Pellikka, Patricia A

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.

Abstract Aims Chronic volume-overload can impair systolic and diastolic myocardial properties. We tested the hypothesis that Intrinsic Cardiac Elastography may detect alterations in passive myocardial elasticity in patients with chronic severe mitral regurgitation (MR) and predict worsening left ventricular (LV) function after mitral valve repair (MVr). Methods and results Comprehensive transthoracic echocardiography and cardiac elastography were performed in 80 patients with primary MR (prolapse and/or flail leaflets) of varying severity and compared with 40 normal subjects. In patients who underwent MVr (n = 51), elastography measurements were related to changes in left ventricular ejection fraction (LVEF) at short-term (3–4 days post-op) and mid-term (1 year) follow-up. Most patients were asymptomatic or mildly symptomatic and had preserved LVEF (>60%). Intrinsic velocity propagation (iVP) of myocardial stretch, a direct measure of myocardial stiffness, was higher in patients with severe MR {median 2.0 [interquartile range (IQR) 1.5–2.2] m/s, range 1.1–3.4 m/s; n = 56} compared to normal subjects [median 1.7 (IQR 1.5–1.8) m/s; n = 40; P = 0.0005], but not in those with mild or moderate MR [median 1.7 (IQR 1.4–1.9) m/s; n = 24]. A higher iVP was associated with more severe LV volume-overload and LV and left atrial enlargement (P < 0.05 for all). In patients undergoing MVr, a higher iVP independently predicted a larger drop in LVEF post-intervention (short-term, P = 0.001; 1 year, P = 0.007), incrementally to pre-operative LVEF (P < 0.05). Conclusion Non-invasive measurements of myocardial stiffness were able to predict functional deterioration after MVr for chronic primary MR. Further studies should investigate the mechanisms and practical utility of this novel measurement.

Background: Inconclusive noninvasive tests complicate the care of patients with suspected coronary artery disease, but their prevalence and impact on management, outcomes, and costs are not well described. Methods: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) patients were randomized to stress testing (n=4533) or computed tomographic angiography (CTA; n=4677). We assessed relationships between inconclusive results, subsequent testing, a composite outcome (death, myocardial infarction, or hospitalization for unstable angina), and healthcare expenditures. Results: Overall, 8.0% of tests were inconclusive (9.7% stress, 6.4% CTA). Compared with negative tests, inconclusive tests were more often referred to a second noninvasive test (stress: 14.6% versus 8.5%, odds ratio [OR], 1.91; CTA: 36.5% versus 8.4%, OR, 5.95; P <0.001) and catheterization (stress: 5.5% versus 2.4%, OR, 2.36; CTA: 23.4% versus 4.1%, OR, 6.49; P <0.001), and composite outcomes were higher for both inconclusive tests (stress: 3.7% versus 2.0%, hazard ratio, 1.81, P =0.034; CTA: 5.0% versus 2.2%, hazard ratio, 1.85; P =0.044) and positive tests (stress: 8.3% versus 2.0%, hazard ratio, 3.50; CTA: 9.2% versus 2.2%, hazard ratio, 3.66; P <0.001). Twenty-four–month costs were higher for inconclusive tests than negative tests by $2905 (stress) and $4030 (CTA). Conclusions: Among patients with stable chest pain undergoing a noninvasive test, inconclusive results occurred in 6% of CTA and 10% of stress tests. Compared with those with conclusive negative tests, individuals with inconclusive results more often underwent subsequent testing, had increased medical costs, and experienced worse outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01174550.

Background: Left ventricular global longitudinal strain (GLS) is associated with long-term outcomes of patients with severe aortic stenosis. However, its prognostic value in patients with moderate aortic stenosis remains unknown. Methods: Patients diagnosed with moderate aortic stenosis (1.0< aortic valve area ≤1.5 cm 2 ) and left ventricular ejection fraction ≥50% were identified. GLS was assessed by 2-dimensional strain imaging using speckle-tracking method. All-cause mortality was assessed according to the median GLS value. Results: Two hundred eighty-seven patients were included (median age 76 years; 47% male). Mean aortic valve area was 1.25 cm 2 , left ventricular ejection fraction 62%, and median GLS −15.2%. During a median follow-up of 3.9 years, there were 103 deaths (36%). Mortality was higher in patients with GLS>−15.2% (hazard ratio 2.62 [95% CI 1.69–4.06]) compared with patients with GLS ≤−15.2% even after adjusting for confounders. Mortality rates at 1, 3, 5 years were 21%, 35%, 48%, respectively, in patients with GLS >−15.2%, and 6%, 15%, 19% in those with GLS ≤−15.2%. Even among those with left ventricular ejection fraction ≥60%, GLS discriminated higher-risk patients ( P =0.0003). During follow-up, 106 (37%) patients underwent aortic valve replacement with median waiting-time of 2.4 years, and their survival was better than patients without aortic valve replacement. Among those patients undergoing aortic valve replacement, prognosis was still worse in patients with GLS >−15.2% ( P =0.04). Mortality rates at 1, 3, 5 years were 2%, 10%, 20%, respectively, in patients with GLS >-15.2% and 2%, 5%, 6% in those with GLS ≤−15.2%. Conclusions: Impaired GLS in moderate aortic stenosis patients is associated with higher mortality rates even among those undergoing aortic valve replacement.

Aortic stenosis (AS) is a common valve disorder in an ageing population in western countries, and women, with longer life expectancy, comprise a substantial percentage of elderly patients with AS. Compared with men, women exhibit distinctive characteristics at the level of stenotic valve leaflets and subsequent compensatory responses of the left ventricle to chronic pressure overload, and in clinical presentation, consequences and response to intervention. Randomised controlled trials of transcatheter aortic valve implantation have yielded new evidence of sex differences in both short-term and long-term outcomes after intervention. A comprehensive knowledge of the existing evidence may inform our understanding of gender differences during assessment and treatment of patients with AS. In this paper, we review the available evidence regarding sex differences in AS in terms of symptoms, clinical presentation, anatomical differences and pathophysiological progression, management and outcomes after aortic valve replacement. Implications for further research are suggested.

Objective To determine whether echocardiography-derived left ventricular filling pressure influences survival in patients with severe aortic stenosis (AS) undergoing aortic valve replacement (AVR). Methods We retrospectively reviewed 1383 consecutive patients with severe AS, normal ejection fraction and interpretable filling pressure undergoing AVR. Left ventricular filling pressure was determined according to current guidelines using mitral inflow, mitral annular tissue Doppler, estimated right ventricular systolic pressure and left atrial volume index. Cox proportional hazards regression was used to assess the influence of various parameters on mortality. Results Age was 75±10 years and 552 (40%) were female. Left ventricular filling pressure was normal in 325 (23%), indeterminate in 463 (33%) and increased in 595 (43%). Mean follow-up was 7.3±3.7 years, and mortality was 1.2%, 4.2% and 18.9% at 30 days and 1 and 5 years, respectively. Compared with patients with normal filling pressure, patients with increased filling pressure were older (78±9 vs 70±12, p<0.001), more often female (45% vs 35%, p=0.002) and were more likely to have New York Heart Association class III–IV symptoms (35% vs 24%, p=0.004), coronary artery disease (55% vs 42%, p<0.001) and concentric left ventricular hypertrophy (63% vs 37%, p<0.001). After correction for other factors, increased left ventricular filling pressure remained an independent predictor of mortality after successful AVR (adjusted HR 1.45 (95% CI 1.16 to 1.81), p=0.005). Conclusions Preoperative increased left ventricular filling pressure is common in patients with AS undergoing AVR and has important prognostic implications, regardless of symptom status. Future prospective studies should consider whether patients with increased filling pressure would benefit from earlier operation.

Abstract Aims Right ventricular dysfunction (RVD) is an important determinant of functional status and survival in various diseases states. Data are sparse on the epidemiology and outcome of patients with severe RVD. This study examined the characteristics, aetiology, and survival of patients with severe RVD. Methods and results Retrospective study of consecutive patients with severe RVD diagnosed by transthoracic echocardiography (TTE) between 2011 and 2015 in a single tertiary referral institution. Patients with prior cardiac surgery, mechanical assist devices, and congenital heart disease were excluded. Primary endpoint was all-cause mortality. In 64 728 patients undergoing TTE, the prevalence of ≥mild RVD was 21%. This study focused on the cohort of 1299 (4%) patients with severe RVD; age 64 ± 16 years; 61% male. The most common causes of severe RVD were left-sided heart diseases (46%), pulmonary thromboembolic disease (18%), chronic lung disease/hypoxia (CLD; 17%), and pulmonary arterial hypertension (PAH; 11%). After 2 ± 2 years of follow-up, 701 deaths occurred, 66% within the first year of diagnosis. The overall probability of survival at 1- and 5 years for the entire cohort were 61% [95% confidence interval (CI) 58–64%] and 35% (95% CI 31–38%), respectively. In left-sided heart diseases, 1- and 5-year survival rates were 61% (95% CI 57–65%) and 33% (95% CI 28–37%), respectively; vs. 76% (95% CI 68–82%) and 50% (95% CI 40–59%) in PAH, vs. 71% (95% CI 64–76%) and 49% (95% CI 41–58%) in thromboembolic diseases, vs. 42% (95% CI 35–49%) and 8% (95% CI 4–15%) in CLD (log-rank P &lt; 0.0001). Presence of ≥moderate tricuspid regurgitation portended worse survival in severe RVD. Conclusion One-year mortality of patients with severe RVD was high (∼40%) and dependent on the aetiology of RVD. Left-sided heart diseases is the most common cause of severe RVD but prognosis was worst in CLD.