Validation of cause of death classification after heart transplantation and cause-specific life expectancy compared to the general population.

BACKGROUND: Post heart-transplant survival has increased, but information is lacking on specific causes of death and life expectancy. We aimed to assess cause-specific loss of life-years compared to the general population, evaluate classification for cause of death after heart transplantation, and assess validity of cause of death data from the International Society of Heart and Lung Transplant (ISHLT) registry. METHODS: In this single center study, we included 239 heart recipients transplanted between 1988 and 2019 in Lund, Sweden (n = 239, 50% of the transplanted population where the cause of death was available). Two cardiologists retrospectively assigned causes of death according to a published classification (CLASS) in the 91 recipients who died during follow-up. Life expectancy was compared to data from the general population. RESULTS: Compared to the average Swedish population, life expectancy for heart transplant recipients was 20 years shorter (IQR 12.9-27.2). The largest number of life-years lost were for deaths due to acute (49 years) and chronic rejection (27 years). Primary graft dysfunction (24 years) accounted for 24% of deaths, followed by malignancy (20 years) and infection (17 years), each accounting for ∼20% of deaths. Use of CLASS revealed moderate inter-rater agreement (56%) and moderate agreement with the ISHLT registry (62%). CONCLUSIONS: Survival after heart transplantation was 20 years lower than in the general population. In the young, more life-years were lost due to acute graft rejection, whereas chronic graft rejection and primary graft failure were more important causes of death in older patients. Agreement was moderate between CLASS and the ISHLT registry classifications.

Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients: Design of the randomized controlled EVOLVD trial.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is characterized by diffuse thickening of the arterial intima. Statins reduce the incidence of CAV, but despite the use of statins, CAV remains one of the leading causes of long-term death after heart transplant. Inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) substantially reduce cholesterol levels but have not been tested in heart transplant recipients. METHODS: The Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients (EVOLVD) trial (ClinicalTrials.gov Identifier: NCT03734211) is a randomized, double-blind trial designed to test the effect of the PCSK9 inhibitor evolocumab on coronary intima thickness in heart transplant recipients. Adults who have received a cardiac transplant within the past 4-8 weeks are eligible. Exclusion criteria include an estimated glomerular filtration rate < 20 mL/min/1.73 m2 , renal replacement therapy, or contraindications to coronary angiography with intravascular ultrasound. 130 patients will be randomized (1:1) to 12-month treatment with evolocumab or matching placebo. The primary endpoint is the coronary artery intima thickness as measured by intravascular ultrasound. CONCLUSION: The EVOLVD trial is a randomized clinical trial designed to show whether treatment with the PCSK9 inhibitor evolocumab can ameliorate CAV over the first year after heart transplant.

Blood lactate is a predictor of short-term mortality in patients with myocardial infarction complicated by heart failure but without cardiogenic shock.

BACKGROUND: Mortality in patients with acute myocardial infarction (AMI) has improved substantially with modern therapy including percutaneous coronary interventions (PCI) but remains high in certain subgroups such as patients presenting with overt cardiogenic shock. However, the risk for AMI in patients presenting acutely with signs of heart failure but without cardiogenic shock is less well described. We aimed to identify risk factors for mortality in AMI patients with heart failure without overt cardiogenic shock. METHODS: Using data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), we identified patients with operator-registered heart failure (Killip class II-IV), and evaluated predictors of mortality based on clinical factors from review of patient records. RESULTS: A total of 1260 unique patients with acute myocardial infarction underwent PCI in 2014, of which 77 patients (7%) showed signs of heart failure (Killip II-IV) Overall 30-day mortality in patients with Killip class II-IV was 20% (N = 15). In patients classified Killip IV (1%), 30-day mortality was 50% (N = 6). In patients presenting with mild to moderate heart failure (Killlip class II-III), 30-day mortality was 14% (N = 9). In patients with Killip class II-III, lactate ≥2.5 mmol/L was associated with 30-day mortality, whereas systolic blood pressure < 90 mmHg, age, sex and BMI were not. In patients with lactate < 2.5 mmol/L 30-day mortality was 5% (N = 2) whereas mortality was 28% (N = 7) with lactate ≥2.5 mmol/L. This cut-off provided discriminative information on 30-day mortality (area under ROC curve 0.74). CONCLUSIONS: In patients with AMI and signs of mild to moderate heart failure, lactate ≥2.5 mmol/L provides additional prognostic information. Interventions to reduce risk may be targeted to these patients.

Waiting list and post-transplant outcome in Sweden after national centralization of heart transplant surgery.

BACKGROUND: Previous studies have demonstrated an association between transplantation rate per center and postoperative mortality after heart transplantation. In 2011, Sweden centralized heart transplants and waiting lists, reducing the number of centers from 3 to 2. We aimed to assess the active waiting time and pre- and post-transplant mortality before and after centralization. METHODS: Heart transplantations performed in Sweden between January 1, 2001 and December 31, 2020 were included. Background and donor organ supply data were collected from Scandiatransplant, the Swedish Thoracic Transplant Registry, and the Swedish Cardiac Surgery Registry. The Fine and Gray methods were applied to visualize cumulative incidence curves and conduct competing risk regressions. A Cox model was used to adjust for factors influencing time to post-transplant death. RESULTS: When comparing the two eras, the median active waiting time increased from 54 to 71 days (p = 0.015). The risk of mortality on the waiting list decreased in the later era (subhazard ratio 0.43; [95% confidence interval {CI} 0.25-0.74]; p = 0.002). The number of heart transplantation procedures (including pediatric patients) increased by 53%. There was a significant difference in organ utilization between eras (p = 0.033; chi-square test). 30-day and 1-year survival post-transplant rates for adults increased from 90.8% to 97.8% (p < 0.001) and from 87.9% to 94.6% (p < 0.001), respectively. 1-year mortality was reduced by 63% (hazard ratio 0.37; 95% CI 0.22-0.61). CONCLUSIONS: This nationwide study examined patients listed for and undergoing heart transplantation before and after the centralization of waiting lists and surgeries in Sweden. Waiting list mortality decreased, and 1-year post-transplantation survival was improved.

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).

Impact of bridging with left ventricular assist device on right ventricular function following heart transplantation.

AIMS: Patients awaiting orthotopic heart transplantation (OHT) can be bridged utilizing a left ventricular assist device (LVAD) that reduces left ventricular filling pressures, decreases pulmonary artery wedge pressure, and maintains adequate cardiac output. This study set out to examine the poorly investigated area of if and how pre-treatment with LVAD impacts right ventricular (RV) function following OHT. METHODS AND RESULTS: We prospectively evaluated 59 (LVAD n = 20) consecutive OHT patients. Transthoracic echocardiography (TTE) was performed in conjunction with right heart catheterization (RHC) at 1, 6, and 12 months after OHT. RV function TTE-parameters included tricuspid annular plane systolic excursion (TAPSE), systolic tissue velocity (S'), fractional area change, two-dimensional RV global longitudinal strain and longitudinal strain from the RV lateral wall (RVfree). At 1 month after OHT, the LVAD group had significantly better longitudinal RV function than the non-LVAD group: TAPSE (15 ± 3 mm vs. 12 ± 2 mm, P < 0.001), RV global longitudinal strain (-19.8 ± 2.1% vs. -14.3 ± 2.8%, P < 0.001), and RVfree (-19.8 ± 2.3% vs. -14.1 ± 2.9%, P < 0.001). At this time point, pulmonary vascular resistance (PVR) was also lower [1.2 ± 0.4 Wood Units (WU) vs. 1.6 ± 0.6 WU, P < 0.05] in the LVAD group compared with the non-LVAD group. At 6 and 12 months, no difference was detected in any of the TTE and RHC measured parameters between the two groups. Between 1 and 12 months, all parameters of RV function improved significantly in the non-LVAD group but remained unaltered in the LVAD group. CONCLUSIONS: Our results indicate that pre-treatment with LVAD decreases PVR and is associated with significantly better RV function early following OHT. During the first year following transplantation, RV function progressively improved in the non-LVAD group such that at 6 and 12 months, no difference in RV function was detected between the groups.

Association between central haemodynamics and renal function in advanced heart failure: a nationwide study from Sweden.

AIMS: Renal dysfunction in patients with heart failure (HF) has traditionally been attributed to declining cardiac output and renal hypoperfusion. However, other central haemodynamic aberrations may contribute to impaired kidney function. This study assessed the relationship between invasive central haemodynamic measurements from right-heart catheterizations and measured glomerular filtration rate (mGFR) in advanced HF. METHODS AND RESULTS: All patients referred for heart transplantation work-up in Sweden between 1988 and 2019 were identified through the Scandiatransplant organ-exchange organization database. Invasive haemodynamic variables and mGFR were retrieved retrospectively. A total of 1001 subjects (49 ± 13 years; 24% female) were eligible for the study. Analysis of covariance adjusted for age, sex, and centre revealed that higher right atrial pressure (RAP) displayed the strongest relationship with impaired GFR [ß coefficient -0.59; 95% confidence interval (CI) -0.69 to -0.48; P < 0.001], followed by lower mean arterial pressure (MAP) (ß coefficient 0.29; 95% CI 0.14-0.37; P < 0.001), and finally reduced cardiac index (ß coefficient 3.51; 95% CI 2.14-4.84; P < 0.003). A combination of high RAP and low MAP was associated with markedly worse mGFR than any other RAP/MAP profile, and high renal perfusion pressure (RPP, MAP minus RAP) was associated with superior renal function irrespective of the degree of cardiac output. CONCLUSIONS: In patients with advanced HF, high RAP contributed more to impaired GFR than low MAP. A higher RPP was more closely related to GFR than was high cardiac index.

Cardiovascular implantable electronic device therapy in patients with left ventricular assist devices: insights from TRAViATA.

BACKGROUND: There is conflicting observational data on the survival benefit cardiac implantable electronic devices (CIED) in patients with LVADs. METHODS: Patients in whom an LVAD was implanted between January 2008 and April 2017 in the multinational Trans-Atlantic Registry on VAD and Transplant (TRAViATA) registry were separated into four groups based on the presence of CIED prior to LVAD implantation: none (n = 146), implantable cardiac defibrillator (ICD) (n = 239), cardiac resynchronization without defibrillator (CRT-P) (n = 28), and CRT with defibrillator (CRT-D) (n = 111). RESULTS: A total of 524 patients (age 52 years ±12, 84.4% male) were followed for 354 (interquartile range: 166-701) days. After multivariable adjustment, there were no differences in survival across the groups. In comparison to no device, only CRT-D was associated with late right ventricular failure (RVF) (hazard ratio 2.85, 95% confidence interval [CI] 1.42-5.72, p = 0.003). There was no difference in risk of early RVF across the groups or risk of ICD shocks between those with ICD and CRT-D. CONCLUSION: In a multinational registry of patients with LVADs, there were no differences in survival with respect to CIED subtype. However, patients with a pre-existing CRT-D had a higher likelihood of late RVF suggesting significant long-term morbidity in those with devices capable of LV­lead pacing post LVAD implantation.

Outcome of patients on heart transplant list treated with a continuous-flow left ventricular assist device: Insights from the TRans-Atlantic registry on VAd and TrAnsplant (TRAViATA).

BACKGROUND: Geographic variations in management and outcomes of individuals supported by continuous-flow left ventricular assist devices (CF-LVAD) between the United States (US) and Europe (EU) is largely unknown. METHODS: We created a retrospective, multinational registry of 524 patients who received a CF-LVAD (either HVAD or Heartmate II) between January 2008 and April 2017. Follow up spanned from date of CF-LVAD implant to post-HTx period with a median follow up of 44.8 months. RESULTS: The cohort included 299 (57.1%) EU and 225 (42.9%) US patients. Although the US cohort was significantly older with a higher prevalence of comorbidities, survival was similar between the cohorts (US 63.1%, EU 68.4% at 5 years, unadjusted log-rank test p = 0.43).Multivariate analyses suggested that older age, higher body mass index, elevated creatinine, use of temporary mechanical circulatory support prior CF-LVAD, and implantation of HVAD were associated with increased mortality. Among CF-LVAD patients undergoing HTx, the median time on CF-LVAD support was shorter in the US, meanwhile US donors were younger. Finally, the pattern of adverse events (stroke, gastrointestinal bleedings, late right ventricular failure, and driveline infection) during support differed significantly between US and EU. CONCLUSIONS: Although waitlisted patients in the US on CF-LVAD have higher risk comorbid conditions, the overall outcome is similar in US and EU. Geographic variations with regards to donor characteristics, duration of CF-LVAD support prior to transplant, and adverse events on support can explain the disparity in the utilization of mechanical bridge to transplant strategy between US and EU.

Does bipolar pacemaker current activate blood platelets?

OBJECTIVE: The aim of this study was to investigate whether bipolar pacemaker current lead can activate blood platelets. The null hypothesis was that 1 minute of electrical stimulation of platelets would not influence their subsequent reactivity to adenosine diphosphate (ADP). BACKGROUND: Both platelets and muscle cells contain actin and myosin filaments, and both cells are activated following calcium influx. Muscle cells open their calcium channels and contract when exposed to an electric current. Current through a bipolar pacemaker lead will expose a small volume of blood, including platelets, to the depolarizing current. Platelet activation may ensue, resulting in aggregation, release reaction, and contraction. In contrast, a unipolar pacemaker system will not depolarize blood, but transmit current directly into the myocardium, and the current afterward passes through other tissues before returning to the pacemaker can. METHODS: Platelet-rich plasma was prepared from two healthy subjects. Platelet reactivity to the agonist ADP was tested in paired samples in an aggregometer in a case/control setup. RESULTS: Eighteen of 46 tested pairs of platelet-rich plasma showed increased reactivity in the paced sample; 26 were unchanged while two showed decreased reactivity in the paced sample. Using a two-sided sign test, the null hypothesis was rejected (P = 0.0004). CONCLUSIONS: The study demonstrates increased reactivity to ADP in platelets exposed in vitro to stimulation by pacemaker current. The clinical relevance of these findings remains to be investigated.