Biomarkers and Personalized Medicine in Cardiovascular Disease Symposium

Serial Lipoprotein(a) Measurements in Heart Transplant Recipients

Andrew S. Kao MD ¹, Antoinette Birs MD ², Jose Cruz Rodriguez MD ²

¹Department of Medicine, UC San Diego Health, La Jolla, CA, USA

²Division of Cardiovascular Medicine, UC San Diego Health, La Jolla, CA, USA

Introduction: Lipoprotein (a), a genetically determined lipid carrier molecule consists of low-density lipoprotein with apolipoprotein B-100 and apolipoprotein (a), is a well-established biomarker with casual association to development of atherosclerotic cardiovascular disease (ASCVD) events.¹ ACC/AHA guidelines recommend lipid lowering therapy for Lp(a) level >50 mg/dL,²  as Lp(a) has a positive association with intima thickening leading to coronary allograft vasculopathy (CAV).^3-4 The following case demonstrates the utility in serial Lp(a) level as a critical biomarker for CAV development in conjunction with surveillance cardiac catheterization.

Case: A 49-year-old man with T2DM, Stage 4 CKD, hyperlipidemia, and a history of end stage ischemic cardiomyopathy with HeartMate 3 LVAD device as a bridge to orthotopic heart transplant (OHT, month 0). His A1c was 8.4% at the time of OHT. Lipoprotein (a) level was 113 mg/dL (Month -10) pre-OHT while on high intensity statin. Aggressive management of his baseline risk factors was continued post-transplant. Maximal intimal thickness (MIT) at post-transplant year 1 (Month 12) catheterization demonstrated left main (LM) 0.23mm, proximal LAD (pLAD) 0.25mm, and mid-LAD 0.22mm; at year 2 (Month 24): LM 0.31 mm, pLAD 0.28mm, and mid-LAD 0.24mm. Both surveillance catheterization showed no angiographically significant CAV with ISHLT class 0 and normal LVEDP. Graft function remained intact (Month 23) and post-transplant Lp(a) level was 37 mg/dL (Month 26).

Discussion: Based on ISHLT classification, CAV may be detected with angiography in 8% of HTx recipients within first year post-transplant, 32% in the first 5 years, and 43% in the first 8 years.⁵ Current data on role on Lp(a) utility as a surveillance biomarker in CAV remain scarce. One recent study of 150 HTx patients at a tertiary center observed that Lp(a) ≥ 30 mg/dL portends a higher risk of early CAV development.³ Our case demonstrates a significant decrease in post-transplant Lp(a) level with aggressive management of cardiovascular risk factors, and a favorable clinical outcome with MIT < 0.5mm on both surveillance angiography. However, it is crucial to acknowledge that immunosuppressive agents have been observed to decrease serum Lp(a) level.^6-7

Conclusion: Lp(a) is a highly prognostic biomarker that informs the risk of future cardiovascular events. In addition to surveillance angiography, we support serial assessment of Lp(a) level to assess for CAV development, and risk stratify for further interventions among cardiac transplant recipients.

References:

1. Bhatia HS, Wilkinson MJ. Lipoprotein(a): Evidence for Role as a Causal Risk Factor in Cardiovascular Disease and Emerging Therapies. J Clin Med. 2022 Oct 13;11(20):6040.

2. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285-e350.

3. González-Quijano M, Grande-Trillo A, Esteve-Ruiz I, Aranda-Dios A, Sobrino-Márquez JM, Rangel-Sousa D. Elevated Lipoprotein A Levels and Development of Moderate or Severe Cardiac Allograft Vasculopathy in Patients with Heart Transplants. Transplant Proc. 2023 Dec;55(10):2295-2298.

4. Parameshwar J, Foote J, Sharples L, Wallwork J, Large S, Schofield P. Lipids, lipoprotein (a) and coronary artery disease in patients following cardiac transplantation. Transpl Int. 1996;9(5):481-5.

5. Taylor DO, Edwards LB, Boucek MM, Trulock EP, Waltz DA, Keck BM, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplantation report: 2006. J Heart Lung Transplant. 2006;25:869 – 879

6. Farmer JA, Ballantyne CM, Frazier OH, Radovancevic B, Payton-Ross C, Patsch W, Morrisett JD, Gotto AM Jr, Young JB. Lipoprotein(a) and apolipoprotein changes after cardiac transplantation. J Am Coll Cardiol. 1991 Oct;18(4):926-30.

7. DeNofrio D, Desai S, Rader DJ, Chang G, Kelley MP, Acker MA, Loh E. Changes in lipoprotein(a) concentration after orthotopic heart transplantation. Am Heart J. 2000 Apr;139(4):729-33.

Disclosures: All authors have no competing interests to declare.

Cardiac magnetic resonance imaging paralleled recurrent pericarditis clinical response to rilonacept treatment over 18 months: a RHAPSODY subgroup analysis

Authors:

Paul C. Cremer, MD¹, Antonio Brucato, MD², Antonella Insalaco, MD³, David Lin, MD⁴, Sushil A. Luis, MBBS, PhD⁵, Deborah H. Kwon, MD¹, Christine L. Jellis, MD, PhD¹, JoAnn Clair, PhD, MBA⁶, Allison Curtis, PhD⁶, Sheldon Wang, PhD⁶, Allan L. Klein, MD¹, Massimo Imazio, MD⁷, John F. Paolini,MD, PhD⁶, for the RHAPSODY investigators. 

¹Department of Cardiovascular Imaging, Center for the Diagnosis and Treatment of Pericardial Diseases, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA;  

²Department of Biomedical and Clinical Science, University of Milano, Fatebenefratelli Hospital, Milano, Italy;  

³Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy;  

⁴Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, Minnesota, USA;  

⁵Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA

⁶Kiniksa Pharmaceuticals, Lexington, Massachusetts, USA;  

⁷Cardiothoracic Department, University Hospital "Santa Maria della Misericordia", ASUFC, Udine, Italy;  

Background: Rilonacept treatment in RHAPSODY resolved active pericarditis recurrences, and long-term treatment led to sustained risk reduction. Prior analysis linked greater baseline Late Gadolinium Enhancement (LGE), with more rapid recurrence upon rilonacept suspension after 12 weeks of treatment.  Serial cardiac magnetic resonance (CMR) imaging (T2-STIR, LGE) enabled longitudinal assessment for tracking clinical improvement, guiding decision-making, and predicting patient outcomes after treatment cessation.

Methods: At the long-term extension (LTE) 18-month decision milestone (18MDM), investigators chose, based on clinical status, to continue rilonacept, suspend rilonacept/observe, or discontinue the LTE.  An imaging core lab blinded to clinical data measured pericardial thickness and graded pericardial edema (T2-STIR) and LGE at baseline and 18MDM. Pericarditis recurrence was assessed clinically following rilonacept suspension. 

Results: Baseline and 18MDM CMRs were available for 13 patients.  Reductions in pericardial thickness, T2-STIR, and LGE from baseline to 18MDM were measured while on treatment.  CMRs were obtained in 7/8 patients suspending rilonacept at 18MDM: LGE was none/trace, and T2-STIR was negative; yet, 5/7 (71%) had pericarditis recurrence within 1-4 months of rilonacept suspension despite prophylactic colchicine (n=2).

Conclusions: Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial edema on T2-STIR, and resolution of LGE. Negative/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup. Larger prospective studies examining CMR parameters in guiding RP treatment duration decisions and informing associated clinical outcomes are warranted.

Disclosure Statement: PC: grants and personal fees from Kiniksa Pharmaceuticals; grants from Novartis Pharmaceuticals; and personal fees from SOBI Pharmaceuticals outside the submitted work. AB: unrestricted research grant from SOBI and ACARPIA; travel and accommodation for advisory committee from SOBI and Kiniksa. AI: travel and accommodation for advisory committee from SOBI. DL: advisory board for Kiniksa Pharmaceuticals. SAL: consultant for Kiniksa Pharmaceuticals, Cardiol Therapeutics and Medtronic. DHK: funding from the National Heart, Lung, and Blood Institute of the National Institute of Health. CJ: none. MI: scientific advisory board for Kiniksa Pharmaceuticals. ALK: research grant and scientific advisory boards for Kiniksa Pharmaceuticals and Cardiol Therapeutics, scientific advisory board for Pfizer, consultant to Kiniksa Pharmaceuticals. AC, JC, SW, AK: employees and shareholders of Kiniksa Pharmaceuticals. JFP: Employee and shareholder of Kiniksa Pharmaceuticals; inventor on patents/patent applications covering the use of rilonacept for the treatment of recurrent pericarditis.

A Case of Olanzapine-Induced Dyslipidemia

Andrew S. Kao MD¹, Harpreet S. Bhatia MD, MAS²

¹Department of Medicine, UC San Diego Health, La Jolla, CA, USA

²Division of Cardiovascular Medicine, UC San Diego Health, La Jolla, CA, USA

Introduction: Elevation in lipid biomarkers, specifically total cholesterol (TC), LDL-C, and triglyceride levels, can be observed within 4 weeks of initiation of atypical anti-psychotic medications without significant HDL-C alteration. Olanzapine use is associated with a five-fold risk increase in risk of developing dyslipidemia and higher predisposition to an ASCVD event. Routine assessment of lipid profile is crucial to minimize cardiovascular risk among patients with psychiatric comorbidities in need of long-term anti-psychotics.

Case: A 51-year-old woman with history of breast cancer on adjuvant hormonal therapy was prescribed olanzapine 5mg daily with venlafaxine and lithium due to an acute manic episode (Month 0). Her lipid profile pre- and post- 3 months of olanzapine initiation: TC 224 to 296 mg/dL, LDL-C 129 to 198 mg/dL, HDL-C 63 to 68 mg/dL, Triglyceride 162 to 138 mg/dL, respectively. She did not have a prior history of cardiac disease, diabetes, hypertension, or family history of hypercholesterolemia. Upon initiation of high intensity statin (Month 16) and discontinuation of olanzapine (Month 17), lipid profile (Month 18) improved as follows: TC 115 mg/dL, LDL-C 47 mg/dL, Triglyceride 76 mg/dL, HDL-C 55mg/dL. She was transitioned from high to moderate intensity statin (Month 18), and follow-up lipid profile (Month 22) was: TC 163 mg/dL, LDL-C 72 mg/dL, Triglyceride 104 mg/dL, HDL-C 70 mg/dL.

Discussion: Among commonly used atypical anti-psychotics, olanzapine and clozapine have the highest efficacy, but also confer the greatest risk for metabolic derangements. Elevation in TC and triglyceride levels are well described with quetiapine, olanzapine, and clozapine. The highest elevation in LDL-C is seen with olanzapine, whereas no strong correlation with HDL-C alteration has been established. The temporal relationship between marked dyslipidemia with olanzapine initiation and resolution upon discontinuation in our case demonstrates the importance of routine lipid profile surveillance in this population. Current guidelines recommend periodic measurement at baseline prior to initiation, followed by 3 and 12 months, then annual screening. This is particularly critical among patients with pre-existing cardiovascular risk factors and prior ASCVD events.

Conclusion: Overall, treatment with anti-psychotics is associated with lower cardiac and all-cause mortality compared to placebo. While psychotropic-induced dyslipidemia is an associated risk, the benefits of long-term control of psychotic symptoms must be weighed. If continuation of anti-psychotics is warranted, clinicians should consider concomitant lipid lowering therapy and lifestyle modifications.

Disclosure Statement: The authors report there are no competing interests to declare.