-
1.
Blood Plasma's Protective Ability against the Degradation of S-Nitrosoglutathione under the Influence of Air-Pollution-Derived Metal Ions in Patients with Exacerbation of Heart Failure and Coronary Artery Disease.
Wądołek, A, Drwiła, D, Oszajca, M, Stochel, G, Konduracka, E, Brindell, M
International journal of molecular sciences. 2021;(19)
Abstract
One of the consequences of long-term exposure to air pollutants is increased mortality and deterioration of life parameters, especially among people diagnosed with cardiovascular diseases (CVD) or impaired respiratory system. Aqueous soluble inorganic components of airborne particulate matter containing redox-active transition metal ions affect the stability of S-nitrosothiols and disrupt the balance in the homeostasis of nitric oxide. Blood plasma's protective ability against the decomposition of S-nitrosoglutathione (GSNO) under the influence of aqueous PM extract among patients with exacerbation of heart failure and coronary artery disease was studied and compared with a group of healthy volunteers. In the environment of CVD patients' plasma, NO release from GSNO was facilitated compared to the plasma of healthy controls, and the addition of ascorbic acid boosted this process. Model studies with albumin revealed that the amount of free thiol groups is one of the crucial factors in GSNO decomposition. The correlation between the concentration of NO released and -SH level in blood plasma supports this conclusion. Complementary studies on gamma-glutamyltranspeptidase activity and ICP-MS multielement analysis of CVD patients' plasma samples in comparison to a healthy control group provide broader insights into the mechanism of cardiovascular risk development induced by air pollution.
-
2.
Routine use of natriuretic peptides: Lessons from a big data analysis.
Goudot, FX, Msadek, S, Boukertouta, T, Schischmanoff, PO, Meune, C
Annals of clinical biochemistry. 2021;(5):481-486
Abstract
BACKGROUND Natriuretic peptides have broad indications during heart failure and the detection of left ventricular dysfunction in high-risk patients. They can also be used for the diagnosis/management of other cardiac diseases. However, very little is known regarding their use in routine practice. METHODS We examined all biological tests performed from February 2010 to August 2015 in two districts from the French Brittany, covering 13,653 km2 and including 22,265 physicians. We report the settings and conditions of N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements (the only locally natriuretic peptide available). RESULTS From a total of 3,606,432 tests requested in 557,650 adult (older than 20 years) patients, only 56,653 (1.6%) included at least one NT-proBNP measurement. NT-proBNP measurements gradually increased, from 9188 in 2011 to 12,938 in 2014 (P < 0.001). Most NT-proBNP tests were measured in urban laboratories (72.7%) and in private (62.9%) non-hospital/clinics laboratories; they were mostly ordered by general practitioners (66% compared with 11% by cardiologists). The number of NT-proBNP measurements increased with age up to 80-90 years, and 70.3% of tests were measured in ≥75 years patients. Creatinine and electrolytes were not associated with NT-proBNP in 15.8% and 19.7% of tests, respectively. CONCLUSION Among a very large cohort, we observed that natriuretic peptides remain largely undermeasured. NT-proBNP is mostly measured in elderly patients, and its interpretation may be hazardous in up to 16% of all individuals because no measurement of creatinine was associated to NT-proBNP.
-
3.
Pharmacokinetics, Disposition, and Biotransformation of [14C]Omecamtiv Mecarbil in Healthy Male Subjects after a Single Intravenous or Oral Dose.
Trivedi, A, Wahlstrom, J, Mackowski, M, Dutta, S, Lee, E
Drug metabolism and disposition: the biological fate of chemicals. 2021;(8):619-628
Abstract
Omecamtiv mecarbil (OM) is a novel cardiac myosin activator that is currently in clinical development for the treatment of heart failure. The absorption and disposition of [14C]OM (60 µCi) were studied after a single intravenous infusion (35 mg over 1 hour) or oral solution dose (35 mg) in 14 healthy male subjects. Mean recovery of the administered [14C]OM dose was 85.1% and 86.5% over 336 hours for the intravenous and oral routes, respectively. After intravenous dosing, 47.8% and 37.3% of the dose was recovered in urine and feces, respectively; after oral dosing, 48.6% and 38.0% was recovered in urine and feces, respectively. Unchanged OM accounted for a minor percentage of radioactivity in urine (mean 7.7% of dose) and feces (mean 4.1% of dose) across all subjects. The major metabolites recovered in urine and feces were M3 (decarbamoylation product) and sequential metabolite M4 (lactam of M3), which accounted for means of 26.5% and 11.6% of the administered dose, respectively. The CYP4 family of enzymes was primarily responsible for the formation of M3 based on in vitro studies. Other metabolic pathways accounted for 14.9% of the administered dose. In pooled plasma, OM, M3, and M4 accounted for 83.8%, 6.0%, and 3.3% of the total [14C]OM-related materials. No other plasma metabolites constituted more than 3% of the administered dose. The bioavailability for OM solution was 93.5% after rapid and extensive absorption. SIGNIFICANCE STATEMENT This study characterized the absorption and disposition of OM, a novel small molecule being developed for the treatment of heart failure. OM was primarily cleared through metabolism by the CYP4 family through oxidative cleavage of a terminal carbamate moiety that resembles hydrolysis.
-
4.
Factors associated with baseline and serial changes in circulating NT-proBNP and high-sensitivity cardiac troponin T in a population-based cohort (Dallas Heart Study).
Puleo, CW, Ayers, CR, Garg, S, Neeland, IJ, Lewis, AA, Pandey, A, Drazner, MH, de Lemos, JA
Biomarkers in medicine. 2021;(16):1487-1498
-
-
Free full text
-
Abstract
Aim: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) associate with structural heart disease and heart failure risk in individuals without known cardiovascular disease (CVD). However, few data are available regarding whether factors influencing levels of these two biomarkers are similar or distinct. We performed serial measurement of NT-proBNP and hs-cTnT in a contemporary multiethnic cohort with extensive phenotyping, with the goal of identifying their respective biological determinants in a population without known or suspected CVD. Methods: We evaluated 1877 participants of the Dallas Heart Study who had NT-proBNP and hs-cTnT measured and were free from clinical CVD at the each of its two examinations (2000-2002 and 2007-2009). Variables collected included demographic and risk factors, high-sensitivity C-reactive protein, body composition via dual-energy x-ray absorptiometry, coronary artery calcium by computed tomography, and cardiac dimensions and function by cardiac MRI. Linear regression was used to identify associations of these factors with each biomarker at baseline and with changes in biomarkers over follow-up. Results: NT-proBNP and hs-cTnT were poorly correlated at baseline (Spearman rho 0.083, p = 0.015), with only moderate correlation between change values (rho 0.18, p < 0.001). hs-cTnT positively associated and NT-proBNP inversely associated with male gender and black race. At baseline, both NT-proBNP and hs-cTnT associated with left ventricular end-diastolic volume and wall thickness, but only NT-proBNP associated with left atrial size. Changes in cardiac dimensions between phases were more strongly associated with changes in NT-proBNP than hs-cTnT. NT-proBNP was more strongly associated with high-sensitivity C-reactive protein and measures of body composition than hs-cTnT. Conclusion: Among individuals without CVD in the general population, NT-proBNP and hs-cTnT are nonredundant biomarkers that are differentially associated with demographic and cardiac factors. These findings indicate that hs-cTnT and NT-proBNP may reflect different pathophysiological pathways.
-
5.
Beneficial effects of the treatment of iron deficiency on clinical condition, left ventricular function, and quality of life in patients with chronic heart failure.
Mirdamadi, A, Arefeh, A, Garakyaraghi, M, Pourmoghadas, A
Acta bio-medica : Atenei Parmensis. 2018;(2):214-218
Abstract
BACKGROUND Anemia is now considered as an important contributing factor to the deterioration of chronic heart failure. The present study aimed to assess the effects of intravenous iron therapy on clinical condition, left ventricular function and also quality of life in patients who suffered of chronic heart failure and concomitant iron deficiency. METHODS In this clinical trial, 25 consecutive patients with concomitant chronic heart failure and iron deficiency referred to Shariati hospital in Isfahan, Iran in 2013. After initial clinical, laboratory, and echocardiography assessments, the patients administered 200 mg intravenous Iron per week until compensating iron deficit. Then, all study parameters were assessed again and compared to parameters before the therapeutic intervention. RESULTS The NYHA class showed a significant improvement after the therapeutic approach. The prevalence of heart failure-related edema was also significantly reduced from 60% before treatment to 48% after that (p = 0.036). The rate of hospitalization was considerably reduced from 42% to 16% (P < 0.001). Moreover, mean 6 minute walk test (6MWT) was increased from 155.18 m to 187.40 m (P < 0.001). Comparing Left Ventricular Ejection Fraction (LVEF) after treatment to figures before the test indicated a significant improvement in this parameter (27.5% versus 33.0%, P = 0.007). The treatment of iron deficiency in this group of subjects got a significant improvement in SF36 total score. CONCLUSION In patients with chronic heart failure, the treatment of iron deficiency results in a marked improvement in functional status, ejection fraction, and also quality of life as well as a reduction in need to re-hospitalization, however renal function was deteriorated and thus more pay attention to renal function is necessary.
-
6.
Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.
Vanninen, SUM, Leivo, K, Seppälä, EH, Aalto-Setälä, K, Pitkänen, O, Suursalmi, P, Annala, AP, Anttila, I, Alastalo, TP, Myllykangas, S, et al
PloS one. 2018;(9):e0203422
Abstract
During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requires extensive family studies. We aimed to characterize the phenotype related to a variant in the junctophilin-2 (JPH2) gene, which is less known non-sarcomeric candidate gene. In addition, we did extensive review of the literature and databases about JPH2 variation in association with cardiac disease. We characterize nine Finnish index patients with HCM and heterozygous for JPH2 c.482C>A, p.(Thr161Lys) variant were included and segregation studies were performed. We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2 p.(Thr161Lys) variant. We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80. Co-segregation of the variant with HCM phenotype was observed in six families. Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block. In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected. In conclusion, we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM.
-
7.
Leptin predicts short-term major adverse cardiac events in patients with coronary artery disease.
Puurunen, VP, Kiviniemi, A, Lepojärvi, S, Piira, OP, Hedberg, P, Junttila, J, Ukkola, O, Huikuri, H
Annals of medicine. 2017;(5):448-454
Abstract
INTRODUCTION Leptin is an adipose tissue-derived hormone associated with cardiovascular risk factors. We examined whether leptin predicts major adverse cardiac events (MACE) in coronary artery disease (CAD) patients. METHODS Fasting plasma leptin levels were measured in 1327 male and 619 female CAD patients. The patients were followed up for two years. The primary endpoint (MACE) was the composite of a hospitalisation for congestive heart failure (CHF) or a cardiac death. The secondary endpoint was the composite of an acute coronary syndrome (ACS) or a stroke. RESULTS In regression analysis including established risk variables, high leptin levels were associated with a significantly increased risk of MACE (HR 3.37; 95%CI 1.64-6.90; p = 0.001) and ACS or stroke (HR 1.95; 95%CI 1.29-2.96; p = 0.002). Adding leptin to the risk model for MACE increased the C-index from 0.78 (95%CI 0.71-0.85) to 0.81 (0.74-0.88) and improved classification (NRI 0.36; 95%CI 0.13-0.60; p = 0.002) and discrimination of the patients (IDI 0.016; 95%CI 0.001-0.030; p = 0.031). CONCLUSIONS High plasma leptin levels predict short-term occurrence of CHF or cardiac death and ACS or stroke in patients with CAD independently of established risk factors. The possible harmful effects of leptin should be thoroughly investigated. Key messages Leptin is a peptide hormone secreted mainly by adipose tissue. It has been associated with several cardiovascular risk factors. High leptin levels predict the short-term occurrence of congestive heart failure or cardiac death and ACS or stroke in patients with CAD independently of established risk factors. The possible detrimental effects of leptin on the cardiovascular system should be thoroughly investigated.
-
8.
[Journal Club].
Dovjak, P, Püllen, R
Zeitschrift fur Gerontologie und Geriatrie. 2016;(5):455-7
-
9.
Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial.
Anker, SD, Kosiborod, M, Zannad, F, Piña, IL, McCullough, PA, Filippatos, G, van der Meer, P, Ponikowski, P, Rasmussen, HS, Lavin, PT, et al
European journal of heart failure. 2015;(10):1050-6
Abstract
AIMS: Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE--a Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies. METHODS AND RESULTS Heart failure patients with evidence of hyperkalaemia (serum potassium ≥5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population. CONCLUSION Compared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population.
-
10.
RyR2 Common Gene Variant G1886S and the Risk of Ventricular Arrhythmias in ICD Patients with Heart Failure.
Francia, P, Adduci, C, Semprini, L, Stanzione, R, Serdoz, A, Caprinozzi, M, Santini, D, Cotugno, M, Palano, F, Musumeci, MB, et al
Journal of cardiovascular electrophysiology. 2015;(6):656-61
Abstract
BACKGROUND Cardiac ryanodine receptor 2 (RyR2) is critical to the electrical homeostasis of cardiomyocytes. Its gene variant rs3766871 entails channel destabilization and enhanced intracellular Ca(2+) oscillation, thus promoting cardiac arrhythmias. We investigated whether the RyR2 rs3766871 variant is associated with aborted sudden cardiac death or ICD therapy for ventricular tachycardia (VT)/fibrillation (VF) in heart failure (HF) patients implanted with a cardioverter defibrillator (ICD). METHODS AND RESULTS A total of 183 HF patients with primary or secondary prevention ICD were divided in 2 groups. A VT/VF group was composed of secondary prevention patients and primary prevention patients with appropriate ICD intervention for VT/VF. An ICD control group was composed of primary prevention patients free from any appropriate ICD intervention after 43 ± 25 months follow-up. Study subjects were genotyped with respect to the rs3766871 RyR2 gene variant. Hazard ratios (HRs) were derived from Cox proportional-hazards regression analysis. In all, 56 patients constituted the VT/VF group and 127 patients the ICD control group. Male sex (HR: 3.02; 95% CI: 0.99-9.18; P = 0.05), atrial fibrillation (AF; HR: 2.33; 95% CI: 0.89-6.10; P = 0.08), and underuse of β-blockers (HR: 2.08; 95% CI: 0.84-5.15; P = 0.11) were associated with the VT/VF phenotype. Prevalence of the rs3766871 minor allele was 2.8% in ICD control patients and 8.0% in the VT/VF group (P = 0.02). After adjustment for age, sex, AF, and use of β-blockers, the rs3766871 minor allele was associated with increased risk of VT/VF (HR: 3.49; 95% CI: 1.14-10.62; P = 0.02). CONCLUSIONS Our study identifies a significant role of RyR2 rs3766871 minor allele for increased susceptibility to VT/VF in a population of ICD patients with HF.