Randomized Trial of Cholesterol Lowering With Evolocumab for Cardiac Allograft Vasculopathy in Heart Transplant Recipients.

BACKGROUND: Cardiac allograft vasculopathy is characterized by increased coronary intimal thickness and is a leading cause of death in heart transplant (HTx) recipients despite the routine use of statins. The experience with inhibitors of proprotein convertase subtilisin-kexin type 9 in HTx recipients is limited. Our hypothesis was that lowering cholesterol with the proprotein convertase subtilisin-kexin type 9inhibitor evolocumab would reduce coronary intimal thickness in these patients without compromising safety. OBJECTIVES: This double blind, randomized trial was conducted to test whether evolocumab reduces the burden of cardiac allograft vasculopathy. METHODS: Patients who had received a cardiac allograft at one of the Nordic transplant centers within the prior 4 to 8 weeks were randomized to monthly subcutaneous injections of evolocumab 420 mg or matching placebo. The primary endpoint was the baseline-adjusted maximal intimal thickness as measured by intracoronary ultrasound after 12 months' treatment. RESULTS: The trial enrolled 128 patients between June 2019 and May 2022. Matched pairs of coronary ultrasound images were available for 56 patients assigned to evolocumab and 54 patients assigned to placebo. At 12 months, the adjusted mean difference in the maximal intimal thickness between the 2 arms was 0.017 mm (95% CI: -0.006 to 0.040; P = 0.14). The mean reduction in low-density lipoprotein cholesterol with evolocumab compared with placebo was 1.11 mmol/L (95% CI: 0.86-1.37 mmol/L). The use of evolocumab was not associated with an increase in adverse events. CONCLUSIONS: Twelve months of treatment with evolocumab substantially reduced low-density lipoprotein cholesterol but did not reduce maximal coronary intimal thickness in HTx recipients. (Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients [EVOLVD]; NCT03734211).

Familial occurrences of cardiac wild-type transthyretin amyloidosis: a case series.

Background: Cardiomyopathy caused by aggregation and deposition of transthyretin amyloid fibrils in the heart (ATTR-CM) is divided into a hereditary (ATTRv) and a wild-type (ATTRwt) forms. While ATTR-CM has been considered a rare disease, recent studies suggest that it is severely underdiagnosed and an important cause of heart failure in elderly patients. Familial occurrence is implicit in ATTRv, but it is not expected in ATTRwt. Case summary: We report a case series of two unrelated families each with two brothers diagnosed with ATTRwt. Genetic testing did not reveal mutations in the transthyretin gene. Family screening with electrocardiogram, echocardiography, and genetic testing did not raise any suspicion of ATTR in first-line family members. Discussion: Familial occurrence of a rare, non-hereditary disease is statistically unlikely. Two siblings in two different families diagnosed with ATTRwt highlight that the aetiology of ATTRwt is poorly understood, and that genetic factors distinct from mutations in the transthyretin gene, as well as environmental factors, might contribute to the pathogenesis. Identifying such factors might reveal new therapeutic targets. To investigate this further, clinicians need to be aware of the possibility of familial occurrence of ATTRwt.

Kinetics of Torque Teno virus in heart transplant patients.

End-stage heart failure often requires heart transplantation as a life-prolonging treatment. Immunosuppressive therapy is necessary to avoid rejection, but is associated with serious adverse effects. New approaches are needed to monitor immune function in heart transplant patients. We here report the kinetics of Torque Teno Virus (TTV) after transplantation in a large cohort of heart transplant patients and examine its possible role in predicting rejection. We included 106 patients from Aarhus University Hospital and Oslo University Hospital. Patients were followed for 3 years with clinical assessments, biopsies, TTV measurements, and flowcytometric phenotyping. We observed TTV levels reaching a maximum 3 months after transplantation for all 106 patients, after which levels gradually declined. 38 patients (38 %) had biopsy-proven rejection within the first year. We did not find evidence of an association between TTV and serum trough levels, events of rejection, nor flow cytometric immunophenotype. We report data on a large cohort of heart transplant patients and contribute to the understanding of how TTV behaves in transplant patients. Despite not finding an association with rejection, our results provide important insights into the kinetics of TTV levels after transplantation, which may be useful in future studies of immune function in heart transplant patients.

Coronary Flow Velocity Reserve and Myocardial Deformation Predict Long-Term Outcomes in Heart Transplant Recipients.

BACKGROUND: After heart transplantation (HTx), invasive coronary angiography is the gold standard for surveillance of cardiac allograft vasculopathy (CAV). Noninvasive CAV surveillance is desirable. The authors examined left ventricular global longitudinal strain (LVGLS) and noninvasive coronary flow velocity reserve (CFVR) related to CAV and prognosis after HTx. METHODS: Doppler echocardiographic CFVR and LVGLS were evaluated in 98 HTx patients. All-cause mortality and major adverse cardiac events (MACE), including hospitalization for heart failure, cardiovascular death, and significant CAV progression, were recorded. RESULTS: Median follow-up duration was 3.3 years (range: 1.7-5.4 years). Patients with low CFVR (<2.0; n = 20) showed reduced MACE-free survival (hazard ratio, 4.3; 95% CI, 2.2-8.4; P < .0001) and increased all-cause mortality (hazard ratio: 4.7; 95% CI: 2.0-11.3; P < .0001) compared with patients with high CFVR (≥2.0; n = 78). Worsened LVGLS (≥-15.5%) was also a strong independent predictor of MACE and cardiovascular and all-cause mortality. Combined low CFVR and worsened LVGLS provided incremental prognostic value, even after adjustment for CAV and time since HTx. The prevalence of low CFVR increased significantly with CAV severity, and the prevalence of combined low CFVR and/or worsened LVGLS was high in patients with moderate CAV (86%) and those with severe CAV (83%). The negative predictive value of combined high CFVR and improved LVGLS to rule out significant CAV was 94.5% (95% CI, 86.2%-98.4%), whereas the positive predictive value was 39.0% (95% CI, 25.3%-54.3%). The model had sensitivity of 84.2% (95% CI, 63.6%-95.3%) and specificity of 67.5% (95% CI, 56.6%-77.2%) for one or more abnormal parameters. CONCLUSIONS: In HTx patients with severe CAV, a higher prevalence of low CFVR and worsened LVGLS was observed. Both measurements were strong independent predictors of MACE and all-cause mortality in HTx patients. Combined CFVR and LVGLS provided incremental prognostic value and showed an excellent ability to rule out significant CAV and may be considered as part of routine CAV surveillance of HTx patients.

Clinical performance and exercise hemodynamics in patients with severe secondary tricuspid regurgitation and chronic atrial fibrillation.

OBJECTIVE: The study aimed to investigate the functional capacity and hemodynamics at rest and during exercise in patients with chronic atrial fibrillation and severe functional symptomatic tricuspid regurgitation (AF-FTR). BACKGROUND: Symptoms and clinical performance of severe AF-FTR mimic the population of patients with heart failure with preserved ejection fraction (HFpEF). Severe AF-FTR is known to be associated with an adverse prognosis whereas less is reported about the clinical performance including exercise capacity and hemodynamics in patients symptomatic AF-FTR. METHODS: Right heart catheterization (RHC) at rest and during exercise was conducted in a group of patients with stable chronic AF-TR and compared with a group of patients with HFpEF diagnosed with cardiac amyloid cardiomyopathy (CA). All patients had preserved ejection fraction and no significant left-sided disease. RESULTS: Patients with AF-FTR demonstrated a low exercise capacity that was comparable to CA patients (TR 4.9 ± 1.2 METS vs. CA 4. 7 ± 1.5 METS; P = 0.78) with an average peak maximal oxygen consumption of 15 mL/min/kg. Right atrium pressure increased significantly more in the AF-FTR patients as compared to CA patients at peak exercise (25 ± 8 vs 19 ± 9, p < 0.01) whereas PCWP increased significantly to a similar extent in both groups (31 ± 4 vs 31 ± 8 mmHg, p = 0.88). Cardiac output (CO) was significantly lower among AF-FTR at rest as compared to CA patients (3.6 ± 0.9 vs 4.4 ± 1.3 l/min; p < 0.05) whereas both groups demonstrated a poor but comparable CO reserve at peak exercise (7.3 ± 2.9 vs 7.9 ± 3.8 l/min, p = 0.59). CONCLUSIONS: AF-FTR contributes to the development of advanced heart failure symptoms and poor exercise capacity reflected in increased atrial filling pressures, reduced cardiac output at rest and during exercise sharing common features seen in HFpEF patients with other etiologies.

Platelet aggregation and response to aspirin therapy in cardiac allograft vasculopathy.

BACKGROUND: Long-term survival after heart transplantation (HTx) is compromised by cardiac allograft vasculopathy (CAV) characterized by coronary macro- and microvascular disease. The pathogenesis of CAV is unclear and may involve coronary thrombosis. We investigated whether HTx patients with CAV had higher platelet aggregation and turnover than HTx patients without CAV and healthy controls. Furthermore, we investigated the anti-platelet effect of low-dose aspirin in HTx patients. METHODS: We included 57 patients who had undergone HTx (median 8.3 years from HTx) and 57 healthy controls. Platelet aggregation was measured on-aspirin and off-aspirin using impedance aggregometry with adenosine diphosphate (ADP) and arachidonic acid (AA). We evaluated platelet turnover by flow cytometry, CAV burden by coronary angiography and echocardiography, and microvascular function by echocardiographic coronary flow velocity reserve (CFVR). RESULTS: Off-aspirin, HTx patients with CAV (n = 21) had higher ADP-induced platelet aggregation than healthy controls (p < 0.01) and HTx patients without CAV (n = 36) (p < 0.05). Aspirin treatment reduced AA-induced platelet aggregation in both HTx groups, but HTx patients with CAV had higher platelet aggregation on-aspirin than HTx patients without CAV (p < 0.05). Platelet turnover did not differ between HTx patients with CAV and HTx patients without CAV (p > 0.34). HTx patients with lower CFVR values had higher platelet aggregation than HTx patients with higher CFVR values (p < 0.05). CONCLUSIONS: Off-aspirin, platelet aggregation was higher in HTx patients with CAV than in HTx patients without CAV and healthy controls. On-aspirin, platelet aggregation was higher in HTx patients with CAV than in HTx patients without CAV. Aspirin monotherapy may not provide sufficient platelet inhibition in HTx patients with CAV.

Survival, graft function, and incidence of allograft vasculopathy in heart transplant patients receiving adverse risk profile donor hearts.

AIM: To clarify if use of adverse cardiovascular risk profile (ARP) grafts is associated with impaired long-term outcomes after heart transplantation (HTx). METHODS: Survival was obtained from Scandia Transplant and a local database. ARP DONOR INCLUSION CRITERIA: ≥55 years, diabetes mellitus, arterial hypertension, hypoxemia-induced death, impaired left ventricular (LV) ejection fraction. ARP donors were compared to donors not meeting the eligibility criteria. Sub-analyses were made for donor age. RESULTS: In total, 302 HTxs were performed in 296 patients from 31 December 1992 to 11 August 2016. Median survival was 16.5 years (95% CI, 14.3-22.9), there was no difference between profiles (HR 0.63 (95% CI, 0.33-1.19), P = 0.15). LV systolic function was significantly better in ARP donors (P < 0.05). Freedom from cardiac allograft vasculopathy (CAV) was comparable between profiles, HR 0.9 (95% CI 0.5-1.5). Donor age predisposes to CAV (high to low age: HR 2.8 (95% CI 1.7-4.5), P < 0.0001). Median survival was comparable in patients receiving allograft ≥55 and <55 years (HR 0.77 (95% CI 0.4-1.4), P = 0.38). CONCLUSION: Long-term survival and graft function were excellent in patients receiving ARP grafts. Older grafts were associated with CAV but did not influence survival. Thus, the strategy of expanding availability using ARP grafts seems safe.

A rare presentation of cardiac amyloid deposits isolated to intramural vessels.

The present case illustrates the diagnostic challenges in symptomatic patients with heart failure of unknown etiology. The patients were previously diagnosed with κ-light chain amyloidosis without cardiac involvement. Echocardiography showed heart failure with mildly reduced ejection fraction but no signs of amyloidosis. Coronary angiogram showed normal arteries and 11C-PIB positron emission tomography was negative for amyloid deposits. Exercise testing revealed severe heart failure and reduced coronary flow velocity reserve. Endomyocardial biopsies showed amyloid in the intramural coronary arteries without interstitial amyloid deposits. Hence, the patient was diagnosed with microvascular dysfunction-induced heart failure due to vessel wall amyloidosis.