Proteomic Profiling of Dilated Cardiomyopathy Plasma Samples ─ Searching for Biomarkers with Potential to Predict the Outcome of Therapy.

Determination of the prognosis and treatment outcomes of dilated cardiomyopathy is a serious problem due to the lack of valid specific protein markers. Using in-depth proteome discovery analysis, we compared 49 plasma samples from patients suffering from dilated cardiomyopathy with plasma samples from their healthy counterparts. In total, we identified 97 proteins exhibiting statistically significant dysregulation in diseased plasma samples. The functional enrichment analysis of differentially expressed proteins uncovered dysregulation in biological processes like inflammatory response, wound healing, complement cascade, blood coagulation, and lipid metabolism in dilated cardiomyopathy patients. The same proteome approach was employed in order to find protein markers whose expression differs between the patients well-responding to therapy and nonresponders. In this case, 45 plasma proteins revealed statistically significant different expression between these two groups. Of them, fructose-1,6-bisphosphate aldolase seems to be a promising biomarker candidate because it accumulates in plasma samples obtained from patients with insufficient treatment response and with worse or fatal outcome. Data are available via ProteomeXchange with the identifier PXD046288.

SETAP: epidemiology and prevention of stroke and transient ischaemic attack in Czech patients with atrial fibrillation.

AIMS: The aim of this study is to analyse the prevalence, epidemiology, and anticoagulation prevention of stroke or transient ischaemic attack (TIA) in Czech patients with atrial fibrillation (AF). METHODS AND RESULTS: Retrospective observational analysis of diagnoses, procedures, and treatment reported to the Czech National Registry of Reimbursed Healthcare Services between 2015 and 2018. Prevalence of AF in 2018 was 4.3% of Czech population and the prevalence of stroke/TIA in AF patients was 22.3% with annual incidence of 181.62 cases per 100 000 inhabitants. In 2018, CHA2DS2-ASc score ≥4 was present in 98% AF patients in secondary and 59% in primary prevention, respectively, while the anticoagulation treatment was used by 71-81% of them. Between 2015 and 2018, the percentage of AF patients treated with warfarin monotherapy in primary prevention decreased from 35% to 31%, with acetylsalicylic acid (ASA) monotherapy from 18% to 16% and non-vitamin K antagonist oral anticoagulants (NOACs) monotherapy increased from 7% to 11%. In secondary prevention, the percentage of warfarin monotherapy treatment decreased from 35% to 32%, with ASA monotherapy from 20% to 18% and with NOACs monotherapy increased from 9% to 15%. CONCLUSION: This study followed all Czech patients with AF. The unadjusted prevalence and incidence of AF was higher compared with other countries and 2019 European Society of Cardiology Statistics. The study identified several gaps in standard of reimbursed care. 20-30% of AF patients with other risk factors were without any prevention medication and the share of ASA monotherapy in treated patients was 16-18%.

Clinical characteristics and mortality in all Czech patients after pacemaker implantation in the last decade.

Background and aims: Analysis of mortality from the national health registries and data from a specific central registry dealing with the implantation of pacemakers (REPACE) in Czech patients. Methods and results: Retrospective observational analysis of pacemakers' implantation in all Czech patients [n = 82,791; 47,070 (56.9%) men, 75.9 ± 10.4 years old] between 2010 and 2021. Almost 114,000 pacemakers were implanted between 2010 and 2021, of which 27.9% were single-chamber, 67.4% were dual-chamber and 4.6% were biventricular. The annual number of implantations has been steadily increasing with a 6% annual decline in 2020 with increased mortality and reductions in care provided, likely related to COVID-19. The observed 5-year relative survival was 88.6% (overall survival 60.6%) and the 10-year relative survival was 75.9% (overall survival 32.7%). Causes of death 5ary according to the age of the patient. The highest difference 1n the reported numbers in the REPACE Registry did not exceed 2% in comparison with the National Register of Reimbursed Health Services. Conclusion: This study followed all Czech patients with pacemaker's implantation in between 2010 and 2021. The annual number of 1mplantations has been steadily 1ncreasing. Patients with implanted pacemakers had a significantly higher mortality than the average population. Number of patients in the registry corresponded almost perfectly with the National Register of Reimbursed Health Services.

Angiotensin-converting enzyme inhibitors, angiotensin-II-receptor antagonists and angiotensin-receptor blocker/neprilysin inhibitor utilization in heart failure patients: Sub-analysis of a nation-wide population-based study in the Czech Republic.

AIMS: Sub-analysis of a retrospective nation-wide observational analysis of heart failure (HF) epidemiology reported to the Czech National Registry of Reimbursed Health Services between 2012 and 2018 aimed at angiotensin-converting enzyme inhibitors (ACEI), angiotensin-II-receptor antagonists (ARB) and angiotensin receptor blocker/neprilysin inhibitor (ARNI) use. METHODS AND RESULTS: ACEi and ARBs were generally used in 87.6% of all HF patients in 2012 (n=154 627); 84.5% in 2013 (n=170 861); 83.5% in 2014 (n=186 963); 81.6% in 2015 (n=198 844); 80.1% in 2016 (n=205 793); 78.0% in 2017 (n=212 152) and in 76.7% in 2018 (n=219 235). In a sub-analysis of patients with a medical procedure and/or examination using an I50.x ICD code accounted for in the given year, ACEi and ARBs were generally used in 99.3% in 2012 (n=63 250); 96% in 2013 (n=62 241); 95.2% in 2014 (n=64 414); 93.3% in 2015 (n=65 217); 91.8% in 2016 (n=65 236); 90.1% in 2017 (n=65 761) and in 88.6% in 2018 (n=66 332). In 2018, the majority of patients with HF were prescribed ramipril (n=49 909; 17.5%) and perindopril (n=44 332; 15.5%). The mostly prescribed ARBs in 2018 were telmisartan (n=18 669; 6.5%); losartan (n=13 935; 4.9%) and valsartan (n=4 849; 1.7%). In 24.5% of cases, ACEIs and ARBs were prescribed in a fixed combination with another drug. ARNI became gradually more prescribed from 2018 (n=9 659 in November 2020). CONCLUSION: In an analysis of ACEIs, ARBs and ARNIs utilization in all patients treated for heart failure in the given year in the whole country, we found a comparable rate of drug prescription in comparison with specific heart failure registries. This indicates a good translation of current standard of care into common clinical practice. Ramipril and perindopril remained the mostly prescribed ACEIs and telmisartan became the mostly prescribed ARB. Since 2018, ARNIs began to be widely prescribed.

Nationwide screening of Fabry disease in patients with hypertrophic cardiomyopathy in Czech Republic.

AIMS: Fabry disease (FD) is a rare X-linked genetic disorder caused by α-galactosidase A (AGALA) deficiency. Whereas 'classic' variant has multisystemic manifestation, the more recently described 'later-onset' variant is characterized by predominant cardiac involvement that often mimics hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Consecutive unrelated patients with HCM were screened for FD in 16 (out of 17) cardiac centres in the Czech Republic covering specialized cardiology care from June 2017 to December 2018. AGALA activity and globotriaosylsphingosine (lyso-Gb3 ) levels were measured in all subjects using the dry blood spot method. FD was suspected in male patients with AGALA activity <1.2 µmol/h/L and in females with either low AGALA activity or lyso-Gb3  > 3.5 ng/mL. Positive screening results were confirmed by genetic testing. We evaluated 589 patients (390 males, 66%) with HCM (mean maximal myocardial thickness 19.1 ± 4.3 mm). The average age was 58.4 ± 14.7 years. In total, 17 patients (11 males, 6 females) had a positive screening result, and subsequently, six of them (four males and two females) had a genetically confirmed pathogenic GLA mutation (total prevalence of 1.02%). Five of these patients were carrying the p.N215S mutation known to cause a typical later-onset cardiac FD. CONCLUSIONS: We confirmed the prevalence of FD repeatedly reported in previous screening programmes (approximately 1% irrespective of gender) in a non-selected HCM population in Central Europe. Our findings advocate a routine screening for FD in all adult patients with HCM phenotype including both genders. The dry blood spot method used led to identification of clearly pathogenic variants.

Cardiac Resynchronization and Defibrillator Therapy (CRT-D) or CRT Alone (CRT-P) in patients with dilated cardiomyopathy and heart failure without late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (CMRI) high-risk markers - CRT-REALITY study - Study design and rationale.

BACKGROUND: Primary preventive implantation of implantable defibrillator (ICD) is according to current guidelines indicated in patients with heart failure NYHA (New York Heart Association) class II/III and LVEF <35%. Thanks to advances in heart failure pharmacotherapy, a decrease in mortality could render a benefit of ICD insufficient to justify its implantation in some patients. METHODS: Study design: multicenter, prospective, randomized, controlled trial evaluating the benefit of implantation of Cardiac Resynchronization and Defibrillator Therapy (CRT-D) or CRT Alone (CRT-P) in non-ischemic patients with reduced left ventricle ejection fraction (LVEF) and optimal pharmacotherapy without significant mid-wall myocardial fibrosis detected by cardiac magnetic resonance (CMR). The primary end-point: Re-hospitalization for heart failure, ventricular tachycardia, major adverse cardiac events (MACE). The secondary end-points: Sudden cardiac death, cardiovascular death, resuscitated cardiac arrest or sustained ventricular tachycardia, device-related complications, and change in quality of life. Course of the study: After a pharmacotherapy is optimized and significant mid-wall myocardial fibrosis excluded, patients will be randomized 1:1 to CRT-P or CRT-D implantation. DISCUSSION: If our hypothesis is confirmed, this could provide evidence for the management of these patients with a significant impact on common daily praxis and health care expenditures. CLINICALTRIALS: gov, NCT04139460.

Beta-blockers utilization in heart failure patients: Sub-analysis of a nation-wide population-based study in the Czech Republic.

AIMS: Sub-analysis of a retrospective nation-wide observational analysis of heart failure (HF) epidemiology reported to the Czech National Registry of Reimbursed Health Services between 2012 and 2018 aimed at beta-blockers (BBs) utilization. METHODS AND RESULTS: The beta-blockers were generally used in 81.8% of all patients treated for HF in 2012 (n=52 140); 81.8% in 2013 (n=53 058); 83.1% in 2014 (n=56 221); 82.1% in 2015 (n=57 421); 83.3% in 2016 (n=59 187); 82.2% in 2017 (60 058) and in 81.4% in 2018 (n=60 966). In 2018, the majority of patients treated for HF were prescribed metoprolol (22 974; 30.7%) and bisoprolol (21 001; 28%). Carvedilol was prescribed in 7 331 patients treated for HF (9.8%), nebivolol in 5 392 HF patients. Despite its primary indication, betaxolol was used in 2 341 patients treated for HF (3.1%). All other beta-blockers were used in less than 1% of HF patients. In some of the mostly used BBs, their prescription in patients treated for HF changed in the last years (metoprolol 32.4% in 2012, 30.7% in 2018; bisoprolol 20.3% in 2012, 28% in 2018; carvedilol 18.3% in 2012, 9.8% in 2018; nebivolol 2.5% in 2012, 7.2% in 2018; betaxolol 4.2% in 2012, 3.1% in 2018). CONCLUSION: In an analysis of beta-blockers utilization in all patients treated for heart failure in the given year in the whole country, we have found only slightly lower amount of drug prescription in comparison with specific heart failure registries. This indicates a good translation of current standard of care into common clinical practice. Metoprolol remained the mostly prescribed drug. The prescription of bisoprolol and nebivolol has increased at the expense of carvedilol.

Trends in the treatment and survival of heart failure patients: a nationwide population-based study in the Czech Republic.

AIMS: A retrospective nationwide observational analysis of diagnoses, procedures, and treatment reported to the Czech National Registry of Reimbursed Health Services between 2012 and 2018. METHODS AND RESULTS: Prevalence of heart failure (HF) patients increased from 176 496 (1679.4 per 100 000 population) in 2012 to 285 745 (2689.0 per 100 000 population) patients in 2018 (mean age 74.4 ± 12.8 years). In the last years, a stable incidence of HF patients was observed (544 per 100 000 population in 2016 vs. 551 per 100 000 population in 2018; P = 0.310). Mortality rate decreased from 20.55% in 2012 to 15.89% in 2018. The number of hospitalized patients remained similar (318.2 per 100 000 population in 2012 vs. 311.8 per 100 000 population in 2018; P = 0.479). The most used drugs were diuretics (173 295; 60.6%) and beta-blockers (178 823; 62.6%), followed by angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (angiotensin-converting enzyme inhibitors 120.581; 42.2%; angiotensin II receptor blockers 47 216; 16.5%). Even though the whole number of implanted devices in HF patients increased steadily (from 25 205 in 2012 to 45 363 in 2018), the prevalence of all devices (pacemakers and defibrillators) in the HF patients remained about the same (14.3% in 2012; 15.9% in 2018). CONCLUSIONS: The study included all patients with HF in the Czech Republic. These are the first nationwide data of HF epidemiology in the Eastern bloc. The incidence of HF remains stable in the last years. Due to aging of the population, the prevalence of HF significantly increased in the last 6 years. Despite a continuous increase in the prevalence of HF and a suboptimal utilization of its pharmacological therapy, mortality decreased, and the number of hospitalized patients remained the same.

Effects of Epoxyeicosatrienoic Acid-Enhancing Therapy on the Course of Congestive Heart Failure in Angiotensin II-Dependent Rat Hypertension: From mRNA Analysis towards Functional In Vivo Evaluation.

This study evaluates the effects of chronic treatment with EET-A, an orally active epoxyeicosatrienoic acid (EETs) analog, on the course of aorto-caval fistula (ACF)-induced heart failure (HF) in Ren-2 transgenic rats (TGR), a model characterized by hypertension and augmented activity of the renin-angiotensin system (RAS). The results were compared with standard pharmacological blockade of the RAS using angiotensin-converting enzyme inhibitor (ACEi). The rationale for employing EET-A as a new treatment approach is based on our findings that apart from increased RAS activity, untreated ACF TGR also shows kidney and left ventricle (LV) tissue deficiency of EETs. Untreated ACF TGR began to die 17 days after creating ACF and were all dead by day 84. The treatment with EET-A alone or ACEi alone improved the survival rate: in 156 days after ACF creation, it was 45.5% and 59.4%, respectively. The combined treatment with EET-A and ACEi appeared to improve the final survival to 71%; however, the difference from either single treatment regimen did not reach significance. Nevertheless, our findings support the notion that targeting the cytochrome P-450-dependent epoxygenase pathway of arachidonic acid metabolism should be considered for the treatment of HF.