Efficacy profile of ivabradine in patients with heart failure plus angina pectoris

Objectives: In the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), slowing of the heart rate with ivabradine reduced cardiovascular death or heart failure hospitalizations among patients with systolic chronic heart failure (CHF). Subsequently, in the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) slowing of the heart rate in patients without CHF provided no benefit for cardiovascular death or nonfatal myocardial infarction (primary composite end point), with secondary analyses suggesting possible harm in the angina subgroup. Therefore, we examined the impact of ivabradine in the patients with CHF plus angina in SHIFT. Methods: SHIFT enrolled adults with stable, symptomatic CHF, a left ventricular ejection fraction ≤35% and a sinus rhythm with a resting heart rate ≥70 bpm. Outcomes were the SHIFT and SIGNIFY primary composite end points and their components. Results: Of 6,505 patients in SHIFT, 2,220 (34%) reported angina at randomization. Ivabradine numerically, but not significantly, reduced the SIGNIFY primary composite end point by 8, 11 and 11% in the SHIFT angina subgroup, nonangina subgroup and overall population, respectively. Ivabradine also reduced the SHIFT primary composite end point in all 3 subgroups. Conclusions: In SHIFT, ivabradine showed consistent reduction of cardiovascular outcomes in patients with CHF; similar results were seen in the subgroup of SHIFT patients with angina

Genetics of heart rate in heart failure patients (GenHRate)

BACKGROUND: Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF. METHODS: Patients who met Framingham criteria for HF and had an ejection fraction \u3c 50% were prospectively enrolled in a genetic HF registry (2007-2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant hits (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX). RESULTS: The cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 x 10(-8)). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population. CONCLUSIONS: These data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts

Genetics of heart rate in heart failure patients (GenHRate)

BACKGROUND: Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF. METHODS: Patients who met Framingham criteria for HF and had an ejection fraction \u3c 50% were prospectively enrolled in a genetic HF registry (2007-2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant hits (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX). RESULTS: The cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 x 10(-8)). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population. CONCLUSIONS: These data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts

Turvetuotannon vesistökuormituksen ennakointi ja uudet hallintamenetelmät

Turvetta nostetaan Suomessa vuosittain n. 25 miljoonaa kuutiometriä, josta energiaturpeen osuus on n. 23 milj. kuutiometriä. Suomessa tuotetaankin yli 50 % maailman energiaturpeesta. Turpeen noston aiheuttamat muutokset valunnassa ja biogeokemiallisissa prosesseissa johtavat kiintoaine- ja ravinnekuormituksen lisääntymiseen alapuolisissa vesistöissä, mikä on nähtävissä erityisesti pohjien liettymisenä. Turvetuotannon kuormitusta onkin pyrittävä vähentämään koko elinkaaren vesistövaikutukset huomioon ottavilla parhailla käyttökelpoisilla tekniikoilla. Pintavalutus on vakiintunut parhaaksi käytettävissä olevaksi tekniikaksi (BAT) turvetuotannon valumavesien puhdistuksessa. Myös ojitettujen vesiensuojelukosteikkojen käyttö käytännön vesiensuojelussa on yleistynyt, koska pinnaltaan ojittamatonta suoaluetta ei enää useinkaan ole tarjolla turvetuotantosoiden läheisyydessä. Myös veden kemiallinen puhdistus on yleistynyt BAT menetelmänä. Kemiallisen puhdistuksen käyttöä rajoittavat korkeat kustannukset. Tämän vuoksi kustannuksiltaan alempi ns. pienemmän mittakaavan kemikalointi on käytössä jo nyt sellaisilla pienillä turvetuotantosoilla, joille on asetettu korkeat puhdistusvaatimukset. Vielä ei kuitenkaan ole riittävästi tietoa mm. ojitettujen kosteikkojen sekä pienkemikaloinnin puhdistustehokkuudesta ja toimintavarmuudesta sekä niihin vaikuttavista tekijöistä. Viime aikoina on myös useissa eri yhteyksissä noussut esiin tarve kyetä entistä paremmin ennustamaan ja arvioimaan turvetuotantosoilta vesistöihin kohdistuvaa kuormitusta turvetuotantosoiden paikallisten ominaisuuksien perusteella. Tätä tietoa tarvitaan erityisesti kuormituksen tason paikallisen arvioinnin tarkentamiseen. Turvetuotannon vesistökuormituksen ennakointi ja uudet hallintamenetelmät (TuVeKu) – hankkeen osatavoitteina oli I) arvioida aiemmin seurannan kohteina olleiden turvetuotantosoiden paikallisten ominaisuuksien vaikutusta syntyvään vesistökuormitukseen sekä löytää syitä pintavalutuskentillä ja ojitetuilla vesiensuojelukosteikoilla havaittuun puhdistuskyvyn vaihteluun sekä II) selvittää millaisin toimenpitein Vapo Oy:llä käytössä olevan rakeisen saostuskemikaalin syöttöön perustuvan pienkemikalointiaseman toimintaa voidaan tehostaa. Osatavoitteen I osalta tutkimuksessa pyrittiin löytämään kuormituksen muodostumiseen ja vesiensuojelukosteikkojen puhdistustehokkuuteen vaikuttavia tekijöitä sekä todentamaan aiempia tutkimustuloksia laajalla aineistolla. Osatutkimuksessa II keskityttiin pienkemikalointimenetelmän saostusprosessin eri osa-alueiden optimointiin laboratorio-olosuhteissa neljälle rakeiselle kemikaalille. Kokeiden tarkoituksena oli selvittää, millaisin edellytyksin puhdistustuloksen saisi maksimoitua, pienentäen samalla käsittelyssä tarvittavia kemikaalimääriä

Altered Calcium Homeostasis Does Not Explain the Contractile Deficit of Diabetic Cardiomyopathy

OBJECTIVE—This study examines the extent to which the contractile deficit of diabetic cardiomyopathy is due to altered Ca2+ homeostasis

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

BACKGROUND AND PURPOSE: Myocardial cAMP elevation confers cardioprotection against ischaemia/reperfusion (I/R) injury. cAMP activates two independent signalling pathways, PKA and Epac. This study investigated the cardiac effects of activating PKA and/or Epac and their involvement in cardioprotection against I/R. EXPERIMENTAL APPROACH: Hearts from male rats were used either for determination of PKA and PKC activation or perfused in the Langendorff mode for either cardiomyocyte isolation or used to monitor functional activity at basal levels and after 30 min global ischaemia and 2 h reperfusion. Functional recovery and myocardial injury during reperfusion (LDH release and infarct size) were evaluated. Activation of PKA and/or Epac in perfused hearts was induced using cell permeable cAMP analogues in the presence or absence of inhibitors of PKA, Epac and PKC. H9C2 cells and cardiomyocytes were used to assess activation of Epac and effect on Ca(2+) transients. KEY RESULTS: Selective activation of either PKA or Epac was found to trigger a positive inotropic effect, which was considerably enhanced when both pathways were simultaneously activated. Only combined activation of PKA and Epac induced marked cardioprotection against I/R injury. This was accompanied by PKCε activation and repressed by inhibitors of PKA, Epac or PKC. CONCLUSION AND IMPLICATIONS: Simultaneous activation of both PKA and Epac induces an additive inotropic effect and confers optimal and marked cardioprotection against I/R injury. The latter effect is mediated by PKCε activation. This work has introduced a new therapeutic approach and targets to protect the heart against cardiac insults

Increased myocardial susceptibility to repetitive ischemia with high-fat diet-induced obesity.

Obesity and diabetes are frequently associated with cardiovascular disease. When a normal heart is subjected to brief/sublethal repetitive ischemia and reperfusion (I/R), adaptive responses are activated to preserve cardiac structure and function. These responses include but are not limited to alterations in cardiac metabolism, reduced calcium responsiveness, and induction of antioxidant enzymes. In a model of ischemic cardiomyopathy inducible by brief repetitive I/R, we hypothesized that dysregulation of these adaptive responses in diet-induced obese (DIO) mice would contribute to enhanced myocardial injury. DIO C57BL/6J mice were subjected to 15 min of daily repetitive I/R while under short-acting anesthesia, a protocol that results in the development of fibrotic cardiomyopathy. Cardiac lipids and candidate gene expression were analyzed at 3 days, and histology at 5 days of repetitive I/R. Total free fatty acids (FFAs) in the cardiac extracts of DIO mice were significantly elevated, reflecting primarily the dietary fatty acid (FA) composition. Compared with lean controls, cardiac FA oxidation (FAO) capacity of DIO mice was significantly higher, concurrent with increased expression of FA metabolism gene transcripts. Following 15 min of daily repetitive I/R for 3 or 5 days, DIO mice exhibited increased susceptibility to I/R and, in contrast to lean mice, developed microinfarction, which was associated with an exaggerated inflammatory response. Repetitive I/R in DIO mice was associated with more profound significant downregulation of FA metabolism gene transcripts and elevated FFAs and triglycerides. Maladaptive metabolic changes of FA metabolism contribute to enhanced myocardial injury in diet-induced obesity