Association Between Rheumatoid Arthritis and Risk of Ischemic and Nonischemic Heart Failure

BackgroundIt is unknown whether the increased risk of heart failure (HF) in rheumatoid arthritis (RA) is independent of ischemic heart disease (IHD).ObjectivesThis study sought to investigate the relative risk of HF overall and by subtype (ischemic and nonischemic HF) in patients with RA and to assess the impact of RA disease factors.MethodsTwo contemporary cohorts of RA subjects were identified from Swedish patient and rheumatology registries and matched 1:10 to general population comparator subjects. A first-ever HF diagnosis (classified as ischemic HF or nonischemic HF based on the presence of IHD) was assessed through registry linkages. Relative risks for a history of HF before RA onset were calculated through odds ratios. Relative risks of incident HF in RA were calculated as hazard ratios (HRs).ResultsBy the time of RA onset, a history of HF was not more common in RA. In the new-onset RA cohort, the overall HRs for subsequent HF (any type), ischemic HF, and nonischemic HF were between 1.22 and 1.27. The risk of nonischemic HF increased rapidly after RA onset, in contrast to the risk of ischemic HF. High disease activity was associated with all HF types but was most pronounced for nonischemic HF. In the cohort of patients with RA of any duration, the HRs were between 1.71 and 1.88 for the different HF subtypes.ConclusionsPatients with RA are at increased risk of HF that cannot be explained by their increased risk of IHD. The increased risk of nonischemic HF occurred early and was associated with RA severity.     

Cardiac Structural and Functional Consequences of Amyloid Deposition by Cardiac Magnetic Resonance and Echocardiography and Their Prognostic Roles

ObjectivesThis cross-sectional study aimed to describe the functional and structural cardiac abnormalities that occur across a spectrum of cardiac amyloidosis burden and to identify the strongest cardiac functional and structural prognostic predictors in amyloidosis using cardiac magnetic resonance (CMR) and echocardiography.BackgroundCardiac involvement in light chain and transthyretin amyloidosis is the main driver of prognosis and influences treatment strategies. Numerous measures of cardiac structure and function are assessed by multiple imaging modalities in amyloidosis.MethodsA total f 322 subjects (311 systemic amyloidosis and 11 transthyretin gene mutation carriers) underwent comprehensive CMR and transthoracic echocardiography. The probabilities of 11 commonly measured structural and functional cardiac parameters being abnormal with increasing cardiac amyloidosis burden were evaluated. Cardiac amyloidosis burden was quantified using CMR-derived extracellular volume. The prognostic capacities of these parameters to predict death in amyloidosis were assessed using Cox proportional hazards models.ResultsLeft ventricular mass and mitral annular plane systolic excursion by CMR along with strain and E/e’ by echocardiography have high probabilities of being abnormal at low cardiac amyloid burden. Reductions in biventricular ejection fractions and elevations in biatrial areas occur at high burdens of infiltration. The probabilities of indexed stroke volume, myocardial contraction fraction, and tricuspid annular plane systolic excursion (TAPSE) being abnormal occur more gradually with increasing extracellular volume. Ninety patients (28%) died during a median follow-up of 22 months (interquartile range: 10 to 38 months). Univariable analysis showed that all imaging markers studied significantly predicted outcome. Multivariable analysis showed that TAPSE (hazard ratio: 1.46; 95% confidence interval: 1.16 to 1.85; p < 0.01) and indexed stroke volume (hazard ratio: 1.24; 95% confidence interval: 1.04 to 1.48; p < 0.05) by CMR were the only independent predictors of mortality.ConclusionsSpecific functional and structural abnormalities characterize different burdens of cardiac amyloid deposition. In a multimodality imaging assessment of a large cohort of amyloidosis patients, CMR-derived TAPSE and indexed stroke volume are the strongest prognostic cardiac functional markers.     

Why and How to Measure Aortic Valve Calcification in Patients With Aortic Stenosis

The first-line evaluation of aortic stenosis severity is Doppler echocardiography. However, in up to 40% of patients, resting echocardiographic assessment of aortic stenosis severity is discordant, leading to clinical uncertainty. Interest has therefore grown in aortic valve calcium scoring by multidetector computed tomography (CT-AVC) as an alternative load independent assessment of aortic stenosis severity. This paper will briefly review the pathophysiology of aortic stenosis and the crucial role that calcification plays in driving progressive obstruction of the valve. Subsequently, it will describe published reports that have investigated CT-AVC, validating this parameter against histology, and establishing its diagnostic accuracy versus echocardiography as well as its powerful independent prognostic capability. Finally, this review seeks to provide a practical guide about how best to acquire and interpret CT-AVC with a close focus on potential pitfalls and how these might be best avoided as this technique becomes more widely adopted in to clinical practice.     

Chronobiology of Natriuretic Peptides and Blood Pressure in Lean and Obese Individuals

BackgroundDiurnal variation of natriuretic peptide (NP) levels and its relationship with 24-h blood pressure (BP) rhythm has not been established. Obese individuals have a relative NP deficiency and disturbed BP rhythmicity.ObjectivesThis clinical trial evaluated the diurnal rhythmicity of NPs (B-type natriuretic peptide [BNP], mid-regional pro-atrial natriuretic peptide [MR-proANP], N-terminal pro–B-type natriuretic peptide [NT-proBNP]) and the relationship of NP rhythm with 24-h BP rhythm in healthy lean and obese individuals.MethodsOn the background of a standardized diet, healthy, normotensive, lean (body mass index 18.5 to 25 kg/m²) and obese (body mass index 30 to 45 kg/m²) individuals, age 18 to 40 years, underwent 24-h inpatient protocol involving ambulatory BP monitoring starting 24 h prior to the visit, controlled light intensity, and repeated blood draws for assessment of analytes. Cosinor analysis of normalized NP levels (normalized to 24-h mean value) was conducted to assess the diurnal NP rhythm and its relationship with systolic BP.ResultsAmong 52 participants screened, 40 participants (18 lean, 22 obese; 50% women; 65% Black) completed the study. The median range spread (percentage difference between the minimum and maximum values) over 24 h for MR-proANP, BNP, and NT-proBNP levels was 72.0% (interquartile range [IQR]: 50.9% to 119.6%), 75.5% (IQR: 50.7% to 106.8%), and 135.0% (IQR: 66.3% to 270.4%), respectively. A cosine wave-shaped 24-h oscillation of normalized NP levels (BNP, MR-proANP, and NT-proBNP) was noted both in lean and obese individuals (p_rhythmicity <0.05 for all). A larger phase difference between MR-proANP BP rhythm (?4.9 h vs. ?0.7 h) and BNP BP rhythm (?3.3 h vs. ?0.9 h) was seen in obese compared with lean individuals.ConclusionsThis human physiological trial elucidates evidence of diurnal NP rhythmicity and the presence of an NP-BP rhythm axis. There exists a misalignment of the NP-BP diurnal rhythm in the obese, which may contribute to the disturbed diurnal BP pattern observed among obese individuals. (The Diurnal Rhythm in Natriuretic Peptide Levels; NCT03834168)     

Sustainability of and Adherence to Preschool Health Promotion Among Children 9 to 13 Years Old

BackgroundLong-term evaluations of child health promotion programs are required to assess their sustainability and the need for reintervention.ObjectivesThis study sought to explore the long-term impact of a preschool health promotion intervention delivered in an urban low-income area of Colombia (phase 1) and to assess the effect of a new community-based intervention (phase 2).MethodsIn phase 1, a cross-sectional analysis of knowledge, attitudes, and habits (KAH) toward a healthy lifestyle and ideal cardiovascular health (ICH) scores of 1,216 children 9 to 13 years old was performed. Of the total, 596 had previously received a preschool health promotion intervention at 3 to 5 years old, whereas the remaining 620 were not previously intervened (intervention-naive group). In phase 2, all children were cluster randomized 1:1 to receive either a 4-month educational intervention (the SI! Program) to instill healthy behaviors in community centers (24 clusters, 616 children) or to control (24 clusters, 600 children). Previously intervened and intervention-naive children were not mixed in the same cluster. The primary outcomes were the change from baseline in KAH and ICH scores. Intervention effects were tested for with linear mixed-effects models.ResultsIn phase 1, ∼85% of children had nonideal cardiovascular health, and those who previously received a preschool intervention showed a negligible residual effect compared with intervention-naive children. In phase 2, the between-group (control vs. intervention) differences in the change of the overall KAH and ICH scores were 0.92 points (95% confidence interval [CI]: −0.28 to 2.13; p = 0.133) and −0.20 points (95% CI: −0.43 to 0.03; p = 0.089), respectively. No booster effect was detected. However, a dose-response effect was observed, with maximal benefit in children attending >75% of the scheduled intervention; the difference in the change of KAH between the high- and low-adherence groups was 3.72 points (95% CI: 1.71 to 5.73; p < 0.001).ConclusionsAlthough overall significant differences between the intervention and control groups were not observed, high adherence rates to health promotion interventions may improve effectiveness and outcomes in children. Reintervention strategies may be required at multiple stages to induce sustained health promotion effects (Salud Integral Colombia [SI! Colombia II]; NCT03119792)     

Pathogenesis and treatment of mitochondrial myopathies: recent advances

In this brief review, I have highlighted recent advances in several areas of mitochondrial medicine, including mtDNA-related diseases, mendelian mitochondrial encephalomyopathies, and therapy. The pathogenic mechanisms of mtDNA mutations, especially those affecting mitochondrial protein synthesis, are still largely unknown. The pathogenicity of homoplasmic mtDNA mutations has become evident but has also called attention to modifying nuclear genes, yet another example of impaired intergenomic signaling. The functional significance of the homoplasmic changes associated with mitochondrial haplogroups has been confirmed. Among the mendelian disorders, a new form of “indirect hit” has been described, in which the ultimate pathogenesis is toxic damage to the respiratory chain. Three therapeutic strategies look promising: (i) allogeneic hematopoietic stem cell transplantation in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy); (ii) bezafibrate, an activator of PGC-1α, has proven effective in animal models of mitochondrial myopathy; and (iii) pronucleus transfer into a normal oocyte is effective in eliminating maternal transmission of mtDNA, thus preventing the appearance of mtDNA-related disorders.Key words: mtDNA-related disorders, mendelian mitochondrial disorders, homoplasmy, pathogenesis, therapyThis paper – as the lecture from which it derives – are dedicated to the memory of Eduardo Bonilla (Fig. 1), a great myologist and a great friend.Open in a separate windowFigure 1.Eduardo Bonilla (1937-2010).Although mitochondria have multiple functions, it is fair to say that the most important is the generation of energy. In Figure 2, an oversimplified schematic view of mitochondrial metabolism, I have highlighted the respiratory chain, the “business end” of oxidative metabolism, where ATP is actually produced. One “green view” of mitochondria is that they approximate ecologically friendly hydrogen engines: the breakfast that you ate this morning (derived from sunlight) is metabolized through pathways residing mostly outside (glycolysis) or inside (β-oxidation) the mitochondria. Electrons generated in the Krebs cycle from the oxidation of acetyl-CoA are carried along the four multimeric components of the electron transport chain (complexes I-IV) embedded in the inner mitochondrial membrane (IMM) and protons are pumped from the inside of the IMM (mitochondrial matrix) to the intermembrane space (IMS) between the IMM and the outer mitochondrial membrane (OMM). The resulting chemosmotic potential is used to operate the tiniest rotary machine, ATP synthase (complex V), where the influx of protons back into the matrix makes the rotor (F0) turns on the stator (F1) at the respectable speed of 1,000 RPM, bringing together ADP and Pi and releasing ATP (1, 2).Open in a separate windowFigure 2.Schematic and simplified view of mitochondrial metabolism. The spirals depict the reactions of the β-oxidation pathway. The red oval highlights the reactions of the respiratory chain.A recent remarkable achievement in our understanding of energy production by the respiratory chain has been the clarification of the α-helical structure of the membrane domain of complex I of E. coli by Leonid Sazanov’s group (3). The transfer of 2 electrons from NADH to quinone is coupled to the transfer of 4 protons across the IMM, and two mechanisms of coupling had been proposed, a direct, redox-driven mechanism or an indirect, conformation-driven mechanism. When the electrons reach the quinone moiety, conformational changes in complex I subunits (called NuoA/J/K/H) push a long α-helix towards other transmembrane subunits (NuoL/M/N) in a piston-like action [as aptly described by Tomoko Onishi in a News & Views article (4)] thus opening up “trapdoors” through which protons can pass.Let me consider first recent progress in our understanding of pathogenesis, which unfortunately is still largely “terra incognita” both for mitochondrial DNA (mtDNA)- and for nuclear DNA (nDNA)-related disorders.     

Sex-Specific Risks of Major Cardiovascular and Limb Events in Patients With Symptomatic Peripheral Artery Disease

BackgroundPatients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD.ObjectivesThe aim of this post hoc analysis was to evaluate sex-specific differences in MACE and limb events in the EUCLID (Examining Use of Ticagrelor in PAD) trial.MethodsCox proportional hazards models were used to compare time-to-event outcomes stratified by sex. Covariates were introduced after adjusted model selection.ResultsEUCLID enrolled 13,885 patients with PAD (28% women [n = 3,888]). PAD severity and medical treatment were comparable between sexes, whereas prior lower extremity revascularization was reported less frequently in women (54.8% vs. 57.3%; p = 0.006). Women were older (mean ± SD age: 67.8 ± 8.9 vs. 66.1 ± 8.2 years; p < 0.001) and more likely to have diabetes mellitus (p = 0.004), hypertension, hyperlipidemia, and chronic kidney disease (all p < 0.001). Over a mean follow-up of 30 months, women had a lower risk of MACE (9.5% vs. 11.2%; adjusted hazard ratio: 0.77; 95% confidence interval: 0.68 to 0.88; p < 0.001) and all-cause-mortality (7.6% vs. 9.7%; adjusted hazard ratio: 0.61; 95% confidence interval: 0.53 to 0.71; p < 0.001). In contrast, risk for major adverse limb events (2.6% vs. 3.0%) and hospitalization for acute limb ischemia (1.6% vs. 1.7%) were not different by sex.ConclusionsAlthough women with PAD are at lower risk for MACE and all-cause mortality, risk for limb events was similar between sexes over a mean follow-up of 30 months. Understanding sex-specific differences and dissociation between baseline cardiovascular risk and subsequent cardiovascular events requires further investigation. (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822)     

Study of the 49 kDa excretory-secretory protein gene of <Emphasis Type="Italic">Trichinella nativa</Emphasis> and <Emphasis Type="Italic">Trichinella spiralis</Emphasis>

Summary To study the function of the 49 kDa excretory-secretory (ES) protein gene (P49) of Trichinella, the genes was amplified by RT-PCR from RNA of Trichinella spiralis and Trichinella nativa and several Chinese Trichinella isolates of domestic animals, and sequenced after being cloned. The amplified products of these parasites produced bands of about 950 bp. The 97.2 % to 100 % nucleotides identity and 94.3 % to 100 % identity of deduced amino acids among P49 gene of these Trichinella strains showed the close relationship of these parasites. The P49 gene of T. nativa was cloned into the BamHI site of the prokaryotic expression vector pET-30a, and the recombinant vector was expressed. The expressed product was 40.8 kDa in size. In Western blot analysis, the expressed product was reactive to sera of mice infected with T. nativa, T. spiralis and their Chinese geographical strains.     

Misconceptions and Facts About ‘Diastolic’ Heart Failure

Heart failure with preserved ejection fraction has become a fashionable diagnosis. An increasing number of elderly patients with dyspnea carry this diagnosis. Evaluation and management of these patients typically labeled as having “diastolic” heart failure are challenging, and misconceptions are common. No drug class has been shown to consistently provide outcome benefit. Therapeutic strategies based on the predominant pathophysiologic mechanism and stage of the disease currently remain the best option in tackling the perplexing syndrome of heart failure with preserved ejection fraction.     

Myocardial ‘no-reflow’ — Diagnosis,pathophysiology and treatment

In acute ST-segment elevation myocardial infarction (STEMI), improvement in reperfusion strategies has contributed to improvement in mortality. Nonetheless up to 40–50% of patients who achieve satisfactory epicardial patency do not necessarily achieve patency at the coronary microvascular level, a condition referred to as the ‘no-reflow’ phenomenon. The ‘no-reflow’ phenomenon is associated with a worse prognosis at follow up. The pathogenic mechanisms underlying the ‘no-reflow’ phenomenon is complex and dynamic. This includes a variable combination of mechanisms including distal atherothrombotic embolisation, ischaemic injury, reperfusion injury and heightened susceptibility of coronary microcirculation to injury. Accurate detection of ‘no-reflow’ is crucial because it is independently associated with adverse ventricular remodelling and patient prognosis. The diagnosis of ‘no-reflow’ can be made using angiography, electrocardiography, nuclear scintigraphy, myocardial contrast echocardiography or cardiovascular magnetic resonance (CMR). Despite our improved understanding on the pathogenesis and diagnosis of ‘no-reflow’, the treatment of ‘no-reflow’ remains the ‘Achilles heel’ in the treatment of patients with acute myocardial infarction. Several therapeutic strategies have been tested for the prevention and treatment of ‘no-reflow’, however none have been associated with improvement in clinical outcomes. Therefore there exists a need for ‘in-lab’ tools that will be able to aid early identification of patients at increased risk of ‘no-reflow’. This may enable patients at heightened risk of ‘no-reflow’ to be treated with the most appropriate individualised treatment early. We review the pathogenic mechanisms and diagnostic techniques of the ‘no-reflow’ phenomenon as well as the prevention and treatment strategies of the candidate mechanisms.     

Morphometrical and molecular characterization of <Emphasis Type="Italic">Bursaphelenchus</Emphasis> species from Slovenia

Summary The environmental conditions in Slovenia are relatively favourrable for the colonisation and spread of the pine wood nematode Bursaphelenchus xylophilus, a very dangerous pathogenic species which was recently identified in Europe in Portugal. To determine the presence of B. xylophilus in Slovenia and to introduce proper measures against its emergence and spread, a survey of Bursaphelenchus species was conducted in Slovenia from 2002 to 2005. Approximately 120 ha of conifer forests in Slovenia were surveyed for the presence of Bursaphelenchus species. In total, 206 wood samples were taken from the conifer forests. B. hofmanni, B. mucronatus were found for the first time in Slovenia, while B. xylophilus was not detected. Additionally, the species Aphelenchoides stammeri which is morphologically very similar to Bursaphelencus was found. All species have been described morphologically and characterized by ITS-RFLP analysis. Sequences of ribosomal DNA for B. hofmanni, B. mucronatus were analysed.     

Burden and Outcomes of Heart Failure Hospitalizations in Adults With Chronic Kidney Disease

BackgroundData on rates of heart failure (HF) hospitalizations, recurrent hospitalizations, and outcomes related to HF hospitalizations in chronic kidney disease (CKD) are limited.ObjectivesThis study examined rates of HF hospitalizations and re-hospitalizations within a large CKD population and evaluated the burden of HF hospitalizations with the risk of subsequent CKD progression and death.MethodsThe prospective CRIC (Chronic Renal Insufficiency Cohort) study measured the estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) at baseline. The crude rates and rate ratios of HF hospitalizations and 30-day HF re-hospitalizations were calculated using Poisson regression models. Cox regression was used to assess the association of the frequency of HF hospitalizations within the first 2 years of follow-up with risk of subsequent CKD progression and death.ResultsAmong 3,791 participants, the crude rate of HF admissions was 5.8 per 100 person-years (with higher rates of HF with preserved ejection fraction vs. HF with reduced ejection fraction). The adjusted rate of HF was higher with a lower eGFR (vs. eGFR >45 ml/min/1.73 m²); the rate ratios were 1.7 and 2.2 for eGFR 30 to 44 and <30 ml/min/1.73 m² (vs. >45 ml/min/1.73 m²), respectively. Similarly, the adjusted rates of HF hospitalization were significantly higher in those with higher urine ACR (vs. urine ACR <30 mg/g); the rate ratios were 1.9 and 2.6 for urine ACR 30 to 299 and ≥300 mg/g, respectively. Overall, 20.6% of participants had a subsequent HF re-admission within 30 days. HF hospitalization within 2 years of study entry was associated with greater adjusted risks for CKD progression (1 hospitalization: hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.40 to 2.67; 2+ hospitalizations: HR: 2.14; 95% CI: 1.30 to 3.54) and all-cause death (1 hospitalization: HR: 2.20; 95% CI: 1.71 to 2.84; 2+ hospitalizations: HR: 3.06; 95% CI: 2.23 to 4.18).ConclusionsWithin a large U.S. CKD population, the rates of HF hospitalizations and re-hospitalization were high, with even higher rates across categories of lower eGFR and higher urine ACR. Patients with CKD hospitalized with HF had greater risks of CKD progression and death. HF prevention and treatment should be a public health priority to improve CKD outcomes.