Tafamidis improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, it is not yet known whether tafamidis affects cardiac amyloid deposition and structural changes in the myocardium. We aimed to determine disease-modifying effects on myocardial amyloid progression and to identify imaging parameters that could be applied for specific therapy monitoring. ATTR-CM patients underwent serial cardiac magnetic resonance (CMR) imaging using T1 mapping techniques to derive extracellular volume (ECV). Patients receiving tafamidis 61 mg (n = 35) or 20 mg (n = 15) once daily showed stable measurements at follow-up (FU) {61 mg: 9.0 [interquartile range (IQR) 7.0–11.0] months, 20 mg: 11.0 (IQR 8.0–18.0) months} in left ventricular (LV) ejection fraction (LVEF; 61 mg: 47.6% vs. 47.5%, P = 0.935; 20 mg: 52.4% vs. 52.1%, P = 0.930), LV mass index (LVMI; 61 mg: 110.2 vs. 106.2 g/m², P = 0.304; 20 mg: 114.5 vs. 115.4 g/m², P = 0.900), and ECV (61 mg: 47.5% vs. 47.7%, P = 0.861; 20 mg: 56.7% vs. 57.5%, P = 0.759), whereas treatment-naïve ATTR-CM patients (n = 19) had clear signs of disease progression at the end of the observation period [12.0 (IQR 10.0–21.0) months; LVEF: 53.3% vs. 45.7%, P = 0.031; LVMI: 98.9 vs. 106.9 g/m², P = 0.027; ECV: 49.3% vs. 54.6%, P = 0.023]. Between-group comparison at FU revealed positive effects in tafamidis 61 mg-treated compared to treatment-naïve patients (LVEF: P = 0.035, LVMI: P = 0.036, ECV: P = 0.030), while those treated with 20 mg showed no difference in the above LV measurements when compared with treatment-naïve (P = 0.120, P = 0.287, P = 0.158). However, both treatment groups showed clinically beneficial effects compared to the natural course [61 mg, 6-min walk distance (6-MWD): P = 0.005, N-terminal prohormone of brain natriuretic peptide (NT-proBNP): P = 0.002; 20 mg, 6-MWD: P = 0.023, NT-proBNP: P = 0.003]. Tafamidis delays myocardial amyloid progression in ATTR-CM patients, resulting in structural, functional, and clinical benefits compared to the natural course. Serial CMR including measurement of ECV may be appropriate for disease-specific therapy monitoring.

Tafamidis treatment positively affects left ventricular (LV) structure and function and improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). We aimed to investigate the relationship between treatment response and cardiac amyloid burden identified by serial quantitative ^99mTc-DPD SPECT/CT. We furthermore aimed to identify nuclear imaging biomarkers that could be used to quantify and monitor response to tafamidis therapy. Forty wild-type ATTR-CM patients who underwent ^99mTc-DPD scintigraphy and SPECT/CT imaging at baseline and after treatment with tafamidis 61 mg once daily [median, 9.0 months (interquartile range 7.0–10.0)] were divided into two cohorts based on the median (−32.3%) of the longitudinal percent change in standardized uptake value (SUV) retention index. ATTR-CM patients with a reduction greater than or equal to the median (n = 20) had a significant decrease in SUV retention index (P < 0.001) at follow-up, which translated into significant benefits in serum N-terminal prohormone of brain natriuretic peptide levels (P = 0.006), left atrial volume index (P = 0.038), as well as LV [LV global longitudinal strain: P = 0.028, LV ejection fraction (EF): P = 0.027, LV cardiac index (CI): P = 0.034] and right ventricular (RV) [RVEF: P = 0.025, RVCI: P = 0.048] functions compared with patients with a decrease less than the median (n = 20). Treatment with tafamidis in ATTR-CM patients results in a significant reduction in SUV retention index, associated with significant benefits for LV and RV function and cardiac biomarkers. Serial quantitative ^99mTc-DPD SPECT/CT imaging with SUV may be a valid tool to quantify and monitor response to tafamidis treatment in affected patients. ^99mTc-DPD SPECT/CT imaging with determination of SUV retention index as part of a routine annual examination can provide evidence of treatment response in ATTR-CM patients receiving disease-modifying therapy. Further long-term studies with ^99mTc-DPD SPECT/CT imaging may help to evaluate the relationship between tafamidis-induced reduction in SUV retention index and outcome in patients with ATTR-CM and will demonstrate whether highly disease-specific ^99mTc-DPD SPECT/CT imaging is more sensitive than routine diagnostic monitoring. Response to tafamidis treatment and effects on cardiac function and biomarkers. Serial quantitative ^99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) single-photon emission computed tomography/computed tomography (SPECT/CT) imaging with standardized uptake value (SUV) of representative patients with wild-type transthyretin amyloid cardiomyopathy treated with tafamidis 61 mg once daily. Patients were divided into two cohorts based on the median (−32.3%) of the longitudinal percent change in SUV retention index. Cohort A patients had a longitudinal percent reduction in SUV retention index greater than or equal to the median (upper panels), which was associated with significant benefits for left ventricular (LV) and right ventricular (RV) function and serum levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP). Cohort B patients had either a percent decrease less than the median or even a percent increase from baseline (lower panels), without significant benefits for LV and RV function and cardiac biomarkers.

In this prospective study of 206 participants with heart failure with preserved ejection fraction, global longitudinal strain by cardiovascular MRI was associated with diffuse fibrosis and clinical... Background In heart failure with preserved ejection fraction (HFpEF), echocardiographic studies suggest that global longitudinal strain (GLS) has an impact on survival. Feature-tracking cardiovascu...

The use of left ventricular assist devices (LVADs) as a treatment method for heart failure patients has been steadily increasing; however, pathological studies showed presence of thrombi around the HeartWare ventricular assist device inflow cannula (IC) in more than 95% of patients after device explantation. Flow fields around the IC might trigger thrombus formation and require further investigation. In this study flow dynamics parameters were evaluated for different patient geometries using computational fluid dynamics (CFD) simulations. Left ventricular (LV) models of two LVAD patients were obtained from CT scans. The LV volumes of Patient 1 (P1) and Patient 2 (P2) were 264 and 114 cm³ with an IC angle of 20° and 9° from the mitral‐IC tip axis at the coronal plane. The IC insertion site at the apex was central for P1, whereas it was lateral for P2. Transient CFD simulations were performed over 9 cardiac cycles. The wedge area was defined from the cannula tip to the wall of the LV apex. Mean velocity magnitude and blood stagnation region (volume with mean velocity <5 mm/s) as well as the wall shear stress (WSS) at the IC surface were calculated. Cardiac support resulted in a flow mainly crossing the ventricle from the mitral valve to the LVAD cannula for P2, while the main inflow jet deviated toward the septal wall in P1. Lower WSS at the IC surface and consequently larger stagnation volumes were observed for P2 (P1: 0.17, P2: 0.77 cm³). Flow fields around an LVAD cannula can be influenced by many parameters such as LV size, IC angle, and implantation site. Careful consideration of influencing parameters is essential to get reliable evaluations of the apical flow field and its connection to apical thrombus formation. Higher blood washout and lower stagnation were observed for a central implantation of the IC at the apex.

Aims: Extracellular chromatin and deoxyribonuclease (DNase) have been identified as important players of thrombosis, inflammation, and homeostasis in a murine model. We previously demonstrated that activated neutrophils release neutrophil extracellular traps (NETs) at the culprit site in ST-elevation myocardial infarction (STEMI), which significantly contribute to extracellular chromatin burden, and are associated with larger infarcts. To understand the correlation between neutrophil activation, extracellular chromatin, and infarct size (IS), we investigated these parameters in a porcine myocardial infarction model, and at different time points and sites in a prospective STEMI trial with cardiac magnetic resonance (CMR) endpoints. Methods and results: In a prospective STEMI trial (NCT01777750), 101 STEMI patients were included and blood samples were obtained from first medical contact until 6 months after primary percutaneous coronary intervention (pPCI) including direct sampling from the culprit site. CMR was performed 4 ± 2 days and 6 months after pPCI. Neutrophil counts, markers of extracellular chromatin, and inflammation were measured. Double-stranded deoxyribonucleic acid (dsDNA), citrullinated histone 3, nucleosomes, myeloperoxidase, neutrophil elastase, and interleukin (IL)-6 were significantly increased, while DNase activity was significantly decreased at the culprit site in STEMI patients. High neutrophil counts and dsDNA levels at the culprit site correlated with high microvascular obstruction (MVO) and low ejection fraction (EF). High DNase activity at the culprit site correlated with low MVO and high EF. In correspondence, dsDNA correlated with IS in the porcine myocardial infarction model. In porcine infarcts, neutrophils and extracellular chromatin were detected in congested small arteries corresponding with MVO. Markers of neutrophil activation, extracellular chromatin, DNase activity and CMR measurements correlated with markers of systemic inflammation C-reactive protein and IL-6 in patients. Conclusions: NETs and extracellular chromatin are important determinants of MVO in STEMI. Rapid degradation of extracellular chromatin by DNases appears to be crucial for microvascular patency and outcome.

Rationale: Left ventricular hypertrophy (LVH) is highly prevalent in patients with chronic kidney disease and increases their risk of cardiac events and mortality. FGF23 (fibroblast growth factor 23) and parathyroid hormone levels, which are associated with the development of LVH, rise progressively with declining renal function. Objectives: To determine whether FGF23 suppression by calcimimetic therapy may reduce LVH progression in comparison to FGF23 elevation under vitamin D analogs at equal parathyroid hormone suppression under either therapy as well as tight volume control. Methods and Results: We conducted a single-blinded trial with 1:1 block randomization to investigate the effect of the intravenous treatment with etelcalcetide versus alfacalcidol on LVH progression in 62 maintenance hemodialysis patients with secondary hyperparathyroidism and LVH. In the intention-to-treat analysis of 59 patients, the mean difference in the change of left ventricular mass index determined by cardiac magnetic resonance imaging from baseline to 12 months of treatment was −6.9 g/m ² (95% CI, −12.6 to −1.2, P =0.022) in the etelcalcetide compared with the alfacalcidol group. The effect estimate was −8.2 g/m ² (95% CI, −14 to −2.4) in the per-protocol analysis on 52 patients. The trajectories of parathyroid hormone, phosphate, and αKlotho were similar in both groups throughout follow-up. FGF23 levels, which showed a strong positive association with left ventricular mass index, were decreasing under etelcalcetide and increasing under alfacalcidol at similar parathyroid hormone suppression. Mild hypocalcemia was the most common adverse event under etelcalcetide. Blood pressure and the distribution of antihypertensive medications were similar between groups. Conclusions: In this trial, we were able to show that FGF23 suppression by etelcalcetide inhibited the progression of LVH compared with alfacalcidol in hemodialysis patients. A successful prevention of increasing hypertrophy may reduce the risk of sudden cardiac death in this population. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03182699.