increased the risk of mortality in patients with amyloidosis.⁴² Another study by Donellan et al. also supported the notion by finding an increased risk of mortality among individuals with advanced stages of ATTR-CM (transthyretin cardiac amyloidosis) and a history of obstructive CAD as univariable with a Hazard Ratio of 1.66 (1.25–2.2); p <0.001.⁴³ Contrary to these findings, another study by Hassan et al. found that the presence of ATTR-CM did not portend an increased risk of hospitalization or mortality in patients with obstructive epicardial CAD (HR 0.72, 95% CI 0.28–1.94, p = 0.53).¹⁸ Furthermore, a study by Tahir et al. also discovered an inverse relationship between the prevalence of CAD and increased RWT (relative wall thickness), an indicator that was found to be one of the significant mortality predictors in AL amyloidosis. The results from the study by Tahir et al. showed that in CA patients with concomitant CAD, 11.4% had RWT ≥0.74, and 26% had RWT <0.74, p value = 0.019.⁴⁴ A number of conducted studies showed that individuals with HF concomitant with cardiac amyloidosis tend to have a lower prevalence of CAD, suggesting that HF caused by amyloidosis might follow a different course of pathogenesis than HF caused by traditional risk factors like CAD, diabetes mellitus, and smoking.^32,45 However, a challenge to the investigation to determine the causal relationship between cardiac amyloidosis and CAD remains a challenge because patients with cardiac amyloidosis tend to carry traditional risk factors of CAD such as diabetes, hypertension, dyslipidemia, and smoking history as well, shown in a large scale study conducted by Oladiran et al., which might ultimately blur the true reciprocal association between the two entities.⁴²

Conclusions

Amyloidosis is associated is higher inpatient mortality and worse outcomes in patients with CAD. The precise etiologies for this result need to be studied but could be related to an increase in various complications in CAD patients as well as in the patients who receive procedural interventions. Further studies are needed in this matter to determine the appropriate management of CAD in patients with amyloidosis.