Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function.

AIMS: Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CM-Pcsk9-/- mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells. METHODS AND RESULTS: Mice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9-/- mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9-/- hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9-/- mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9-/- mice. Circulating lipid levels were unchanged in CM-Pcsk9-/- mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9-/- mice had an increased number of mitochondria-endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism. CONCLUSION: PCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production.

Technological readiness and implementation of genomic-driven precision medicine for complex diseases.

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.

[Lung ultrasound promising method for assessing acute dyspnea and monitoring decompensated heart failure]. / Lungultraljud ­ en uppseglande metod vid dyspné och hjärtsvikt.

Ultrasound plays an important role in several medical fields. The heart was the first organ for which ultrasound gained clinical utility, followed by obstetric and gynecological applications. Shortly thereafter, abdominal organs and blood vessels became targets for ultrasound examination. The lung was long considered inaccessible for ultrasound due to its high air content. Work since the 1990s has however established a role for lung ultrasound, in leveraging several technical artefacts generated in the normal lung and in conditions with reduced air content, to allow rapid diagnosis of interstitial fluid accumulation, pneumothorax, pneumonia among others. In this article, we provide an overview of the potential of lung ultrasound, particularly as a promising method for assessment of patients presenting with acute dyspnea in the emergency department and for monitoring residual fluid in patients with decompensated heart failure. We also discuss limitations and caveats of the method.

Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis.

BACKGROUND: Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS. METHODS: We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls. RESULTS: In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24-1.52, p = 6.9 × 10-10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31-1.79) compared to those with CAD (OR 1.27; 95%CI 1.12-1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88-0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27-1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95-1.02). CONCLUSIONS: Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS.

Concomitant use of warfarin and ticagrelor as an alternative to triple antithrombotic therapy after an acute coronary syndrome.

INTRODUCTION: Treatment with warfarin in combination with clopidogrel has been shown to reduce the incidence of major bleeding as compared to triple antithrombotic therapy (TT; warfarin, clopidogrel and aspirin). However, there are uncertainties regarding the risk for thrombosis since poor-responsiveness to clopidogrel is common. Ticagrelor is a more potent platelet inhibitor, but data supporting concurrent use of ticagrelor and warfarin (dual antithrombotic therapy, DT) is limited. This study therefore sought to evaluate the risk of bleeding and thrombosis associated with DT after an acute coronary syndrome (ACS). MATERIALS AND METHODS: We identified all ACS patients on DT upon discharge from Helsingborg Hospital and Skåne University Hospital in Malmö and Lund, Sweden, during 2013. Patients on DT were compared with historical controls discharged with TT. Major bleeding was defined in accordance with the HAS-BLED derivation study. Patients were retrospectively followed for three months. RESULTS: In total, 107 DT patients were identified and compared with 159 controls on TT. Mean HAS-BLED bleeding risk score and duration of treatment were similar between the groups (HAS-BLED 2.2+/-0.8 vs 2.2+/-1.0 units, p=NS; duration 2.7+/-0.8 vs 2.5+/-0.9months, p=NS; DT vs TT). The incidence of spontaneous major bleeding was similar between the groups, as was a composite of all thrombotic events, i.e. peripheral embolism, stroke/TIA and acute coronary syndrome (bleeding 8/106 (7.5%) vs 11/157 (7.0%), p=NS; thrombosis 5/106 (4.7%) vs 5/157 (3.2%), p=NS; DT vs TT). CONCLUSIONS: Rates of thrombotic and bleeding events were similar in patients with TT and patients with ticagrelor and warfarin.

Noncardiac surgery in patients with aortic stenosis: a contemporary study on outcomes in a matched sample from the Danish health care system.

BACKGROUND: Past research has identified aortic stenosis (AS) as a major risk factor for adverse outcomes in noncardiac surgery; however, more contemporary studies have questioned the grave prognosis. To further our understanding of this, the risks of a 30-day major adverse cardiovascular event (MACE) and all-cause mortality were investigated in a contemporary Danish cohort. HYPOTHESIS: AS is not an independent risk factor for adverse outcomes in noncardiac surgery. METHODS: All patients with and without diagnosed AS who underwent noncardiac surgery in 2005 to 2011 were identified through nationwide administrative registers. AS patients (n = 2823; mean age, 75.5 years, 53% female) were matched with patients without AS (n = 2823) on propensity score for AS and surgery type. RESULTS: In elective surgery, MACE (ie, nonfatal myocardial infarction, ischemic stroke, or cardiovascular death) occurred in 66/1772 (3.7%) of patients with AS and 52/1772 (2.9%) of controls (P = 0.19), whereas mortality occurred in 67/1772 (3.8%) AS patients and 51/1772 (2.9%) controls (P = 0.13). In emergency surgery, 163/1051 (15.5%) AS patients and 120/1051 (11.4%) controls had a MACE (P = 0.006), whereas 225/1051 (21.4%) vs 179/1051 (17.0%) AS patients and controls died, respectively (P = 0.01). Event rates were higher for those with symptoms (defined as use of nitrates, congestive heart failure, or use of loop diuretics), compared with those without symptoms (P < 0.0001). CONCLUSIONS: AS is associated with high perioperative rates of MACE and mortality, but perhaps prognosis is, in practice, not much worse for patients with AS than for matched controls. Symptomatic patients and patients undergoing emergency surgery are at considerable risks of a MACE and mortality.

Nationwide trends in development of heart failure and mortality after first-time myocardial infarction 1997-2010: A Danish cohort study.

AIMS: Pharmacological and revascularization strategies following myocardial infarction (MI) have changed substantially during the last two decades. We investigated the temporal trends in heart failure (HF) incidence and mortality during the first 90 days following first-time MI between 1997 and 2010 in Denmark. METHODS AND RESULTS: Through administrative nationwide registers we identified 89,389 patients without prior HF hospitalized with first MI. The number of patients treated with percutaneous coronary intervention (PCI) days 0-1 after index MI increased from 2.5% in 1997-98 to 38.2% in 2009-10. Treatment with clopidogrel increased from 0.02% in 1997-98 to 68.1% in 2009-10 and statins from 8.1% in 1997-98 to 78.3% in 2009-10. The incidence of HF (defined as HF diagnosis or incident use of loop diuretics) decreased from 23.6% in 1997-98 to 19.6% in 2009-10 (p<0.001). Adjusted for age, sex, and comorbidity, hazard ratio was 0.77 (95% confidence interval [CI] 0.74-0.79) for developing HF in 2009-10, compared with 1997-98. Adjusted for coronary interventions, and pharmacotherapy HR increased to 0.82 (95% confidence interval (CI) 0.79-0.85) compared with 1997-98. The 90-day mortality decreased from 19.6% in 1997-98 to 11.7% in 2009-10 (p<0.001). Adjusted for age, sex, and comorbidity HR was 0.59 (CI 0.55-0.64) in 2009-10 compared with 1997-98; upon additional adjustment for coronary interventions and pharmacotherapy the estimate was 0.75 (95% CI 0.69-0.81). CONCLUSION: We found a temporal decrease in HF incidence and mortality during the first 90 days after MI in 1997-2010. This could partly be explained by changes in interventional and pharmacological treatment strategies.

Delay from first medical contact to primary PCI and all-cause mortality: a nationwide study of patients with ST-elevation myocardial infarction.

BACKGROUND: Early reperfusion in the setting of an ST-elevation myocardial infarction (STEMI) is of utmost importance. However, the effects of early versus late reperfusion in this patient group undergoing primary percutaneous coronary intervention (PCI) have so far been inconsistent in previous studies. The purpose of this study was to evaluate in a nationwide cohort the effects of delay from first medical contact to PCI (first medical contact [FMC]-to-PCI) and secondarily delay from symptom-to-PCI on clinical outcomes. METHODS AND RESULTS: Using the national Swedish Coronary Angiography and Angioplasty Register (SCAAR) registry, STEMI patients undergoing primary PCI between the years 2003 and 2008 were screened for. A total of 13 790 patients were included in the FMC-to-PCI analysis and 11 489 patients were included in the symptom-to-PCI analyses. Unadjusted as well as multivariable analyses showed an overall significant association between increasing FMC-to-PCI delay and 1-year mortality. A statistically significant increase in mortality was noted at FMC-to-PCI delays exceeding 1 hour in an incremental fashion. FMC-to-PCI delays in excess of 1 hour were also significantly associated with an increase in severe left ventricular dysfunction at discharge. An overall significant association between increasing symptom-to-PCI delays and 1-year mortality was noted. However, when stratified into time delay cohorts, no symptom-to-PCI delay except for the highest time delay showed a statistically significant association with increased mortality. CONCLUSIONS: Delays in FMC-to-PCI were strongly associated with increased mortality already at delays of more than 1 hour, possibly through an increase in severe heart failure. A goal of FMC-to-PCI of less than 1 hour might save patient lives.

Orthostatic hypotension and long-term incidence of atrial fibrillation: the Malmö Preventive Project.

OBJECTIVES: Orthostatic hypotension (OH), a common manifestation of autonomic dysfunction, has been identified as an independent risk factor for all-cause mortality and incident cardiovascular disease. However, the role of OH in the development of atrial fibrillation has not been studied. DESIGN: We investigated the incidence of atrial fibrillation in relation to baseline presence of OH according to international consensus criteria in the Swedish population-based prospective cohort of the Malmö Preventive Project. The study sample consisted of 33,346 individuals (67.3% men; mean age, 45.6 ± 7.4 years; range, 26-61 years). The association between OH and incidence of atrial fibrillation during follow-up was assessed using the Kaplan-Meier method and multivariable Cox proportional hazard models, taking into account conventional risk factors for atrial fibrillation. RESULTS: At baseline, 1987 participants (6.1%) met the diagnostic criteria for OH. Over a follow-up period of approximately 24 years, 2312 individuals (3.0 events/1000 person-years) were diagnosed with new-onset atrial fibrillation. Of these, 196 had OH at baseline (4.6 events/1000 person-years amongst all OH-positive individuals). In a multivariable Cox regression analysis, OH predicted incidence of atrial fibrillation independently of other risk factors (hazard ratio [HR]: 1.30; 95% confidence interval [CI]: 1.05-1.61; P = 0.016), and this association was significant in hypertensive (HR: 1.44; 95%CI: 1.10-1.88; P = 0.008), but not in normotensive participants (HR: 1.10; 95%CI: 0.77-1.58; P = 0.60). CONCLUSIONS: The presence of OH predicts the incidence of atrial fibrillation in middle-aged hypertensive individuals, independently of conventional risk factors. Further studies of the association of autonomic dysfunction and OH with atrial fibrillation are needed.