Baseline characteristics
In our study of patients admitted with acute myocardial injury, we found 0.06% had FH, like findings by Elbadawi et al from a study of patients with acute MI who found a prevalence of 0.07% using the NIS.8 Our study is the second NIS-based study to estimate prevalence of FH among hospitalised patients in the USA. Data on all-comers or patients with ACS with FH are lacking in the USA. Reported prevalence is very varied globally and is dependent on the population, the setting and clinical criteria used. For instance, Schmidt et al estimated that among patients with ACS, prevalence of FH was 0.35%,9 but a similar analysis by De Luca et al stated a prevalence of 3.3%.10 We observed a higher proportion of males which is likely due to the higher prevalence of ischaemic heart disease among men. Patients with FH were 8 years younger but had a higher prevalence of CAD which is similar to findings in most observational studies.8 11
Myocardial injury pattern
Patients with FH had a higher prevalence of STEMI and NSTEMI, consistent with what is widely reported in literature. Prevalence of non-type 1 MI among patients with FH has not been previously reported. It is widely reported that hyperlipidaemia is a risk factor for takotsubo cardiomyopathy.12 13 There are no previous studies that specifically investigated an association of takotsubo cardiomyopathy or type 2 MI with FH. Our study observed a lower prevalence of type 2 MI, takotsubo cardiomyopathy and other forms of acute myocardial injury among patients with FH compared with those without. Our stated rate of takotsubo cardiomyopathy of 1.69% agrees with the incidence rate of takotsubo cardiomyopathy among patients with acute MI in the HORIZONS-AMI trial of 0.5–2.1%.14 The lower comorbidity burden and younger age are likely protective against the occurrence of demand ischaemia and takotsubo among patients with FH.15 16 This favourable outcome of lower odds of non-type 1 MI persisted after accounting for age and comorbidity burden. Studies have reported a better lifestyle among patients with FH, starting from an early age compared with the general population. This could explain a potentially robust cardiometabolic reserve in times of stress compared with the general population.17 It has been hypothesised in many translational studies that there are other factors such as enhanced thrombogenicity that plays a role in the pathogenesis of coronary disease in patients with FH besides elevated LDL.18 This likely makes patients with FH prone to type 1 MI compared with others such as type 2 MI or takotsubo.
Primary and secondary clinical outcomes
Like observations made by Kheiri et al, we also observed increased utilisation of mechanical circulatory support among patients with FH.19 Additionally, we studied the rate of intracardiac thrombus and observed increased odds among those with FH, a problem that was previously not studied. The concept of enhanced platelet activation has been studied and reported to be higher in patients with elevated serum cholesterol. This, together with a higher rate of transmural infarction, may explain these observations.20
We also believe that higher prevalence of STEMI with transmural ischaemia and myocardial stunning is the likely cause of increased mechanical circulatory support device use as well as higher risk of intracardiac thrombosis.
In our study, we observed a paradoxically lower all-cause mortality among patients with FH admitted with acute myocardial injury and this reduction remained significant among patients with type 1 MI after stratification. Our findings agree with the findings of prior similar studies. For instance, in an analysis of a readmission database between 2016 and 2018, Elbadawi et al found that patients with FH admitted with acute MI had a non-significant trend towards lower mortality.8 Similarly, an NIS-based study that looked at outcomes of acute MI between 2016 and 2018 found lower odds of inpatient mortality among patients with FH.5 Several studies have found a negative correlation between serum LDL and short-term mortality after MI.21 22 The relationship between serum LDL and mortality is however not present linearly across all spectra of hypercholesterolaemia. For example, in a Danish population-based study, Johannesen et al found a U-shaped relationship between serum LDL and mortality following acute MI, with mortality reduction occurring between LDL level of 70 mg/dL and 140 mg/dL. They added that these observations applied only to patients who were not on statin therapy.23 Explaining this well-known lipid-ACS paradox has however been challenging. Some authors believe that the negative relationship between moderately elevated serum LDL and mortality may be a simple case of lead-time bias. It is thought that early screening offers patients with FH earlier treatment with statins which are known to improve outcomes during acute MI.24 25 There have been some postulates about the mitigating effect of increased remnant lipoproteins. They are often elevated in patients with FH and their levels have been shown to correlate negatively with mortality and adverse outcomes after MI.26
Additionally, Ravnskov et al, in a systematic review, found no significant difference in mortality between cohorts with and without elevated LDL-C and confirmed a similar U-shaped association as stated above. They reported that this observation was present independent of statin therapy.27 Studies have found a better lifestyle, including higher physical activity and less smoking among patients with FH which may portend an overall improved cardiovascular health. Patients with FH, though at increased risk of coronary atherosclerosis, may have a more robust cardiometabolic reserve to survive acute stress such as MI.17
Finally, ischaemic preconditioning, a concept widely proven to be protective in animal models but without much empirical backing in humans, has been considered as well.28 29
We also found a higher rate of revascularisation among patients with FH. This may be due to more STEMI and high-risk NSTEMI in this group. Evidence from previous studies supports this observation. For instance, in a case series of 45 young patients who underwent coronary angiography, those with FH had more complex CAD compared with those without FH.30 Similarly, a French registry study with 5147 patients found a higher prevalence of triple-vessel CAD among those with FH.31 Another review of the RICO database in 2021 by Yao et al found that definite FH, as determined by a Dutch lipid clinic network score >6, was associated with more complex coronary lesions, including a higher syntax score, more bifurcation lesions and more multivessel disease.32 In addition to the clinical outcomes, it is worth noting the healthcare utilisation among patients with FH. We observed a reduced length of stay in the hospital but no significant difference in total charges. However, a study by Patel et al, based on electronic record reviews, found high annual total revenue among patients with FH.33
Study strengths and limitations
Our study was based on large, pooled data, which increased its power. With FH being an uncommon condition, our study design and large database of the NIS provide a good basis for hypothesis generation. The NIS is generated at the hospital level and weighted to reflect the US population thus a reliable source to make hypotheses about population-wide problems in the inpatient setting. One limitation is that the NIS may be subject to coding errors which puts it at risk of misclassification bias. Using a specific and sensitive endpoint such as all-cause mortality as a primary outcome minimises such risk. Our study includes data from 2018 to 2020 during which the NIS relies on ICD-10 codes that have improved specificity and are universally comparable. Additionally, most diagnoses of FH are made in the outpatient setting, often by experts in their field and often may require further testing including genetic study and thus are less likely to be misclassified.
Another limitation is that the NIS does not include information on outpatient care. An important limitation pertaining to this study is that the NIS does not contain codes for medical therapeutics. Nonetheless, the observations made raise pertinent hypotheses that may need future robust controlled trials to ascertain.
Conclusion and future research
Our study found that patients with FH who were hospitalised with acute myocardial injury had a higher prevalence of STEMI and NSTEMI, but a lower prevalence of type 2 MI and takotsubo cardiomyopathy. Additionally, they required a higher number of multiple stents and bypasses and had greater need for mechanical circulatory support devices. FH was associated with lower all-cause mortality and mechanical ventilation rates, and there were no significant differences in cardiac arrest, cardiogenic shock, ventricular tachycardia, cardioversion or new ICD implantation. Moving forward, longitudinal studies are needed to further investigate the long-term outcomes, including major adverse cardiovascular events, among patients with FH. These studies should consider the evolving diagnostic testing, clinical criteria and novel therapies available for FH. We also look forward to reviewing this concept using a database in which the impact of statin therapy on outcomes in patients with FH can be assessed.
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