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Background: The incorporation of artificial intelligence (AI) into point-of-care ultrasound (POCUS) platforms has rapidly increased. The number of B-lines present on lung ultrasound (LUS) serve as a useful tool for the assessment of pulmonary congestion. Interpretation, however, requires experience and therefore AI automation has been pursued. This study aimed to test the agreement between the AI software embedded in a major vendor POCUS system and visual expert assessment. Methods: This single-center prospective study included 55 patients hospitalized for various respiratory symptoms, predominantly acutely decompensated heart failure. A 12-zone protocol was used. Two experts in LUS independently categorized B-lines into 0, 1–2, 3–4, and ≥ 5. The intraclass correlation coefficient (ICC) was used to determine agreement. Results: A total of 672 LUS zones were obtained, with 584 (87%) eligible for analysis. Compared with expert reviewers, the AI significantly overcounted number of B-lines per patient (23.5 vs. 2.8, p < 0.001). A greater proportion of zones with > 5 B-lines was found by the AI than by the reviewers (38% vs. 4%, p < 0.001). The ICC between the AI and reviewers was 0.28 for the total sum of B-lines and 0.37 for the zone-by-zone method. The interreviewer agreement was excellent, with ICCs of 0.92 and 0.91, respectively. Conclusion: This study demonstrated excellent interrater reliability of B-line counts from experts but poor agreement with the AI software embedded in a major vendor system, primarily due to overcounting. Our findings indicate that further development is needed to increase the accuracy of AI tools in LUS. [ABSTRACT FROM AUTHOR]

The genetic contributions to early onset heart failure (HF) are incompletely understood. Genetic testing in advanced HF patients undergoing heart transplantation (HTx) may yield clinical benefits, but data is limited. We performed deep-coverage whole genome sequencing (WGS) in 102 Swedish HTx recipients. Gene lists were compiled through a systematic literature review. Variants were prioritized for pathogenicity and classified manually. We also compared polygenic HF risk scores to a population-based cohort. We found a pathogenic (LP/P) variant in 34 individuals (34%). Testing yield was highest in hypertrophic (63% LP/P carriers), dilated (40%) and arrhythmogenic right ventricular (33%) cardiomyopathy and lower in ischemic cardiomyopathy (10%). A family history was more common in LP/P variant carriers than in non-carriers but was present in less than half of carriers (44% vs 13%, P < 0.001), whereas age was similar. Polygenic risk scores were similar in HTx recipients and the population cohort. In conclusion, we observed a high prevalence of pathogenic cardiomyopathy gene variants in individuals with early-onset advanced HF, which could not accurately be ruled out by family history and age. In contrast, we did not observe higher polygenic risk scores in early onset advanced HF cases than in the general population. [ABSTRACT FROM AUTHOR]

Background: Post heart‐transplant survival has increased, but information is lacking on specific causes of death and life expectancy. We aimed to assess cause‐specific loss of life‐years compared to the general population, evaluate classification for cause of death after heart transplantation, and assess validity of cause of death data from the International Society of Heart and Lung Transplant (ISHLT) registry. Methods: In this single center study, we included 239 heart recipients transplanted between 1988 and 2019 in Lund, Sweden (n = 239, 50% of the transplanted population where the cause of death was available). Two cardiologists retrospectively assigned causes of death according to a published classification (CLASS) in the 91 recipients who died during follow‐up. Life expectancy was compared to data from the general population. Results: Compared to the average Swedish population, life expectancy for heart transplant recipients was 20 years shorter (IQR 12.9–27.2). The largest number of life‐years lost were for deaths due to acute (49 years) and chronic rejection (27 years). Primary graft dysfunction (24 years) accounted for 24% of deaths, followed by malignancy (20 years) and infection (17 years), each accounting for ∼20% of deaths. Use of CLASS revealed moderate inter‐rater agreement (56%) and moderate agreement with the ISHLT registry (62%). Conclusions: Survival after heart transplantation was 20 years lower than in the general population. In the young, more life‐years were lost due to acute graft rejection, whereas chronic graft rejection and primary graft failure were more important causes of death in older patients. Agreement was moderate between CLASS and the ISHLT registry classifications. [ABSTRACT FROM AUTHOR]

Key Points: Question: What is the value of cardiovascular biomarkers when added to established risk factors to predict incident cardiovascular events in the population? Findings: In this large, individual-level data analysis from 28 general population–based cohorts from 12 countries, high-sensitivity cardiac troponins I and T, B-type natriuretic peptide, and high-sensitivity C-reactive protein were associated with fatal and nonfatal events. Meaning: The addition of biomarkers to established risk factors leads to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality. Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population–based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality. This study evaluates the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors in the identification of individuals at high risk for atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Plasma metabolomics holds potential for precision medicine, but limited information is available to compare the performance of such methods across multiple cohorts. We compared plasma metabolite profiles after an overnight fast in 11,309 participants of five population-based Swedish cohorts (50–80 years, 52% women). Metabolite profiles were uniformly generated at a core laboratory (Metabolon Inc.) with untargeted liquid chromatography mass spectrometry and a comprehensive reference library. Analysis of a second sample obtained one year later was conducted in a subset. Of 1629 detected metabolites, 1074 (66%) were detected in all cohorts while only 10% were unique to one cohort, most of which were xenobiotics or uncharacterized. The major classes were lipids (28%), xenobiotics (22%), amino acids (14%), and uncharacterized (19%). The most abundant plasma metabolome components were the major dietary fatty acids and amino acids, glucose, lactate and creatinine. Most metabolites displayed a log-normal distribution. Temporal variability was generally similar to clinical chemistry analytes but more pronounced for xenobiotics. Extensive metabolite-metabolite correlations were observed but mainly restricted to within each class. Metabolites were broadly associated with clinical factors, particularly body mass index, sex and renal function. Collectively, our findings inform the conduct and interpretation of metabolite association and precision medicine studies. [ABSTRACT FROM AUTHOR]

Objectives: Peripartum cardiomyopathy (PPCM) is a rare disease carrying a risk of death and chronic heart failure.It is unknown if women with PPCM have a family history of heart failure. We investigated the prevalence of heart failure and hypertension in first-degree relatives to women with PPCM.Methods: A cohort of 61 women with PPCM was identified through the nationwide Danish registers from 2005 to 2014, and each individual diagnosis of PPCM was validated through review of patient records. We excluded 13 women due to lack of data on relatives. In a case-control design, the 48 remaining women were matched (on age, year of childbirth, parity and number of siblings) to 477 birth-giving Danish women without heart failure. We obtained information on first-degree relatives (parents and siblings) through the National Danish Registers.Results: The cohort of 48 women with PPCM had a mean age of 31 years (SD 6). The prevalence of heart failure in any first-degree relative was higher in women with PPCM, compared with controls (23% vs 10%, p=0.011). A first-degree relative with any cardiovascular diagnosis was not more frequent in women with PPCM versus controls (77% vs 70%, p=0.280), but for siblings only, any cardiovascular diagnosis was more frequent in siblings to women with PPCM (29% vs 16%, p=0.026).Conclusion: Having a first-degree relative with heart failure was significantly more frequent in a cohort of validated PPCM cases than in controls, supporting the notion of shared aetiology between PPCM and other forms of heart failure. [ABSTRACT FROM AUTHOR]

Whereas autonomic dysfunction and the metabolic syndrome are clinically associated, the relationships with the plasma metabolome is unknown. We explored the association between orthostatic blood pressure responses and 818 plasma metabolites in middle-aged subjects from the general population. We included 3803 out of 6251 subjects (mean age, 57 years; 52% women) from the Malmö sub-cohort of The Swedish CardioPulmonary bioImage Study with information on smoking habits, diabetes, antihypertensive drug treatment, anthropometrics, hemodynamic measurements and 818 plasma metabolites (mass-spectrometry). The associations between each metabolite and orthostatic systolic blood pressure responses were determined using multivariable linear regression analysis and p values were corrected using the Bonferroni method. Six amino acids, five vitamins, co-factors and carbohydrates, nine lipids and two xenobiotics were associated with orthostatic blood pressure after adjusting for age, gender and systolic blood pressure. After additional adjustments for BMI, diabetes, smoking and antihypertensive treatment, the association remained significant for six lipids, four amino acids and one xenobiotic. Twenty-two out of 818 plasma metabolites were associated with orthostatic blood pressure responses. Eleven metabolites, including lipids in the dihydrosphingomyelin and sphingosine pathways, were independently associated with orthostatic systolic blood pressure responses after additional adjustment for markers of cardio-metabolic disease. [ABSTRACT FROM AUTHOR]

Whereas autonomic dysfunction and the metabolic syndrome are clinically associated, the relationships with the plasma metabolome is unknown. We explored the association between orthostatic blood pressure responses and 818 plasma metabolites in middle-aged subjects from the general population. We included 3803 out of 6251 subjects (mean age, 57 years; 52% women) from the Malmö sub-cohort of The Swedish CardioPulmonary bioImage Study with information on smoking habits, diabetes, antihypertensive drug treatment, anthropometrics, hemodynamic measurements and 818 plasma metabolites (mass-spectrometry). The associations between each metabolite and orthostatic systolic blood pressure responses were determined using multivariable linear regression analysis and p values were corrected using the Bonferroni method. Six amino acids, five vitamins, co-factors and carbohydrates, nine lipids and two xenobiotics were associated with orthostatic blood pressure after adjusting for age, gender and systolic blood pressure. After additional adjustments for BMI, diabetes, smoking and antihypertensive treatment, the association remained significant for six lipids, four amino acids and one xenobiotic. Twenty-two out of 818 plasma metabolites were associated with orthostatic blood pressure responses. Eleven metabolites, including lipids in the dihydrosphingomyelin and sphingosine pathways, were independently associated with orthostatic systolic blood pressure responses after additional adjustment for markers of cardio-metabolic disease. [ABSTRACT FROM AUTHOR]

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development. The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. Methods and results A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10−8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2–SORT1 , NLRP6 , and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26–1.35; P = 2.7 × 10−51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08–1.37; P = 1.4 × 10−3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90–5.12; P = 2.1 × 10−20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17–1.23; P = 4.8 × 10−73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05–1.9; P = 1.9 × 10−12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA , SORT1 , ACTR2 , NOTCH4 , IL6R , and FADS. Conclusion Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies. [ABSTRACT FROM AUTHOR]

Aims Infection is a serious complication of cardiac implantable electronic device (CIED) therapy. An antibiotic-eluting absorbable envelope has been developed to reduce the infection rate, but studies investigating the efficacy and a reasonable number needed to treat in high-risk populations for infections are limited. Methods and results One hundred and forty-four patients undergoing CIED implantation who received the antibacterial envelope were compared with a matched cohort of 382 CIED patients from our institution. The primary outcome was the occurrence of local infection, and secondary outcomes were any CIED-related local or systemic infections, including endocarditis, and all-cause mortality. The results were stratified by a risk score for CIED infection, PADIT. The envelope group had a higher PADIT score, 5.9 ± 3.1 vs. 3.9 ± 3.0 (P < 0.0001). For the primary endpoint, no local infections occurred in the envelope group, compared with 2.6% in the control group (P = 0.04), with a more pronounced difference in the stratum with a high (>7 points) PADIT score, 0 vs. 9.9% (P = 0.01). The total CIED-related infections were similar between groups, 6.3% compared with 5.0% (P = 0.567). Mortality after 1600 days of follow-up did not differ between groups, 22.9 vs. 26.4%, P = 0.475. Conclusion Our study confirms the clinical efficacy of an antibacterial envelope in the prevention of local CIED infection in patients with a higher risk according to the PADIT score. In an effort to improve cost–benefit ratios, ration of use guided by the PADIT score is advocated. Further prospective randomized studies in high-risk populations are called for. [ABSTRACT FROM AUTHOR]

Aims: Bioactive adrenomedullin (bio‐ADM) is a vascular‐derived peptide hormone that has emerged as a promising biomarker for assessment of congestion in decompensated heart failure (HF). We aimed to evaluate diagnostic and prognostic performance of bio‐ADM for HF in comparison to amino‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), with decision thresholds derived from invasive haemodynamic and population‐based studies. Methods and results: Normal reference ranges for bio‐ADM were derived from a community‐based cohort (n = 5060). Correlations with haemodynamic data were explored in a cohort of HF patients undergoing right heart catheterization (n = 346). Mortality and decision cutoffs for bio‐ADM was explored in a cohort of patients presenting in the ER with acute dyspnoea (n = 1534), including patients with decompensated HF (n = 570). The normal reference range was 8–39 pg/mL. The area under the receiver operating characteristic curve (AUROC) for discrimination of elevated mean right atrial pressure (mRAP) and pulmonary arterial wedge pressure (PAWP) was 0.74 (95% CI = 0.67–0.79) and 0.70 (95% CI = 0.64–0.75), respectively, with optimal bio‐ADM decision cutoff of 39 pg/mL, concordant with cubic spline analyses. NT‐proBNP discriminated PAWP slightly better than mRAP (AUROC 0.73 [95% CI = 0.68–0.79] and 0.68 [95% CI = 0.61–0.75]). Bio‐ADM correlated with (mRAP, r = 0.55) while NT‐proBNP correlated with PAWP. Finally, a bio‐ADM decision cutoff of 39 pg/mL associated with 30 and 90 day mortality and conferred a two‐fold increased odds of HF diagnosis, independently from NT‐proBNP. Conclusions: Bio‐ADM tracks with mRAP and associates with measures of systemic congestion and with mortality in decompensated HF independently from NT‐proBNP. Our findings support utility of bio‐ADM as a biomarker of systemic venous congestion in HF and nominate a decision threshold. [ABSTRACT FROM AUTHOR]

Human gut microbiota produce a variety of molecules, some of which enter the bloodstream and impact health. Conversely, dietary or pharmacological compounds may affect the microbiota before entering the circulation. Characterization of these interactions is an important step towards understanding the effects of the gut microbiota on health. In this cross-sectional study, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for a detailed characterization of the gut microbiota and plasma metabolome, respectively, of 8583 participants invited at age 50 to 64 from the population-based Swedish CArdioPulmonary bioImage Study. Here, we find that the gut microbiota explain up to 58% of the variance of individual plasma metabolites and we present 997 associations between alpha diversity and plasma metabolites and 546,819 associations between specific gut metagenomic species and plasma metabolites in an online atlas (https://gutsyatlas.serve.scilifelab.se/). We exemplify the potential of this resource by presenting novel associations between dietary factors and oral medication with the gut microbiome, and microbial species strongly associated with the uremic toxin p-cresol sulfate. This resource can be used as the basis for targeted studies of perturbation of specific metabolites and for identification of candidate plasma biomarkers of gut microbiota composition. Here, Dekkers et al. characterize associations of 1528 gut metagenomic species with the plasma metabolome in 8583 participants of the SCAPIS Study, and find that gut microbiota explain up to 58% of the variance of individual plasma metabolites. [ABSTRACT FROM AUTHOR]

Background: A clustering of cardiovascular risk factors is denoted the metabolic syndrome (MetS), but the mechanistic underpinnings of this clustering is not clear. Using large-scale metabolomics, we aimed to find a metabolic profile common for all five components of MetS. Methods and findings: 791 annotated non-xenobiotic metabolites were measured by ultra-performance liquid chromatography tandem mass spectrometry in five different population-based samples (Discovery samples: EpiHealth, n = 2342 and SCAPIS-Uppsala, n = 4985. Replication sample: SCAPIS-Malmö, n = 3978, Characterization samples: PIVUS, n = 604 and POEM, n = 501). MetS was defined by the NCEP/consensus criteria. Fifteen metabolites were related to all five components of MetS (blood pressure, waist circumference, glucose, HDL-cholesterol and triglycerides) at a false discovery rate of <0.05 with adjustments for BMI and several life-style factors. They represented different metabolic classes, such as amino acids, simple carbohydrates, androgenic steroids, corticosteroids, co-factors and vitamins, ceramides, carnitines, fatty acids, phospholipids and metabolonic lactone sulfate. All 15 metabolites were related to insulin sensitivity (Matsuda index) in POEM, but only Palmitoyl-oleoyl-GPE (16:0/18:1), a glycerophospholipid, was related to incident cardiovascular disease over 8.6 years follow-up in the EpiHealth sample following adjustment for cardiovascular risk factors (HR 1.32 for a SD change, 95%CI 1.07–1.63). Conclusion: A complex metabolic profile was related to all cardiovascular risk factors included in MetS independently of BMI. This profile was also related to insulin sensitivity, which provide further support for the importance of insulin sensitivity as an important underlying mechanism in the clustering of cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Kinetic energy (KE) of intracardiac blood flow reflects myocardial work spent on accelerating blood and provides a mechanistic window into diastolic Alling dynamics. Diastolic dysfunction may represent an early stage in the development of heart failure (HF). Here we evaluated the hemodynamic effects of impaired diastolic function in subjects with and without HF, testing the hypothesis that left ventricular KE differs between controls, subjects with subclinical diastolic dysfunction (SDD), and patients with HF. We studied 77 subjects [16 controls, 20 subjects with SDD, 16 heart failure with preserved ejection fraction (HFpEF), 9 heart failure with mildly reduced ejection fraction (HFmrEF), and 16 heart failure with reduced ejection fraction (HFrEF) patients, age- and sex-matched at the group level]. Cardiac magnetic resonance at 1.5 T included intracardiac four-dimensional (4-D) flow and cine imaging. Left ventricular KE was calculated as 0.5 x m x v². Systolic KE was similar between groups (P > 0.4), also after indexing to stroke volume (P = 0.25), and was primarily driven by ventricular emptying rate (P < 0.0001, R² = 0.52). Diastolic KE was higher in patients with heart failure than in controls (P < 0.05) but similar between SDD and HFpEF (P > 0.18), correlating with inflow conditions (E-wave velocity, P < 0.0001, R² = 0.24) and end-diastolic volume (P = 0.0003, R² = 0.17) but not with average e' (P = 0.07). Diastolic KE differs between controls and heart failure, suggesting more work is spent Alling the failing ventricle, whereas systolic KE does not differentiate between well-matched groups with normal ejection fractions even in the presence of relaxation abnormalities and heart failure. Mechanistically, KE reflects the acceleration imparted on the blood and is driven by variations in ventricular emptying and Alling rates, volumes, and heart rate, regardless of underlying pathology. NEW & NOTEWORTHY Here we present the first study of left ventricular kinetic energy in individuals with subclinical diastolic dysfunction and in heart failure patients with preserved or impaired systolic function. Kinetic energy differs between groups in diastole, and reflects altered Alling and emptying processes. Kinetic energy analysis should be considered in studies seeking to characterize myocardial energetics comprehensively. [ABSTRACT FROM AUTHOR]

Aims: Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a progressive condition caused by deposition of transthyretin amyloid fibrils in the heart and is associated with poor quality of life and a shortened lifespan. This study aimed to describe the prevalence, clinical characteristics, and mortality of patients with ATTR‐CM, using multiple national health registers in Denmark, Finland, Norway, and Sweden. Methods and results: Transthyretin amyloid cardiomyopathy patients were identified during 2008–2018 using a combination of diagnosis codes for amyloidosis and heart disease and were matched to patients with non‐ATTR heart failure (HF). An identical study design was used in each country to facilitate comparison and aggregation of results. A total of 1930 ATTR‐CM patients were identified from national health registers in the four countries. In 2018, prevalence of ATTR‐CM per 100 000 inhabitants ranged from 1.4 in Denmark to 5.0 in Sweden; a steep increase over time was observed in Sweden and Norway. Median survival from diagnosis was 30 months for ATTR‐CM patients and 67 months for matched HF patients. Survival was significantly lower for female than for male ATTR‐CM patients (median survival: 22 and 36 months), while no significant difference was observed in the HF cohort. Conclusions: This study provides the first nationwide estimates of the prevalence, clinical characteristics, and mortality of patients with ATTR‐CM, using identical study design across several countries. Findings corroborate previous case series showing high mortality in ATTR‐CM, two‐fold higher than for other HF patients and higher in women than men, highlighting the need for more precise and early diagnosis to reduce the disease burden. [ABSTRACT FROM AUTHOR]

Aims Patients awaiting orthotopic heart transplantation (OHT) can be bridged utilizing a left ventricular assist device (LVAD) that reduces left ventricular filling pressures, decreases pulmonary artery wedge pressure, and maintains adequate cardiac output. This study set out to examine the poorly investigated area of if and how pre-treatment with LVAD impacts right ventricular (RV) function following OHT. Methods and results We prospectively evaluated 59 (LVAD n = 20) consecutive OHT patients. Transthoracic echocardiography (TTE) was performed in conjunction with right heart catheterization (RHC) at 1, 6, and 12 months after OHT. RV function TTE-parameters included tricuspid annular plane systolic excursion (TAPSE), systolic tissue velocity (S0), fractional area change, two-dimensional RV global longitudinal strain and longitudinal strain from the RV lateral wall (RVfree). At 1 month after OHT, the LVAD group had significantly better longitudinal RV function than the non-LVAD group: TAPSE (15 ± 3 mm vs. 12 ± 2 mm, P < 0.001), RV global longitudinal strain (19.8 ± 2.1% vs. 14.3 ± 2.8%, P < 0.001), and RVfree (19.8 ± 2.3% vs. 14.1 ± 2.9%, P < 0.001). At this time point, pulmonary vascular resistance (PVR) was also lower [1.2 ± 0.4 Wood Units (WU) vs. 1.6 ± 0.6 WU, P < 0.05] in the LVAD group compared with the non-LVAD group. At 6 and 12 months, no difference was detected in any of the TTE and RHC measured parameters between the two groups. Between 1 and 12 months, all parameters of RV function improved significantly in the non-LVAD group but remained unaltered in the LVAD group. Conclusions Our results indicate that pre-treatment with LVAD decreases PVR and is associated with significantly better RV function early following OHT. During the first year following transplantation, RV function progressively improved in the non-LVAD group such that at 6 and 12 months, no difference in RV function was detected between the groups. [ABSTRACT FROM AUTHOR]

Context: There is a dispute whether obesity without major metabolic derangements may represent a benign condition or not. Objective: We aimed to compare the plasma metabolome in obese subjects without metabolic syndrome (MetS) with normal-weight subjects without MetS and with obese subjects with MetS. Methods: This was a cross-sectional study at 2 academic centers in Sweden. Individuals from 3 population-based samples (EpiHealth, n = 2342, SCAPIS-Uppsala, n = 4985, and SCAPIS-Malmö, n = 3978) were divided into groups according to their body mass index (BMI) and presence/ absence of MetS (National Cholesterol Education Program [NCEP]/consensus criteria). In total, 791 annotated endogenous metabolites were measured by ultra-performance liquid chromatography–tandem mass spectrometry. Results: We observed major differences in metabolite profiles (427 metabolites) between obese (BMI ≥ 30 kg/m²) and normal-weight (BMI < 25 kg/m²) subjects without MetS after adjustment for major lifestyle factors. Pathway enrichment analysis highlighted branch-chained and aromatic amino acid synthesis/metabolism, aminoacyl-tRNA biosynthesis, and sphingolipid metabolism. The same pathways, and similar metabolites, were also highlighted when obese subjects with and without MetS were compared despite adjustment for BMI and waist circumference, or when the metabolites were related to BMI and number of MetS components in a continuous fashion. Similar metabolites and pathways were also related to insulin sensitivity (Matsuda index) in a separate study (POEM, n = 501). Conclusion: Our data suggest a graded derangement of the circulating metabolite profile from lean to obese to MetS, in particular for metabolites involved in amino acid synthesis/metabolism and sphingolipid metabolism. Insulin resistance is a plausible mediator of this gradual metabolic deterioration. [ABSTRACT FROM AUTHOR]

Hemodynamic force analysis has been proposed as a novel tool for early detection of subclinical systolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Here we investigated the ability of hemodynamic forces to discriminate between healthy subjects and heart failure patients with varying degrees of systolic dysfunction. We studied 34 controls, 16 HFpEF patients, and 25 heart failure patients with mid-range (HFmrEF) or reduced ejection fraction (HFrEF) using cardiac magnetic resonance with acquisition of cine images and 4D flow at 1.5 T. The Navier–Stokes equation was used to compute global left ventricular hemodynamic forces over the entire cardiac cycle. Forces were analyzed for systole, diastole, and the entire heartbeat, with and without normalization to left ventricular volume. Volume-normalized hemodynamic forces demonstrated significant positive correlation with EF (r2 = 0.47, p < 0.0001) and were found significantly lower in heart failure with reduced ejection fraction compared to controls (p < 0.0001 for systole and diastole). No difference was seen between controls and HFpEF (p > 0.34). Non-normalized forces displayed no differences between controls and HFpEF (p > 0.24 for all analyses) and did not correlate with EF (p = 0.36). Left ventricular hemodynamic force analysis, whether indexed to LV volumes or not, is not ready for clinical trials on HFpEF assessment. [ABSTRACT FROM AUTHOR]

Introduction: Primary graft dysfunction (PGD) is a leading cause of 30‐day mortality following heart transplantation, and early intervention in PGD may correlate to improved survival. Our analysis aimed to determine the feasibility of measuring cardiac biomarkers from the donor heart in the early phase for use as a predictor of PGD. Methods: Blood samples from the coronary sinus were obtained at the time of transplantation in hearts preserved by cold static storage. The samples were analyzed for CK‐MB and cTnI with a point‐of‐care method. The primary outcome was severe PGD or the need for veno‐arterial extracorporeal membrane oxygenation within 7 days, referred to as severe graft dysfunction. Results: Of the total cohort (n = 63), eight patients (13%) were diagnosed with severe graft dysfunction within 7 days. Patients with high CK‐MB had an increased risk for severe graft dysfunction with unadjusted Odds Ratio (OR) of 4.5 (95%CI.96–21.11 P =.057) and adjusted OR of 7.4 (95%CI 1.13–48.46, P =.037. Similar but non significant trends were observed for cTnI. Conclusion: By measuring CK‐MB from the coronary effluent in the donor heart, it may be possible to identify patients at increased risk for severe PGD after heart transplantation. [ABSTRACT FROM AUTHOR]

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. [ABSTRACT FROM AUTHOR]

The natriuretic peptide system (NPS) plays a fundamental role in maintaining cardiorenal homeostasis, and its potent filling pressure-regulated diuretic and vasodilatory effects constitute a beneficial compensatory mechanism in heart failure (HF). Leveraging the NPS for therapeutic benefit in HF has been the subject of intense investigation during the last three decades and has ultimately reached widespread clinical use in the form of angiotensin receptor-neprilysin inhibition (ARNi). NPS enhancement via ARNi confers beneficial effects on mortality and hospitalization in HF, but inhibition of neprilysin leads to the accumulation of a number of other vasoactive peptides in the circulation, often resulting in hypotension and raising potential concerns over long-term adverse effects. Moreover, ARNi is less effective in the large group of HF patients with preserved ejection fraction. Alternative approaches for therapeutic augmentation of the NPS with increased specificity and efficacy are therefore warranted, and are now becoming feasible particularly with recent development of RNA therapeutics. In this review, the current state-of-the-art in terms of experimental and clinical strategies for NPS augmentation and their implementation will be reviewed and discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to use Mendelian randomization (MR) techniques to estimate the causal relationships between genetic liability to type 2 diabetes (T2D), glycemic traits, and risk of heart failure (HF).Research Design and Methods: Summary-level data were obtained from genome-wide association studies of T2D, insulin resistance (IR), glycated hemoglobin, fasting insulin and glucose, and HF. MR was conducted using the inverse-variance weighted method. Sensitivity analyses included the MR-Egger method, weighted median and mode methods, and multivariable MR conditioning on potential mediators.Results: Genetic liability to T2D was causally related to higher risk of HF (odds ratio [OR] 1.13 per 1-log unit higher risk of T2D; 95% CI 1.11-1.14; P < 0.001); however, sensitivity analysis revealed evidence of directional pleiotropy. The relationship between T2D and HF was attenuated when adjusted for coronary disease, BMI, LDL cholesterol, and blood pressure in multivariable MR. Genetically instrumented higher IR was associated with higher risk of HF (OR 1.19 per 1-log unit higher risk of IR; 95% CI 1.00-1.41; P = 0.041). There were no notable associations identified between fasting insulin, glucose, or glycated hemoglobin and risk of HF. Genetic liability to HF was causally linked to higher risk of T2D (OR 1.49; 95% CI 1.01-2.19; P = 0.042), although again with evidence of pleiotropy.Conclusions: These findings suggest a possible causal role of T2D and IR in HF etiology, although the presence of both bidirectional effects and directional pleiotropy highlights potential sources of bias that must be considered. [ABSTRACT FROM AUTHOR]

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target. [ABSTRACT FROM AUTHOR]

A hydraulic force generated by blood moving the atrioventricular plane is a novel mechanism of diastolic function. The direction and magnitude of the force is dependent on the geometrical relationship between the left atrium and ventricle and is measured as the short-axis atrioventricular area difference (AVAD). In short, the net hydraulic force acts from a larger area toward a smaller one. It is currently unknown how cardiac remodeling affects this mechanism. The aim of the study was therefore to investigate this diastolic mechanism in patients with pathological or physiological remodeling. Seventy subjects [n = 11 heart failure with preserved ejection fraction (HFpEF), n = 10 heart failure with reduced ejection fraction (HFrEF), n = 7 signs of isolated diastolic dysfunction, n = 10 hypertrophic cardiomyopathy, n = 10 cardiac amyloidosis, n = 18 triathletes, and n = 14 controls] were included. Subjects underwent cardiac MR, and short-axis images of the left atrium and ventricle were delineated. AVAD was calculated as ventricular area minus atrial area and used as an indicator of net hydraulic force. At the onset of diastole, AVAD in HFpEF was −9.2 cm2 (median) versus −4.4 cm2 in controls, P = 0.02. The net hydraulic force was directed toward the ventricle for both but was larger in HFpEF. HFrEF was the only group with a positive median value (11.6 cm2), and net hydraulic force was throughout diastole directed toward the atrium. The net hydraulic force may impede cardiac filling throughout diastole in HFpEF, worsening diastolic dysfunction. In contrast, it may work favorably in patients with dilated ventricles and aid ventricular filling.NEW & NOTEWORTHY It is a previously unrecognized physiological mechanism of the heart that diastolic filling occurs with the help of hydraulics. In patients with heart failure with preserved ejection fraction, atrial dilatation may cause the net hydraulic force to work against cardiac filling, thus further augmenting diastolic dysfunction. In contrast, it may work favorably in patients with dilated ventricles, as in heart failure with reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans.Methods and Results: Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the PLA2G7 locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351).Conclusions: Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS. [ABSTRACT FROM AUTHOR]

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci. [ABSTRACT FROM AUTHOR]

Background: Long term β-blocker therapy after myocardial infarction (MI) reduces mortality and recurrent MI but evidence for this treatment predates contemporary acute coronary care. β-blocker treatment is a key quality of care indicator in the Swedish national quality register for acute coronary care, Riks-HIA. Between 2011 and 2015 a declining number of MI-patients discharged with a β-blocker from the coronary care unit (CCU) at Helsingborg and other hospitals was reported. This retrospective observational study aimed to investigate the causes for discharge without a β-blocker and relate it to outcome, compared to patients discharged with a β-blocker.Methods: MI-patients registered in Riks-HIA discharged without β-blocker during 2011-2015 (no-β-group) and a control group (β-group) comprised of patients discharged with β-blocker treatment between January 1 to December 31, 2013, were matched by RIKS-HIA criteria for β-blocker use. Clinical characteristics, date of death, readmission for MI, other cardiovascular events were collected from Riks-HIA and medical records.Results: The no-β-group included 141 patients, where 65.2% had a justified reason for non-β-blocker use. The β-group included 206 patients. There was no difference in cardiovascular risk factor profile. There were a trend towards a higher number of readmissions for MI in the no-β-group was (n = 8 (5.7%) vs n = 2 (1.0%), p = 0.02), but not mortality (6 (4.3%) vs 2 (1.0%), p = 0.07) and combined readmission for angina pectoris, heart failure, arrhythmias or stroke/TIA (n = 23 (16.3%) vs n = 25 (12.1%), p = 0.27).Conclusion: A majority of the patients in the no-β-group had a justified absence of a β-blocker. β-blocker treatment post-MI showed a trend towards fewer readmissions for MI. But important quality information is lacking to make a firm conclusion of the effect on outcome. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies. Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development. Heart failure is a major health issue worldwide. Here, Egerstedt et al. perform proteomic profiling of human plasma at different stages of heart failure, providing a comprehensive analysis of changes in the plasma proteome during disease progression. [ABSTRACT FROM AUTHOR]

Summary: Aims: Assessment following heart transplantation (HTx) is routinely performed using transthoracic echocardiography. Differences in long‐term mortality following HTx related to donor‐recipient matching have been reported, but effects of gender on cardiac size and function are not well studied. The aims of this study were to evaluate differences in echocardiographic characteristics of HTx recipients defined by gender. Methods and results: The study prospectively enrolled 123 (n = 34 female) HTx recipients of which 23 recipients was donor‐recipient gender mismatched. Patients were examined with 2‐dimensional echocardiography using Philips iE33 ultrasound system. Data were analysed across strata based on recipient gender and gender mismatch. Male recipients had larger left ventricular (LV) mass, thicker septal wall (P<0·001) and larger absolute LV volumes (P<0·001). Mean LV ejection fraction (EF) was higher in females (P<0·05), but no differences in conventional parameters of right ventricular (RV) function were found. Ventricular strain was higher in females than in males: LV global longitudinal strain (P<0·01), RV global longitudinal strain (P<0·05) and RV lateral free wall (P<0·05). The male group receiving a female donor heart had comparable EF and strain parameters to the female group receiving a gender‐matched heart. Conclusion: We found that female recipient gender was associated with smaller chamber size, higher LV EF and better LV and RV longitudinal strain. Gender‐mismatched male recipients appeared to exhibit function parameters similar to gender‐matched female recipients. Our results indicate that the gender aspect, analogous to current reference guidelines in general population, should be taken into consideration when examining patients post‐HTx. [ABSTRACT FROM AUTHOR]

Background: Whole-genome sequencing (WGS) of heart transplant recipient- and donor-derived cardiac biopsies may facilitate organ matching, graft failure prediction, and immunotolerance research. The objective of this study was to determine the feasibility of WGS based on formalin-fixed paraffin-embedded endomyocardial biopsies. Methods and results: The study included serial donor- and recipient samples from patients who had undergone heart transplantation at Skane University Hospital, Lund, Sweden, between 1988 and 2009. DNA extraction and WGS were conducted. Additional WGS sequencing quality metrics and coverage were obtained with the Genome Analysis Toolkit (GATK). 455 endomyocardial samples from 37 heart transplant recipients were acquired from routine rejection monitoring and stored as formalin-fixed paraffin-embedded samples. They were analyzed after 3–26 years of storage. DNA was extracted from 114 samples and WGS was run on 85 samples. DNA extraction yielded 313 ng (IQR 96–601) for all samples. A coverage of 11.3x (IQR 9.0–15.9) was recorded for all WGS samples. Three samples stored for > 25 years yielded a coverage of > 25x. Data were generated for 1.7 billion reads per sample (IQR 1.4–2.7). A Transition/Transversion (TiTv) ratio of 2.09 ± 0.05 was calculated for all WGS samples. No associations were found among storage time, DNA yield, or sequencing quality metrics. Conclusions: The present study demonstrated the feasibility of whole-genome sequencing based on endomyocardial biopsies. This process could enable large-scale retrospective genomic studies using stored histopathological samples. [ABSTRACT FROM AUTHOR]

Objective: Vascular endothelial growth factor D (VEGF-D) has important functions in lymphangiogenesis and angiogenesis. High plasma levels of VEGF-D have been associated with incidence of heart failure. The association of VEGF-D with atrial fibrillation (AF) and stroke is unclear and we hypothesised that VEGF-D could also be associated with incidence of AF and ischaemic stroke.Methods: VEGF-D was measured in fasting blood samples of 4689 subjects (40% men) without a history of AF from the Malmö Diet and Cancer Study, a prospective, population-based study in Sweden. Median age was 58 years (range 46-68). Cox regression analyses, adjusted for multiple risk factors, was used to assess AF and ischaemic stroke risk in relation to VEGF-D levels.Results: During a median follow-up time of 20.6 years, there were 637 cases of incident AF and 322 cases of first ischaemic stroke. After adjustment, VEGF-D was significantly associated with AF (HR 1.13(95% CI 1.04 to 1.23) per 1 SD increase) and ischaemic stroke (HR 1.14(95% CI 1.02 to 1.28) per 1 SD). The association with ischaemic stroke was explained by an increased incidence of AF-related stroke. HRs per 1 SD were 1.34 (95% CI 1.04 to 1.71) for AF-related ischaemic stroke and 1.04 (95% CI 0.90 to 1.19) for ischaemic stroke without AF.Conclusions: Increased VEGF-D concentrations were associated with AF and ischaemic stroke. The relationship with ischaemic stroke was more pronounced in subjects with a diagnosis of AF. [ABSTRACT FROM AUTHOR]

Summary: Background: Right ventricular (RV) systolic function is an important determinant of outcome in patients with pulmonary hypertension (PH). Conventional echocardiographic measures of RV are mainly based on longitudinal contractility. Recently, measurement of RV global longitudinal strain derived from multiple windows (RVGLS) has emerged as an option but has not been well evaluated. The aim of the present study was to evaluate which echocardiographic RV function parameter correlates best with RV ejection fraction derived from cardiac magnetic resonance imaging (RVEFCMR). Methods and results: Fifty‐five patients evaluated for PH underwent RV assessment with echocardiography and CMR. Conventional echocardiographic parameters of RV function including tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (S′), RV fractional area change (RVFAC) and RV index of myocardial performance (RIMP). RVGLS was measured from three separate apical views using a 17‐segment model and strain from the lateral free wall was calculated separately (RVfree). The study included 55 patients, whereas assessment of RVGLS could be obtained in 29 patients. The Pearson correlation coefficient with RVEFCMR was strong for RVGLS (r = 0·814, P<0·001) and RVfree (r = 0·778, P<0·001), modest for RVFAC (r = 0·681, P<0·001), TAPSE (r = 0·592, P<0·001) and RIMP (r=−0·521, P<0·01), and weak for S′ (r = 0·385, P<0·01). Conclusion: The echocardiographic RV measures, RVGLS and RVfree correlated well with RVEFCMR, whereas correlation with TAPSE, RIMP and S′ was unsatisfactory. Our findings suggest that RVGLS and RVfree are the preferred echocardiographic methods for clinical practice. RVfree is easiest to perform but RVGLS could provide incremental value in selected patients. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) often results in the devastating loss of motor, sensory, and autonomic function. After SCI, the interruption of descending sympathoexcitatory pathways disrupts supraspinal control of blood pressure (BP). A common clinical consequence of cardiovascular dysfunction after SCI is orthostatic hypotension (OH), a debilitating condition characterized by rapid profound decreases in BP when assuming an upright posture. OH can result in a diverse array of insidious and pernicious health consequences. Acute effects of OH include decreased cardiac filling, cerebral hypoperfusion, and associated presyncopal symptoms such as lightheadedness and dizziness. Over the long term, repetitive exposure to OH is associated with a drastically increased prevalence of heart attack and stroke, which are leading causes of death in those with SCI. Current recommendations for managing BP after SCI primarily include pharmacologic interventions with prolonged time to effect. Because most episodes of OH occur in less than 3 minutes, this delay in action often renders most pharmacologic interventions ineffective. New innovative technologies such as epidural and transcutaneous spinal cord stimulation are being explored to solve this problem. It might be possible to electrically stimulate sympathetic circuitry caudal to the injury and elicit rapid modulation of BP to manage OH. This review describes autonomic control of the cardiovascular system before injury, resulting cardiovascular consequences after SCI such as OH, and the clinical assessment tools for evaluating autonomic dysfunction after SCI. In addition, current approaches for clinically managing OH are outlined, and new promising interventions are described for managing this condition. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) often results in the devastating loss of motor, sensory, and autonomic function. After SCI, the interruption of descending sympathoexcitatory pathways disrupts supraspinal control of blood pressure (BP). A common clinical consequence of cardiovascular dysfunction after SCI is orthostatic hypotension (OH), a debilitating condition characterized by rapid profound decreases in BP when assuming an upright posture. OH can result in a diverse array of insidious and pernicious health consequences. Acute effects of OH include decreased cardiac filling, cerebral hypoperfusion, and associated presyncopal symptoms such as lightheadedness and dizziness. Over the long term, repetitive exposure to OH is associated with a drastically increased prevalence of heart attack and stroke, which are leading causes of death in those with SCI. Current recommendations for managing BP after SCI primarily include pharmacologic interventions with prolonged time to effect. Because most episodes of OH occur in less than 3 minutes, this delay in action often renders most pharmacologic interventions ineffective. New innovative technologies such as epidural and transcutaneous spinal cord stimulation are being explored to solve this problem. It might be possible to electrically stimulate sympathetic circuitry caudal to the injury and elicit rapid modulation of BP to manage OH. This review describes autonomic control of the cardiovascular system before injury, resulting cardiovascular consequences after SCI such as OH, and the clinical assessment tools for evaluating autonomic dysfunction after SCI. In addition, current approaches for clinically managing OH are outlined, and new promising interventions are described for managing this condition. [ABSTRACT FROM AUTHOR]