Abstract
Background
In primary hyperoxaluria Type 1 (PH1), endogenous oxalate overproduction significantly elevates urinary oxalate excretion, resulting in recurrent urolithiasis and/or progressive ...nephrocalcinosis and often early end-stage renal disease (ESRD). In ESRD, dialysis cannot sufficiently remove oxalate; plasma oxalate (Pox) increases markedly, inducing systemic oxalate deposition (oxalosis) and often death. Interventions to reduce Pox in PH1 subjects with ESRD could have significant clinical impact. This ongoing Phase II, open-label trial aimed to evaluate whether long-term Oxabact™ (Oxalobacter formigenes, OC5, OxThera Intellectual Property AB, Sweden) lowers Pox in PH1 ESRD subjects, ameliorating clinical outcome.
Methods
PH1 ESRD subjects on stable dialysis regimens were examined. Subjects were administered one OC5 capsule twice daily for up to 36 months or until transplantation. Total Pox values, cardiac function and safety were evaluated. Free Pox was evaluated in a comparative non-treated PH1 dialysis group using retrospective chart reviews and analyses.
Results
Twelve subjects enrolled in an initial 6-week treatment phase. Following a washout of up to 4 weeks, eight subjects entered a continuation study; outcomes after 24 months of treatment are presented. After 24 months, all subjects had reduced or non-elevated Pox compared with baseline. Cardiac function improved, then stabilized. No treatment-related serious adverse events were reported.
Conclusions
Compared with an untreated natural control cohort, 24 months OC5 administration was beneficial to PH1 ESRD subjects by substantially decreasing Pox concentrations, and improving or stabilizing cardiac function and clinical status, without increasing dialysis frequency. OC5 was safe and well-tolerated.
Graphical Abstract
Patients with chronic kidney disease (CKD) have a high prevalence of atherosclerotic cardiovascular disease, likely reflecting the presence of traditional risk factors. A greater distinguishing ...feature of atherosclerotic cardiovascular disease in CKD is the severity of the disease, which is reflective of an increase in inflammatory mediators and vascular calcification secondary to hyperparathyroidism of renal origin that are unique to patients with CKD. Additional components of atherosclerotic cardiovascular disease that are prominent in patients with CKD include microvascular disease and myocardial fibrosis. Therapeutic interventions that minimize cardiovascular events related to atherosclerotic cardiovascular disease in patients with CKD, as determined by well-designed clinical trials, are limited to statins. Data are lacking regarding other available therapeutic measures primarily due to exclusion of patients with CKD from major trials studying cardiovascular disease. Data from well-designed randomized controlled trials are needed to guide clinicians who care for this high-risk population in the management of atherosclerotic cardiovascular disease to improve clinical outcomes.
Objectives This study sought to assess sex differences in ventricular-arterial interactions. Background Heart failure with preserved ejection fraction is more prevalent in women than in men, but the ...basis for this difference remains unclear. Methods Echocardiography and arterial tonometry were performed to quantify arterial and ventricular stiffening and interaction in 461 participants without heart failure (189 men, age 67 ± 9 years; 272 women, age 65 ± 10 years). Aortic characteristic impedance (Zc ), total arterial compliance (pulsatile load), and systemic vascular resistance index (steady load) were compared between men and women, and sex-specific multivariable regression analyses were performed to assess associations of these arterial parameters with diastolic dysfunction and ventricular-arterial coupling (effective arterial elastance/left ventricular end-systolic elastance Ea/Ees) after adjustment for potential confounders. Results Zc was higher and total arterial compliance was lower in women, whereas systemic vascular resistance index was similar between sexes. In women but not men, higher log Zc was associated with mitral inflow E/A ratio (β ± SE: −0.17 ± 0.07), diastolic dysfunction (odds ratio: 7.8; 95% confidence interval: 2.0 to 30.2) and Ea/Ees (β ± SE: 0.13 ± 0.04) (p ≤ 0.01 for all). Similarly, total arterial compliance was associated with E/A ratio (β ± SE: 0.12 ± 0.04), diastolic dysfunction (odds ratio: 0.33; 95% confidence interval: 0.12 to 0.89), and Ea/Ees (β ± SE: −0.09 ± 0.03) in women only (p ≤ 0.03 for all). Systemic vascular resistance index was not associated with diastolic dysfunction or Ea/Ees. Conclusions Proximal aortic stiffness (Zc ) is greater in women than men, and women may be more susceptible to the deleterious effects of greater pulsatile and early arterial load on diastolic function and ventricular-arterial interaction. This may contribute to the greater risk of heart failure with preserved ejection fraction in women.
Although right ventricular (RV) dysfunction is a major determinant of outcome in patients with pulmonary hypertension (PH), the optimal measure of RV function is poorly defined. We hypothesized that ...RV strain measured by speckle-tracking echocardiography predicts outcome in PH over a broad range of pulmonary pressures.
Prospective peak RV longitudinal systolic strain measurement was performed on 575 patients (mean age, 56 ± 18 years; 63% women) referred for echocardiography for known or suspected PH. Survival status was assessed over a median of 16.5 (interquartile range, 7.6-20.0) months. There were 406 patients with PH (71%) (74% group 1, 14% group 3, and 12% group 4) and 169 patients without evidence of PH (29%). Among patients with PH, 46% were World Health Organization functional class III-IV. The mean RV strain was -21.2 ± 6.7% for all patients. RV strain declined with worse functional class, shorter 6-minute walk distances, higher N-terminal pro-B-type natriuretic peptide levels, and the presence of right heart failure. RV strain predicted outcome across pulmonary pressures and groups of PH. Eighteen-month survival was 92%, 88%, 85%, and 71% according to RV strain quartile (P<0.001), with a 1.46 higher risk of death (95% confidence interval, 1.05-2.12) per 6.7% decline in RV strain. RV strain predicted survival when adjusted for pulmonary pressure, pulmonary vascular resistance, and right atrial pressure and provided incremental prognostic value over conventional clinical and echocardiographic variables.
Quantitative assessment of RV free-wall systolic strain is feasible and is a powerful predictor of the clinical outcome of patients with known or suspected PH.
Objectives We sought to identify a novel gene for dilated cardiomyopathy (DCM). Background DCM is a heritable, genetically heterogeneous disorder that remains idiopathic in the majority of patients. ...Familial cases provide an opportunity to discover unsuspected molecular bases of DCM, enabling pre-clinical risk detection. Methods Two large families with autosomal-dominant DCM were studied. Genome-wide linkage analysis was used to identify a disease locus, followed by fine mapping and positional candidate gene sequencing. Mutation scanning was then performed in 278 unrelated subjects with idiopathic DCM, prospectively identified at the Mayo Clinic. Results Overlapping loci for DCM were independently mapped to chromosome 10q25-q26. Deoxyribonucleic acid sequencing of affected individuals in each family revealed distinct heterozygous missense mutations in exon 9 of RBM20 , encoding ribonucleic acid (RNA) binding motif protein 20. Comprehensive coding sequence analyses identified missense mutations clustered within this same exon in 6 additional DCM families. Mutations segregated with DCM (peak composite logarithm of the odds score >11.49), were absent in 480 control samples, and altered residues within a highly conserved arginine/serine (RS)-rich region. Expression of RBM20 messenger RNA was confirmed in human heart tissue. Conclusions Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain. RBM20 is preferentially expressed in the heart and encodes motifs prototypical of spliceosome proteins that regulate alternative pre-messenger RNA splicing, thus implicating a functionally distinct gene in human cardiomyopathy. RBM20 mutations are associated with young age at diagnosis, end-stage heart failure, and high mortality.
Objectives
We sought to validate a deep learning algorithm designed to predict an ejection fraction (EF) less than or equal to 35% based on the 12‐lead electrocardiogram (ECG) in a large prospective ...cohort.
Background
Patients undergoing routine ECG may have undetected left ventricular (LV) dysfunction that warrants further echocardiographic assessment. However, identification of these patients can be challenging.
Methods
We applied the algorithm to all ECGs interpreted by the Mayo Clinic ECG laboratory in September 2018. The performance of the algorithm was tested among patients with recent echocardiographic assessments of LV function. We also applied the algorithm in patients with no recent echocardiographic assessments of LV function to determine the rate of new “positive screens.”
Results
Among 16 056 adult patients who underwent routine ECG, 8600 (age 67.1 ± 15.2 years, 45.6% male), had a transthoracic echocardiogram (TTE) and 3874 patients had a TTE and ECG less than 1 month apart. Among these patients, the algorithm was able to detect an EF less than or equal to 35% with 86.8% specificity, 82.5% sensitivity, and 86.5% accuracy, (area under the curve, 0.918). Among 474 “false‐positives screens,” 189 (39.8%) had an EF of 36% to 50%. Among patients with no prior TTE, the algorithm identified 3.5% of the patients with suspected EF less than or equal to 35%. Exploratory analysis suggests false positives could be reduced by assessing NT‐pro‐BNP after the initial “positive screen.”
Conclusions
A deep learning algorithm detected depressed LV function with good accuracy in routine practice. Further studies are needed to validate the algorithm in patients with no prior echocardiogram and to assess the impact on echocardiography utilization, cost, and clinical outcomes.
Abstract Left ventricular (LV) wall thickness is a prognostic marker in hypertrophic cardiomyopathy (HC). LV wall thickness ≥30 mm (massive hypertrophy) is independently associated with sudden ...cardiac death. Presence of massive hypertrophy is used to guide decision making for cardiac defibrillator implantation. We sought to determine whether measurements of maximal LV wall thickness differ between cardiac magnetic resonance imaging (MRI) and transthoracic echocardiography (TTE). Consecutive patients were studied who had HC without prior septal ablation or myectomy and underwent both cardiac MRI and TTE at a single tertiary referral center. Reported maximal LV wall thickness was compared between the imaging modalities. Patients with ≥1 modality reporting massive hypertrophy received subset analysis. In total, 618 patients were evaluated between January 1, 2003, and December 21, 2012 (mean SD age, 53 15 years; 381 men 62%). In 75 patients (12%), reported maximal LV wall thickness was identical between MRI and TTE. Median difference in reported maximal LV wall thickness between the modalities was 3 mm (maximum difference, 17 mm). Of the 63 patients with ≥1 modality measuring maximal LV wall thickness ≥30 mm, 44 patients (70%) had discrepant classification regarding massive hypertrophy. MRI identified 52 patients (83%) with massive hypertrophy; TTE, 30 patients (48%). Although guidelines recommend MRI or TTE imaging to assess cardiac anatomy in HC, this study shows discrepancy between the modalities for maximal reported LV wall thickness assessment. In conclusion, because this measure clinically affects prognosis and therapeutic decision making, efforts to resolve these discrepancies are critical.
The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a ...survival benefit. However, the efficacy of this approach is uncertain.
In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds.
Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval CI, 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53).
The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).
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