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"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

This installment: A noteworthy case study.

What can be done for a 16-year-old girl with chest pain and worsening dyspnea? That's what clinicians had to determine when she presented for emergency care. As Muhammad Liaquat Raza, MPhil, PhD, of Al Fatima Hospital in Karachi, Pakistan, and colleagues, explained in , the team learned that she had a confirmed diagnosis of familial hypercholesterolemia (FH), a rare autosomal dominant genetic disorder.

FH, which is characterized by elevated low-density lipoprotein cholesterol (LDL-C), premature coronary heart disease, and vascular atherosclerosis, can be challenging to treat.

The first step in the evaluation was cardiac auscultation, which detected a distinct ejection systolic murmur along the right upper edge of the sternum. The case authors also observed defined yellow papules scattered on the patient's hands, elbows, and legs, and extensor surface of the hands.

An electrocardiogram revealed, as Raza and co-authors described, "inadequate progression of R waves in anterior leads," accompanied by depression of the ST segment and inverted T waves in the lateral leads. Lab tests identified high troponin I levels of 17.15 ng/dL, and evidence of dyslipidemia, including total cholesterol of 569 mg/dL, high-density lipoprotein (HDL) cholesterol of 59 mg/dL, LDL-C of 484 mg/dL, and triglycerides of 129 mg/dL. Results of other laboratory tests were unremarkable.

Transthoracic echocardiogram revealed severe generalized left ventricular systolic dysfunction, with an ejection fraction of 20%, as well as significant secondary mitral regurgitation and aortic valve stenosis, with mean and peak pressure gradients of 14 and 22 mmHg, respectively.

CT angiogram confirmed these findings, showing thickening of the aortic wall along with calcification in the ascending aorta -- i.e., distinct wall thickening that encompassed coronary ostia and branches of the aortic arch.

Aortic measurements were as follows:

• Annulus: 14.9 mm

• Sinus: 10.6 mm

• Sinotubular junction: 11.5 mm

• Ascending aorta: 19.8 mm

• Arch: 18.3 mm

• Descending thoracic aorta: 13.2 mm

• Abdominal aorta: 7.8 mm

A coronary angiogram showed significant ostial stenosis affecting the left anterior descending (LAD) and right coronary arteries. After consultation with the hospital's multidisciplinary team, the patient underwent a percutaneous coronary intervention for LAD and right coronary artery.

Follow-up echocardiogram showed that the procedure improved the patient's left ventricular systolic function considerably, achieving an ejection fraction of 40%, reducing the mitral regurgitation, and notably, increasing the supravalvular stenosis pressure gradient.

Following revascularization, the case authors reported, the patient received optimized medical therapy with high-dose statin and ezetimibe, and the combined approaches led to a marked improvement in her symptoms. At 1-month follow-up, she was asymptomatic and receiving regular clinical monitoring.

Discussion

As this case illustrates, familial hypercholesterolemia – which affects only 1 in a million individuals – is characterized by elevated LDL-C, formation of xanthomas, development of premature coronary heart disease, and vascular atherosclerosis. FH is thought to occur due to mutations in the LDL receptor gene, and tends to result in accelerated atherogenesis primarily affecting the aorta, and associated narrowing of the aortic root.

Raza and co-authors noted that there are a variety of strategies that can be used to FH. There is strong evidence to support the use of high-dose statin therapy with concomitant ezetimibe to reduce LDL levels.

"For , lipid apheresis and innovative pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as alirocumab and evolocumab, offer promising alternatives. PCSK9 inhibitors augment LDL receptor availability, promoting enhanced LDL absorption and consequent reduction in cardiovascular risk," the case authors wrote.

The extent of the condition's impact on the heart and aortic system can be assessed using noninvasive , which plays a pivotal role in the evaluation process, the team said.

The process may involve a range of imaging techniques including echocardiography, MRI, and CT scans, each of which provide detailed insights into the heart, aorta, and coronary arteries, Raza and co-authors noted. An echocardiogram can help delineate valvular function and blood flow parameters; CT scans reveal calcification of the coronary arteries indicating atherosclerosis; and "left heart catheterization guides treatment planning by delineating coronary involvement," the team explained.

Management options range from use of percutaneous stents and conventional coronary artery bypass grafts to surgical and a combination of these approaches, depending on the disease severity and the patient's condition.

Conclusion

"Early-onset coronary atherosclerosis resulting in ischemic heart disease imposes a substantial burden," given its tendency to lead to acute coronary events in patients at a younger age, the authors said, noting that the case highlights the importance of detecting and managing cholesterol disorders in early stages to minimize the possibility of substantial morbidity and mortality.

The genetic condition is also associated with complications including aortic root involvement, supravalvular aortic stenosis, and premature coronary ostial stenosis, and is responsible for a significantly increased risk of morbidity and mortality in a youthful population.

Unraveling complications that occur due to FH requires comprehensive evaluation using both non-invasive and invasive diagnostic tools, and clinicians should consider use of novel therapeutic agents to mitigate disease progression, the authors said.

"The case study underscores the urgency of comprehensive management strategies in confronting the myriad challenges of FH, emphasizing the value of early intervention, innovative therapies, and rigorous imaging modalities for unraveling the intricate cardiovascular manifestations of this condition," Raza and co-authors concluded.

Read previous installments in this series:

Part 1: Hypercholesterolemia: A Complex System

Part 2: Consequences of Hypercholesterolemia

Part 3: Genetics of Hypercholesterolemia

Part 4: Case Study: High Lipoprotein(a) Levels in Younger Patients Are Not So Clear Cut

Part 5: The Shifting Epidemiology of Hypercholesterolemia

Part 6: Diagnosing Hypercholesterolemia

Part 7: Primary Prevention in Hypercholesterolemia