PCSK9 Inhibitors in Heart Transplant Patients: Safety, Efficacy, and Angiographic Correlates.

BACKGROUND: Statins are recommended in heart transplant patients, but are sometimes poorly tolerated. Alternative agents are often considered including proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i). We sought to investigate the use of PCSK9i after heart transplantation. METHODS AND RESULTS: We identified patients who received a heart transplant from 1999 to 2019 and were started on PCSK9i at our institution. Clinical, laboratory, and coronary angiography with intravascular ultrasound results were compared. Among 65 patients initiated on PCSK9i (48 for statin intolerance and 17 for refractory hyperlipidemia), the median time from transplant was 5.5 years (interquartile range [IQR], 2.8-9.9 years) with a median PCSK9 treatment duration of 1.6 years (IQR, 0.8-3.2 years) and 80% still on treatment. Evolocumab was used in 73.8%, alirocumab in 12.3%, and both in 13.8% owing to insurance coverage. All patients required prior authorization; initial denial occurred in 18.5% and 32.3% had denials in subsequent years. The median low-density lipoprotein cholesterol decreased from 130 mg/dL (IQR, 102-148 mg/dL) to 55 mg/dL (IQR, 35-74 mg/dL) after starting PCSK9i (P < .001), with 72% of patients achieving a low-density lipoprotein cholesterol of <70 mg/dL after treatment. There were also significant reductions of total cholesterol, non-high-density lipoprotein cholesterol, total/high-density lipoprotein cholesterol ratio, and triglycerides, with a modest increase in high-density lipoprotein cholesterol. These changes were durable at latest follow-up. In 33 patients with serial coronary angiography and intravascular ultrasound, PCSK9i were associated with stable coronary plaque thickness and lumen area. CONCLUSIONS: Among heart transplant recipients, PCSK9i are effective in lowering cholesterol levels and stabilizing coronary intimal hyperplasia with minimal side effects. Despite favorable effects, access and affordability remain a challenge.

Single-center utilization of donor-derived cell-free DNA testing in the management of heart transplant patients.

BACKGROUND: Gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) are useful in acute rejection (AR) surveillance in orthotopic heart transplant (OHT) patients. We report a single-center experience of combined GEP and dd-cfDNA testing for AR surveillance. METHODS: GEP and dd-cfDNA are tested together starting at 2 months post-OHT. After 6 months, combined testing was obtained before scheduled endomyocardial biopsy (EMB), and EMB was canceled with a negative dd-cfDNA. This approach was compared to using a GEP-only approach, where EMB was canceled with a negative GEP. We evaluated for frequency of EMB cancellation with dd-cfDNA usage. RESULTS: A total of 153 OHT patients over a 13-month period underwent 495 combined GEP/dd-cfDNA tests. 82.2% of dd-cfDNA tests were below threshold. Above threshold results identified high-risk patients who developed AR. 378 combined tests ≥6 months post-OHT resulted in cancellation of 83.9% EMBs as opposed to 71.2% with GEP surveillance alone. There were 2 acute cellular and 2 antibody-mediated rejection episodes, and no significant AR ≥6 months. CONCLUSION: Routine dd-cfDNA testing alongside GEP testing yielded a significant reduction in EMB volume by re-classifying GEP (+) patients into a lower risk group, without reduction in AR detection. The addition of dd-cfDNA identified patients at higher risk for AR.

Influence of Donor Transmitted and Rapidly Progressive Coronary Vascular Disease on Long-Term Outcomes After Heart Transplantation: A Contemporary Intravascular Ultrasound Analysis.

BACKGROUND: Donor-transmitted atherosclerosis (DTA) and rapidly progressive cardiac allograft vasculopathy (CAV) at 1 year are intravascular ultrasound (IVUS)-derived measures shown to predict adverse cardiovascular outcomes in the setting of early generation immunosuppressive agents. Given the paucity of data on the prognostic value of IVUS-derived measurements in the current era, we sought to explore their association with adverse outcomes after heart transplantation. METHODS AND RESULTS: This is a retrospective cohort analysis of patients who underwent heart transplantation at our center between January 2009 and June 2016 with baseline and 1-year IVUS. Five IVUS sections were prospectively analyzed for intimal thickness and lumen area. DTA was defined as maximum intimal thickness of 0.5 mm or greater at baseline, and rapidly progressive CAV as an increase in maximum intimal thickness by 0.5 mm or more at 1 year. Our primary analysis assessed the relationship of IVUS and other clinical data on a composite outcome: coronary intervention, CAV stage 2 or 3 (defined by the International Society for Heart and Lung Transplantation 2010 nomenclature), or cardiovascular death. Among 249 patients (mean age 51.0 ± 12.2 years and 74.3% male) included in the analysis, DTA was detected in 118 patients (51.4%). Over a median follow-up of 6.1 years (interquartile range 4.2-8.0 years), 45 patients met the primary end point (23 percutaneous coronary intervention, 11 CAV 2 or 3, and 11 cardiovascular deaths as first event). DTA and rapidly progressive CAV were not associated with the primary end point, all-cause mortality, or retransplantation. In an additional analysis including post-transplant events, incident rejection was strongly associated with poor outcomes, although cytomegalovirus infection was not. CONCLUSIONS: In this contemporary cohort, IVUS-derived DTA and rapidly progressive CAV were not associated with medium- to long-term adverse events after heart transplantation.

Cholesterol crystal embolization following plaque rupture: a systemic disease with unusual features.

Cholesterol crystal embolic (CCE) syndrome is often a clinically challenging condition that has a poor prognostic implication. It is a result of plaque rupture with release of cholesterol crystals into the circulation that embolize into various tissue organs. Plaque rupture seems to be triggered by an expanding necrotic core during cholesterol crystallization forming sharp tipped crystals that perforate and tear the fibrous cap. Embolizing cholesterol crystals then initiate both local and systemic inflammation that eventually lead to vascular fibrosis and obstruction causing symptoms that can mimic other vasculitic conditions. In fact, animal studies have demonstrated that cholesterol crystals can trigger an inflammatory response via NLRP3 inflammasome similar to that seen with gout. The diagnosis of CCE syndrome often requires a high suspicion of the condition. Serum inflammation biomarkers including elevated sedimentation rate, abnormal renal function tests and eosinophilia are useful but non-specific. Common target organ involvement includes the skin, kidney, and brain. Various testing including fundoscopic eye examination and other non-invasive procedures such as trans-esophageal echocardiography and magnetic resonance imaging may be helpful in identifying the embolic source. Treatment includes aspirin and clopidogrel, high dose statin and possibly steroids. In rare cases, mechanical intervention using covered stents may help isolate the ruptured plaque. Anticoagulation with warfarin is not recommended and might even be harmful. Overall, CCE syndrome is usually a harbinger of extensive and unstable atherosclerotic disease that is often associated with acute cardiovascular events.

A case of comorbid myxoma and chronic lymphocytic leukemia: not just a coincidence?

Background. It is unclear why cardiac myxomas develop. We describe a case of comorbid myxoma and chronic lymphocytic leukemia (CLL) to offer insights into the tumor's pathophysiology. Case. A 56-year-old female with recurrent venous thromboembolism developed embolic stroke. Transesophageal echocardiogram showed a 1.7 × 1 cm sessile left atrial mass at the interatrial septum. Histopathology revealed myxoma with a B cell lymphocytic infiltrate suggestive of a low grade lymphoproliferative disorder. Bone marrow biopsy and flow cytometry of blood and the cardiac infiltrate supported the diagnosis of atypical CLL. She was followed clinically in the absence of symptoms, organ infiltration, or cytopenia. After eighteen months, she developed cervical and axillary lymphadenopathy. Biopsy confirmed B cell CLL/small lymphocytic lymphoma. She elected to undergo chemotherapy with fludarabine, cyclophosphamide, and rituximab, with clinical remission. Conclusions. The coexistence of two neoplastic processes may be coincidental, but the cumulative likelihood is estimated at 0.002 per billion people per year. A shared pathogenic mechanism is more likely. Possibilities include chronic inflammation, vascular endothelial growth factor A, shared genetic mutations, changes in posttranslational regulation, or alterations in other cellular signaling pathways. Additional studies could expand our current understanding of the molecular biology of both myxomas and CLL.

Secondary causes of dyslipidemia.

The causes of the lipid disorders in patients referred to specialty clinics for difficult-to-treat dyslipidemias are likely multifactorial. However, the importance of evaluating for secondary causes is unclear. The investigators performed a chart review of new patients referred to the University of Michigan Lipid Clinic from January 2004 to June 2011 (n = 824) to evaluate for the prevalence of several secondary causes of dyslipidemia. In addition to lipoproteins, new patients were assessed for secondary dyslipidemias by a standardized protocol consisting of laboratory testing, a nutritional evaluation, and medical history. These data were evaluated to determine the prevalence of several secondary causes of dyslipidemia. A total of 363 separate factors were identified in the 824 patients that were thought to be potential secondary causes of dyslipidemia. Because some patients (n = 83 [10%]) had multiple conditions, there were 230 (28% of the cohort) with ≥1 potential secondary dyslipidemias. The most common conditions were excessive alcohol intake (n = 82 [10%]), uncontrolled diabetes mellitus (n = 68 [8%]), and overt albuminuria. Although other causes occurred less frequently (each individually found in <5% of patients), altogether they were present in a substantial portion of patients (n = 102 [12%]). In conclusion, nearly 1/3 of patients referred to a specialty clinic had identifiable secondary conditions plausibly contributing to their dyslipidemia. Numerous disorders were identified, with diabetes mellitus and excessive alcohol being the most common.

Lipoprotein (a): perspectives from a lipid-referral program.

BACKGROUND: Lipoprotein (a) [Lp(a)] has a strong association with coronary disease (CHD). We evaluated the implications of implementing a niacin strategy in persons above low risk by the Framingham risk score (FRS). METHODS: Patients referred to a university lipid management program from January 2004 to June 2010 had an Lp(a) level measured at initial evaluation. Factors associated with an increase in Lp(a) and predictors of a high risk Lp(a) (≥50 mg/dL) were assessed. FRS and Lp(a) levels were used to assess eligibility for niacin with an Lp(a) ≥50 mg/dL. RESULTS: A total of 692 patients (57% male, mean age 52 ± 14 years) had a mean Lp(a) of 32 ± 40 mg/dL. In a multiple logistic regression model, African-American race, female gender, presence of CHD, and lower triglyceride levels were significant predictors of high risk Lp(a). Ten percent were determined to be intermediate and 44% high risk by FRS. A total of 9% of intermediate- and 26% of high-risk patients had an Lp(a) ≥50 mg/dL, and 84% were not taking niacin. A total of 19% of moderate- and high-risk patients were eligible for initiation of niacin based upon values ≥50 mg/dL. If niacin were also used for an high-density lipoprotein cholesterol levels ≤40 mg/dL, only 5.1% additional patients would require niacin. CONCLUSION: High-risk levels of Lp(a) are associated with female gender, African- American race, and CHD. 19% of moderate and high risk patients would be candidates for treatment with niacin if the indication is a cutpoint Lp(a) ≥50 mg/dL.

Medical management of the patient with intermittent claudication.

Intermittent claudication (IC) due to peripheral arterial disease (PAD) causes substantial impairment in quality of life, and is strongly associated with increased cardiovascular morbidity and mortality. The overall medical approach to management focuses on reducing cardiovascular events, preventing progression of underlying PAD (eg, limb loss), and improving symptoms. Aggressive secondary prevention strategies (eg, statins and smoking cessation) are of critical importance. Cilostazol treatment should be considered for those with persistent IC symptoms despite exercise and risk factor control. Management of IC requires a comprehensive approach toward symptomatic relief of pain with strategies that prolong life and prevent limb loss.

Potential effects on clinical management of treatment algorithms on the basis of apolipoprotein-B/A-1 and total/high-density lipoprotein-cholesterol ratios.

BACKGROUND: Apolipoprotein-B/A-1 (apoB/A-R) and total/high-density lipoprotein-cholesterol ratios (TC/HDL-R) outperform non-high-density lipoprotein-cholesterol (non-HDL-C) suggested by Adult Treatment Panel (ATP) III guidelines for predicting cardiovascular (CV) outcomes. OBJECTIVE: To evaluate the potential effects that implementing our proposed apoB/A-R and TC/HDL-R treatment algorithms would have on clinical management. METHODS: We performed a chart review of all patients referred to the University of Michigan Lipid Clinic from January 2004 to June 2010. ATP III guidelines, including Framingham Risk Scores, were used to determine whether patients met non-HDL-C goals upon referral. Next, we evaluated whether subsequent management would differ if algorithms based upon potential apoB/A-R or TC/HDL-R targets derived from the literature were followed. RESULTS: Among patients (n = 692), mean non-HDL-C, apoB/A-R, and TC/HDL-R were 192.2 ± 85.8 mg/dL, 0.92 ± 0.64, and 6.7 ± 8.0, respectively. Although moderately well correlated with apoB (r = 0.56, P < .01), non-HDL-C was less related to apoB/A-R (r = 0.20, P < .01) and TC/HDL-R (r = 0.39, P < .01). Most low-risk patients (<2 risk factors; n = 207) at non-HDL-C goal (<190 mg/dL) also met apoB/A-R <0.9 (79%) and TC/HDL-R <6.0 (92%) targets. However, a minority of high-risk patients (Framingham Risk Score >20%, cardiovascular disease or risk equivalent; n = 307) meeting non-HDL-C goal (<130 mg/dL) achieved targets for apoB/A-R <0.5 (21%) or TC/HDL-C <3.5 (42%). The percentages of intermediate-risk patients meeting both non-HDL-C and ratio goals varied; nonetheless, few met an aggressive apoB/A-R <0.6 (36%-50%) target. CONCLUSIONS: Most high- and many intermediate-risk patients at non-HDL-C goals would require more aggressive treatment to reach the suggested apoB/A-R or TC/HDL-R targets. Whether this strategy yields superior outcomes merits future investigation.

Acute chest pain: Acute coronary syndrome versus lead perforation: A case report.

BACKGROUND: Diagnosing pacemaker lead perforation in the setting of chest pain and EKG changes is difficult and usually not considered unless we have awareness and high index of suspicion. This kind of clinical scenario represents one of the diagnostic challenges. CASE PRESENTATION: A 77 year-old Caucasian female came to emergency room with left sided non-exertional chest pain radiating to her back for the past two days. A week prior to this presentation, she had a stent supported angioplasty for in-stent re-stenosis and subsequently dual chamber pacemaker implantation for sick sinus syndrome. On physical exam she is very obese, had normal vital signs, peripheral pulses and cardio-respiratory exam. Electrocardiogram revealed new T- wave inversions in inferior and anterior leads. Initial chest X-ray, 2D-Echocardiogram and cardiac enzymes were normal. Acute coronary syndrome was considered as an initial probable diagnosis. She was anticoagulated with heparin and eptifibatide. Patient continued to have chest pain with negative cardiac biomarkers. She developed hypotension, oliguria, elevated white count, pyuria and renal failure. Because of a normal 2D-echocardiogram, cardiac etiology for shock was not suspected. After initial fluid challenge, empiric treatment for septic shock was initiated with antibiotics and vasopressors. Work up for pulmonary embolism and intra-abdominal hemorrhage was negative. Because of persistent chest pain, shock with cold & clammy extremities and elevated central venous pressure cardiogenic shock was considered and a repeat 2D-echocardiogram was done on third day of hospitalization which revealed pericardial effusion. Non-contrast CT-scan chest done to look for lead position confirmed that she had hemorrhagic pericardial effusion along with lead perforation. Patient underwent pericardial window placement along with over-sewing of atrial wall to seal the leakage point. The patient improved and was then discharged from the hospital. CONCLUSION: Lead perforation presenting with chest pain and EKG changes is often not appreciated resulting in significant delay in diagnosis and inappropriate treatment.