Cardiovascular magnetic resonance (CMR) is emerging as an important tool for cardiac allograft assessment. Native T1 mapping may add value in identifying rejection and in assessing graft dysfunction ...and myocardial fibrosis burden. We hypothesized that CMR native T1 values and features of textural analysis of T1 maps would identify acute rejection, and in a secondary analysis, correlate with markers of graft dysfunction, and with fibrosis percentage from endomyocardial biopsy (EMB).
Fifty cases with simultaneous EMB, right heart catheterization, and 1.5 T CMR with breath-held T1 mapping via modified Look-Locker inversion recovery (MOLLI) in 8 short-axis slices and subsequent quantification of mean and peak native T1 values, were performed on 24 pediatric subjects. A single mid-ventricular slice was used for image texture analysis using nine gray-level co-occurrence matrix features. Digital quantification of Masson trichrome stained EMB samples established degree of fibrosis. Markers of graft dysfunction, including serum brain natriuretic peptide levels and hemodynamic measurements from echocardiography, catheterization, and CMR were collated. Subjects were divided into three groups based on degree of rejection: acute rejection requiring new therapy, mild rejection requiring increased ongoing therapy, and no rejection with no change in treatment. Statistical analysis included student's t-test and linear regression.
Peak and mean T1 values were significantly associated with acute rejection, with a monotonic trend observed with increased grade of rejection. Texture analysis demonstrated greater spatial heterogeneity in T1 values, as demonstrated by energy, entropy, and variance, in cases requiring treatment. Interestingly, 2 subjects who required increased therapy despite low grade EMB results had abnormal peak T1 values. Peak T1 values also correlated with increased BNP, right-sided filling pressures, and capillary wedge pressures. There was no difference in histopathological fibrosis percentage among the 3 groups; histopathological fibrosis did not correlate with T1 values or markers of graft dysfunction.
In pediatric heart transplant patients, native T1 values identify acute rejection requiring treatment and may identify graft dysfunction. CMR shows promise as an important tool for evaluation of cardiac grafts in children, with T1 imaging outperforming biopsy findings in the assessment of rejection.
Chronic kidney disease progresses through the replacement of functional tissue compartments with fibrosis, a maladaptive repair process. Shifting kidney repair toward a physiologically intact ...architecture, rather than fibrosis, is key to blocking chronic kidney disease progression. Much research into the mechanisms of fibrosis is performed in rodent models with less attention to the human genetic context. Recently, human induced pluripotent stem cell (iPSC)-derived organoids have shown promise in overcoming the limitation. In this study, we developed a fibrosis model that uses human iPSC-based 3-dimensional renal organoids, in which exogenous transforming growth factor-β1 (TGF-β1) induced the production of extracellular matrix. TGF-β1-treated organoids showed tubulocentric collagen 1α1 production by regulating downstream transcriptional regulators, Farnesoid X receptor, phosphorylated mothers against decapentaplegic homolog 3 (p-SMAD3), and transcriptional coactivator with PDZ-binding motif (TAZ). Increased nuclear TAZ expression was confirmed in the tubular epithelium in human kidney biopsies with tubular injury and early fibrosis. A dual bile acid receptor agonist (INT-767) increased Farnesoid X receptor and reduced p-SMAD3 and TAZ, attenuating TGF-β1-induced fibrosis in kidney organoids. Finally, we show that TAZ interacted with TEA-domain transcription factors and p-SMAD3 with TAZ and TEA-domain transcription factor 4 coregulating collagen 1α1 gene transcription. In summary, we establish a novel, readily manipulable fibrogenesis model and posit a role for bile acid receptor agonism early in renal parenchymal fibrosis.
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease with no proven pharmacologic therapies. Cardiac amyloidosis shares common features of HFpEF, however endomyocardial ...biopsy data are only available on limited subsets of HFpEF patients. To our knowledge, this is the first study to comprehensively characterize biopsy data for patients referred for HFpEF evaluation.
We included patients referred to the Johns Hopkins HFpEF Clinic who underwent right heart catheterization and endomyocardial biopsy. HFpEF diagnosis was based on signs and symptoms of HF, LVEF ≥50%, and at least 2 of the following: 1) structural heart disease by echocardiogram, 2) invasive hemodynamics with elevated pulmonary capillary wedge pressure, or 3) NT-proBNP >100 pg/mL. We excluded patients with severe valvular heart disease, known infiltrative or restrictive cardiomyopathy, or constrictive pericarditis. We evaluated clinical characteristics, hemodynamics, echocardiography, and histology. Cardiac amyloidosis was diagnosed on Congo red stain if greater than mild deposition was present. Data were analyzed using median tests or Fisher's exact tests.
Of 108 HFpEF patients, cardiac amyloidosis was diagnosed in 15 patients (14%). Non-amyloid HFpEF patients had high incidence of myocyte hypertrophy and fibrosis on endomyocardial biopsy (Figure). HFpEF-Amyloid were older (74y v. 65y, p<0.01), predominantly male (60% v. 40%, p=0.09), with less hypertension (60% v. 98%, p<0.001), diabetes (27% v. 58%, p<0.05), and a lower BMI (29.4 kg/m2 v. 37.6 kg/m2, p<0.01), compared to non-amyloid HFpEF. HFpEF-Amyloid had higher NT-proBNP (3245 pg/mL v. 339 pg/mL, p<0.01), troponin-I (0.09 ng/mL v. 0.0 ng/mL, p<0.001), LV mass index (126.1 g/m2 v. 90.9 g/m2, p<0.05) and greater septal wall thickness (1.3 cm v. 1.1 cm, p=0.01), however lower cardiac output (4.13 L/min v. 5.74 L/min, p<0.01), compared to non-amyloid HFpEF.
Endomyocardial biopsy diagnosed cardiac amyloidosis in 14% of HFpEF patients not suspected to have amyloidosis, with markedly different characteristics between the subgroups. These findings have important diagnostic and therapeutic implications given recent advances in therapies for cardiac amyloidosis.
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