Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

Prognostic impact of baseline and residual SYNTAX scores in cardiogenic shock.

OBJECTIVES: The aim was to assess the extent of coronary artery disease and revascularization using baseline SYNTAX Score (bSS) and residual SYNTAX Score (rSS) in patients with cardiogenic shock (CS) secondary to ST-segment elevation myocardial infarction (STEMI). The prognostic impact of SYNTAX Score (SS) was evaluated and assessed for additive value over clinical risk scores. BACKGROUND: bSS and rSS have been proven to be useful in risk stratification in stable coronary artery disease as well as in acute coronary syndromes, but they have not been studied in STEMI related CS. METHODS: Patients from a multinational prospective study of CS were analyzed. The study population was divided into tertiles according to bSS. The Cox regression and receiver operating characteristic (ROC) curves were used to assess the predictive power of SS. RESULTS: Of the 61 studied patients, 85% were male and the mean age was 67 years. Median bSS was 22 (15-32) and rSS 7 (0-13). Ninety-day mortality was 43%. bSS had negative prognostic value in multivariable analysis (HR 1.06, 95% CI 1.01-1.10). However, additive value over clinical risk scores was limited. rSS was not associated with mortality, whereas post-percutaneous coronary intervention (PCI) TIMI flow 3 of infarct-related artery (IRA) predicted better survival. CONCLUSIONS: In STEMI related CS, the added value of bSS and rSS over clinical assessment and risk scores is limited. Our results suggest that while immediate PCI in order to restore blood flow to the IRA is essential, deferring the treatment of residual lesions does not seem to be associated with worse prognosis.

Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths.

Aims: Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization. Methods and results: We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture. Conclusion: Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

Genetically determined height and coronary artery disease.

BACKGROUND: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. CONCLUSIONS: There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).

Saliva and serum biomarkers in periodontitis and coronary artery disease.

AIM: Matrix metalloproteinase (MMP)-8, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1 and myeloperoxidase (MPO) participate in extracellular matrix breakdown both in periodontium and atherosclerotic plaques. We investigated the diagnostic value of serum and saliva biomarkers in periodontitis and acute coronary syndrome (ACS). MATERIALS AND METHODS: The population was PAROGENE (n = 481), a random cohort of patients with an indication for coronary angiography. All patients underwent a clinical and radiographic oral examination. Groups consisting of periodontitis versus non-periodontitis, and ACS versus non-ACS patients were compared. RESULTS: Saliva MMP-8, MMP-9 and MPO provided significant area-under-curve (AUC) values for periodontitis, 0.69 (<0.001), 0.66 (<0.001) and 0.68 (<0.001), respectively. Serum MMP-8, MMP-9 and MPO levels distinguished ACS from non-ACS patients with AUCs of 0.73 (<0.001), 0.58 (0.03) and 0.68 (<0.001), respectively. Periodontitis confounded the use of serum MMP-9 in diagnostics of ACS. Cardiac status complicated the use of saliva TIMP-1 in periodontal diagnostics. Saliva biomarkers could not be used in ACS diagnosis, and serum biomarkers were not useful in diagnosis of periodontitis. CONCLUSIONS: MMP-8, MMP-9, TIMP-1and MPO are valuable biomarkers for both ACS and periodontitis, but the selection of sample material is crucial; serum is suitable for ACS and saliva for periodontal diagnostic aid.

Aggregatibacter actinomycetemcomitans serotypes associate with periodontal and coronary artery disease status.

AIM: We investigated the association between the Aggregatibacter actinomycetemcomitans serotypes, periodontal status and coronary artery disease (CAD). MATERIALS AND METHODS: The study population included 497 patients who underwent coronary angiography, and clinical oral examination. Quantitative polymerase chain reaction assays were designed to identify the serotypes from saliva samples. RESULTS: Aggregatibacter actinomycetemcomitans serotype frequencies were as follows: serotype "c" 35.7%, "b" 28.6%, "a" 26.2%, "e" 7.1%, "d" 2.4% and "f" 0%. The subjects with a detectable serotype had less teeth and higher bleeding on probing than those with no serotype. Serotypes "b" and "c" associated with periodontal probing depths and periodontal inflammatory burden. The saliva and subgingival bacterium quantities and serum antibody levels against A. actinomycetemcomitans were highest in patients harbouring serotype "c." Serotypes "b" and "c" were most frequent (59.3%) in patients with CAD (p = .040), and they associated with the risk of stable CAD with an odds ratio of 2.67 (95% confidence interval 1.06-7.44). Also, the severity of CAD (p = .018) associated with serotypes "b" and "c." CONCLUSIONS: Aggregatibacter actinomycetemcomitans serotypes "b" and "c" associate with both periodontal and CAD status. Detectable serotypes associate with the quantity and the serology of the bacterium emphasizing both local and systemic effect of the A. actinomycetemcomitans serotypes.

Predictive value of the baseline electrocardiogram ST-segment pattern in cardiogenic shock: Results from the CardShock Study.

BACKGROUND: The most common aetiology of cardiogenic shock (CS) is acute coronary syndrome (ACS), but even up to 20%-50% of CS is caused by other disorders. ST-segment deviations in the electrocardiogram (ECG) have been investigated in patients with ACS-related CS, but not in those with other CS aetiologies. We set out to explore the prevalence of different ST-segment patterns and their associations with the CS aetiology, clinical findings and 90-day mortality. METHODS: We analysed the baseline ECG of 196 patients who were included in a multinational prospective study of CS. The patients were divided into 3 groups: (a) ST-segment elevation (STE). (b) ST-segment depression (STDEP). (c) No ST-segment deviation or ST-segment impossible to analyse (NSTD). A subgroup analysis of the ACS patients was conducted. RESULTS: ST-segment deviations were present in 80% of the patients: 52% had STE and 29% had STDEP. STE was associated with the ACS aetiology, but one-fourth of the STDEP patients had aetiology other than ACS. The overall 90-day mortality was 41%: in STE 47%, STDEP 36% and NSTD 33%. In the multivariate mortality analysis, only STE predicted mortality (HR 1.74, CI95 1.07-2.84). In the ACS subgroup, the patients were equally effectively revascularized, and no differences in the survival were noted between the study groups. CONCLUSION: ST-segment elevation is associated with the ACS aetiology and high mortality in the unselected CS population. If STE is not present, other aetiologies must be considered. When effectively revascularized, the prognosis is similar regardless of the ST-segment pattern in ACS-related CS.

Lipopolysaccharide, a possible molecular mediator between periodontitis and coronary artery disease.

AIM: We aimed to study how lipopolysaccharide (LPS) in saliva and serum associates with each other, periodontal microbial burden, periodontitis and coronary artery disease (CAD). MATERIALS AND METHODS: The used Parogene cohort comprised N = 505 Finnish adults. Coronary diagnosis was acquired by coronary angiography, and the main outcomes were as follows: no significant CAD (n = 123), stable CAD (n = 184) and acute coronary syndrome (n = 169). Periodontitis was defined according to clinical and radiographic examinations. Levels for 75 strains of subgingival bacteria were determined by checkerboard DNA-DNA hybridization. Saliva and serum LPS activity was analysed by Limulus amebocyte lysate assay. RESULTS: The level of 11 bacterial strains, which were mainly oral and respiratory Gram-negative species, associated with salivary LPS levels in an age- and gender-adjusted linear regression. A total of 4.9% of the serum LPS, that is endotoxemia, variation was explainable by saliva LPS among patients with periodontitis (n = 247, R2  = .049, Pearson's r = .222, p < .001). Endotoxemia associated with stable CAD in a confounder adjusted multinomial logistic regression model (OR 1.99, 95% CI 1.04-3.81, p = .039, 3rd tertile). CONCLUSIONS: In particular in periodontitis patients, subgingival microbial burden contributes to endotoxemia. LPS is a possible molecular mediator between periodontitis and CAD.

The potential of the inodilator levosimendan in maintaining quality of life in advanced heart failure.

Maintaining adequate quality of life (QoL) is an important therapeutic objective for patients with advanced heart failure and, for some patients, may take precedence over prolonging life. Achieving good QoL in this context may involve aspects of patient care that lie outside the familiar limits of heart failure treatment. The inodilator levosimendan may be advantageous in this setting, not least because of its sustained duration of action, ascribed to a long-acting metabolite designated OR-1896. The possibility of using this drug in an outpatient setting is a notable practical advantage that avoids the need for patients to attend a clinic appointment. Intermittent therapy can be integrated into a wider system of outreach and patient monitoring. Practical considerations in the use of levosimendan as part of a palliative or end-of-life regimen focused on preserving QoL include the importance of starting therapy at low doses and avoiding bolus administration unless immediate effects are required and patients have adequate baseline arterial blood pressure.

Incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities - a nationwide population-based study.

BACKGROUND: Scant data exist on incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities in the general population. METHODS: We recorded ECG and measured conventional cardiovascular risk factors in 5667 Finns who were followed up for incident atrial fibrillation (AF). We obtained repeat ECGs from 3089 individuals 11years later. RESULTS: The incidence rates of prolonged P-wave duration, abnormal P terminal force (PTF), left P-wave axis deviation, and right P-wave axis deviation were 16.0%, 7.4%, 3.4%, and 2.2%, respectively. Older age and higher BMI were associated with incident prolonged P-wave duration and abnormal PTF (P≤0.01). Higher blood pressure was associated with incident prolonged P-wave duration and right P-wave axis deviation (P≤0.01). During follow-up, only prolonged P-wave duration predicted AF (multivariable-adjusted hazard ratio, 1.38; P=0.001). CONCLUSIONS: Modifiable risk factors associate with P-wave abnormalities that are common and may represent intermediate steps of atrial cardiomyopathy on a pathway leading to AF.

Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol.

AIMS: The aim was to study the prognostic value of plasma ceramides (Cer) as cardiovascular death (CV death) markers in three independent coronary artery disease (CAD) cohorts. METHODS AND RESULTS: Corogene study is a prospective Finnish cohort including stable CAD patients (n = 160). Multiple lipid biomarkers and C-reactive protein were measured in addition to plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1). Subsequently, the association between high-risk ceramides and CV mortality was investigated in the prospective Special Program University Medicine-Inflammation in Acute Coronary Syndromes (SPUM-ACS) cohort (n = 1637), conducted in four Swiss university hospitals. Finally, the results were validated in Bergen Coronary Angiography Cohort (BECAC), a prospective Norwegian cohort study of stable CAD patients. Ceramides, especially when used in ratios, were significantly associated with CV death in all studies, independent of other lipid markers and C-reactive protein. Adjusted odds ratios per standard deviation for the Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio were 4.49 (95% CI, 2.24-8.98), 1.64 (1.29-2.08), and 1.77 (1.41-2.23) in the Corogene, SPUM-ACS, and BECAC studies, respectively. The Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio improved the predictive value of the GRACE score (net reclassification improvement, NRI = 0.17 and ΔAUC = 0.09) in ACS and the predictive value of the Marschner score in stable CAD (NRI = 0.15 and ΔAUC = 0.02). CONCLUSIONS: Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently used lipid markers. This may improve the identification of high-risk patients in need of more aggressive therapeutic interventions.

Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy.

AIMS: Despite our increased understanding of the genetic basis of dilated cardiomyopathy (DCM), the clinical utility and yield of clinically meaningful findings of comprehensive next-generation sequencing (NGS)-based genetic diagnostics in DCM has been poorly described. We utilized a high-quality oligonucleotide-selective sequencing (OS-Seq)-based targeted sequencing panel to investigate the genetic landscape of DCM in Finnish population and to evaluate the utility of OS-Seq technology as a novel comprehensive diagnostic tool. METHODS AND RESULTS: Using OS-Seq, we targeted and sequenced the coding regions and splice junctions of 101 genes associated with cardiomyopathies in 145 unrelated Finnish patients with DCM. We developed effective bioinformatic variant filtering strategy and implemented strict variant classification scheme to reveal diagnostic yield and genotype-phenotype correlations. Implemented OS-Seq technology provided high coverage of the target region (median coverage 410× and 99.42% of the nucleotides were sequenced at least 15× read depth). Diagnostic yield was 35.2% (familial 47.6% and sporadic 25.6%, P = 0.004) when both pathogenic and likely pathogenic variants are considered as disease causing. Of these, 20 (53%) were titin (TTN) truncations (non-sense and frameshift) affecting all TTN transcripts. TTN truncations accounted for 20.6% and 14.6% of the familial and sporadic DCM cases, respectively. CONCLUSION: Panel-based, high-quality NGS enables high diagnostic yield especially in the familial form of DCM, and bioinformatic variant filtering is a reliable step in the process of interpretation of genomic data in a clinical setting.

Assessment of myocardial infarct size with body surface potential mapping: validation against contrast-enhanced cardiac magnetic resonance imaging.

BACKGROUND: Assessment of myocardial infarct (MI) size is important for therapeutic and prognostic reasons. We used body surface potential mapping (BSPM) to evaluate whether single-lead electrocardiographic variables can assess MI size. METHODS: We performed BSPM with 120 leads covering the front and back chest (plus limb leads) on 57 patients at different phases of MI: acutely, during healing, and in the chronic phase. Final MI size was determined by contrast-enhanced cardiac magnetic resonance imaging (DE-CMR) and correlated with various computed depolarization- and repolarization-phase BSPM variables. We also calculated correlations between BSPM variables and enzymatic MI size (peak CK-MBm). RESULTS: BSPM variables reflecting the Q- and R wave showed strong correlations with MI size at all stages of MI. R width performed the best, showing its strongest correlation with MI size on the upper right back, there representing the width of the "reciprocal Q wave" (r = 0.64-0.71 for DE-CMR, r = 0.57-0.64 for CK-MBm, P < 0.0001). Repolarization-phase variables showed only weak correlations with MI size in the acute phase, but these correlations improved during MI healing. T-wave variables and the QRSSTT integral showed their best correlations with DE-CMR defined MI size on the precordial area, at best r = -0.57, P < 0.0001 in the chronic phase. The best performing BSPM variables could differentiate between large and small infarcts at all stages of MI. CONCLUSIONS: Computed, single-lead electrocardiographic variables can estimate the final infarct size at all stages of MI, and differentiate large infarcts from small.

Genetic variation on the BAT1-NFKBIL1-LTA region of major histocompatibility complex class III associates with periodontitis.

Periodontitis is a chronic inflammatory disease with a multifactorial etiology. We investigated whether human major histocompatibility complex (MHC) polymorphisms (6p21.3) are associated with periodontal parameters. Parogene 1 population samples (n = 169) were analyzed with 13,245 single nucleotide polymorphisms (SNPs) of the MHC region. Eighteen selected SNPs (P ≤ 0.001) were replicated in Parogene 2 population samples (n = 339) and the Health 2000 Survey (n = 1,420). All subjects had a detailed clinical and radiographic oral health examination. Serum lymphotoxin-α (LTA) concentrations were measured in the Parogene populations, and the protein was detected in inflamed periodontal tissue. In the Parogene 1 population, 10 SNPs were associated with periodontal parameters. The strongest associations emerged from the parameters bleeding on probing (BOP) and a probing pocket depth (PPD) of ≥6 mm with the genes BAT1, NFKBIL1, and LTA. Six SNPs, rs11796, rs3130059, rs2239527, rs2071591, rs909253, and rs1041981 (r(2), ≥0.92), constituted a risk haplotype. In the Parogene 1 population, the haplotype had the strongest association with the parameter BOP, a PPD of ≥6 mm, and severe periodontitis with odds ratios (95% confidence intervals) of 2.63 (2.21 to 3.20), 2.90 (2.37 to 3.52), and 3.10 (1.63 to 5.98), respectively. These results were replicated in the other two populations. High serum LTA concentrations in the Parogene population were associated with the periodontitis risk alleles of the LTA SNPs (rs909253 and rs1041981) of the haplotype. In addition, the protein was expressed in inflamed gingival connective tissue. We identified a novel BAT1-NFKBIL1-LTA haplotype as a significant contributor to the risk of periodontitis. The genetic polymorphisms in the MHC class III region may be functionally important in periodontitis susceptibility.

Acute heart failure with and without concomitant acute coronary syndromes: patient characteristics, management, and survival.

BACKGROUND: Acute coronary syndromes (ACS) may precipitate up to a third of acute heart failure (AHF) cases. We assessed the characteristics, initial management, and survival of AHF patients with (ACS-AHF) and without (nACS-AHF) concomitant ACS. METHODS AND RESULTS: Data from 620 AHF patients were analyzed in a prospective multicenter study. The ACS-AHF patients (32%) more often presented with de novo AHF (61% vs. 43%; P < .001). Although no differences existed between the 2 groups in mean blood pressure, heart rate, or routine biochemistry on admission, cardiogenic shock and pulmonary edema were more common manifestations in ACS-AHF (P < .01 for both). Use of intravenous nitrates, furosemide, opioids, inotropes, and vasopressors, as well as noninvasive ventilation and invasive coronary procedures (angiography, percutaneous coronary intervention, coronary artery bypass graft surgery), were more frequent in ACS-AHF (P < .001 for all). Although 30-day mortality was significantly higher for ACS-AHF (13% vs. 8%; P = .03), survival in the 2 groups at 5 years was similar. Overall, ACS was an independent predictor of 30-day mortality (adjusted odds ratio 2.0, 95% confidence interval 1.07-3.79; P = .03). CONCLUSIONS: Whereas medical history and the manifestation and initial treatment of AHF between ACS-AHF and nACS-AHF patients differ, long-term survival is similar. ACS is, however, independently associated with increased short-term mortality.

Salivary biomarkers of bacterial burden, inflammatory response, and tissue destruction in periodontitis.

AIM: Chronic periodontitis has an episodic and multifactorial character, with fluctuations in bacterial burden, inflammatory response, and tissue destruction. We investigated the association of selected salivary biomarkers with periodontal parameters and validated the use of a novel salivary diagnostic approach, the cumulative risk score (CRS), in detection of periodontitis in subjects with angiographically verified coronary artery disease diagnosis. MATERIALS AND METHODS: The concentrations of matrix metalloproteinase (MMP)-8, interleukin (IL)-1ß, and Porphyromonas gingivalis were analysed from saliva of 493 subjects. The subjects participated in a detailed clinical and radiographic oral examination. The CRS index, combining the three salivary biomarkers, was calculated for each subject. RESULTS: High salivary concentrations of MMP-8, IL-1ß, and P. gingivalis were associated with deepened periodontal pockets and alveolar bone loss, and MMP-8 and IL-1ß with bleeding on probing. The CRS index had a stronger association with moderate to severe periodontitis (OR 6.13; 95% CI 3.11-12.09) than any of the markers alone. CONCLUSIONS: Salivary concentrations of MMP-8, IL-1ß, and P. gingivalis are associated with various clinical and radiographic measures of periodontitis. The CRS index, combining the three salivary biomarkers, is associated with periodontitis more strongly than any of the markers alone regardless of the coronary artery disease status of the patients.

Differences in ST-elevation and T-wave amplitudes do not reliably differentiate takotsubo cardiomyopathy from acute anterior myocardial infarction.

BACKGROUND: Previous efforts to distinguish acute anterior ST-elevation myocardial infarction (anterior-STEMI) from various forms of takotsubo cardiomyopathy (TTC) by electrocardiography (ECG) have produced differing results. METHODS: We performed a retrospective comparison of acute ECGs between 48 apical and 9 mid-ventricular TTC patients, with 96 anterior-STEMI patients. ECG was recorded in acute phase (<24h from onset of pain), and analyzed for ST-changes, negative T-waves, abnormal Q-waves and QT-interval duration. Time from onset of pain to ECG was gathered from patient records. RESULTS: Anterior-STEMI patients had ST-elevation in lead V1 more frequently than apical (70% vs 15%, p<0.0001) or mid-ventricular TTC patients (70% vs 0%, p<0.0001), and higher ST-elevation amplitudes in leads V2-V5 (p<0.02). Lack of ST-elevation in lead V1 and ST-elevation amplitude <2mm in lead V2 distinguished TTC from anterior-STEMI patients with 63% sensitivity and 93% specificity, with 79% predictive value. CONCLUSIONS: In patients with anterior ST-elevation and acute chest pain, lack of ST-elevation in lead V1 and ST-elevation amplitude <2mm in lead V2 suggests a TTC diagnosis. However, this criterion is not reliable enough in clinical practice to distinguish between TTC and anterior-STEMI patients.

Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure.

AIMS: Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator. This study evaluated the haemodynamic effect and safety of cinaciguat added to standard therapy in patients with acute decompensated heart failure (ADHF). METHODS AND RESULTS: In this placebo-controlled, phase IIb study (NCT00559650), 139 patients admitted with ADHF, pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, left ventricular ejection fraction <40%, and a pre-existing need for invasive haemodynamic monitoring were randomized 2:1 to cinaciguat:placebo (continuous i.v. infusion). The dose was titrated for 8 h and maintained for 16-40 h (starting dose: 100 µg/h). At 8 h, mean PCWP changed from 25.7 ± 5.0 mmHg by -7.7 mmHg with cinaciguat and from 25.0 ± 5.3 mmHg by -3.7 mmHg with placebo (P < 0.0001). The mean right atrial pressure changed from 12.4 ± 5.3 mmHg by -2.7 mmHg with cinaciguat and from 11.8 ± 4.9 mmHg by -0.6 mmHg with placebo (P= 0.0019). Cinaciguat also decreased the pulmonary and systemic vascular resistance and the mean arterial pressure, and increased the cardiac index (all P < 0.0001 vs. placebo). Systolic blood pressure changed by -21.6 ± 17.0 mmHg with cinaciguat and -5.0 ± 14.5 mmHg with placebo. Adverse events were experienced by 71 and 45% of patients receiving cinaciguat and placebo, respectively. No adverse effects on the 30-day mortality were seen; however, the trial was stopped prematurely due to an increased occurrence of hypotension at cinaciguat doses ≥200 µg/h. CONCLUSION: Cinaciguat unloaded the heart in patients with ADHF. However, high doses were associated with hypotension.

Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.

BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)). INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. FUNDING: US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

Cardiac steatosis and left ventricular function in men with metabolic syndrome.

BACKGROUND: Ectopic accumulation of fat accompanies visceral obesity with detrimental effects. Lipid oversupply to cardiomyocytes leads to cardiac steatosis, and in animal studies lipotoxicity has been associated with impaired left ventricular (LV) function. In humans, studies have yielded inconclusive results. The aim of the study was to evaluate the role of epicardial, pericardial and myocardial fat depots on LV structure and function in male subjects with metabolic syndrome (MetS). METHODS: A study population of 37 men with MetS and 38 men without MetS underwent cardiovascular magnetic resonance and proton magnetic spectroscopy at 1.5 T to assess LV function, epicardial and pericardial fat area and myocardial triglyceride (TG) content. RESULTS: All three fat deposits were greater in the MetS than in the control group (p <0.001). LV diastolic dysfunction was associated with MetS as measured by absolute (471 mL/s vs. 667 mL/s, p = 0.002) and normalized (3.37 s⁻¹ vs. 3.75 s⁻¹, p = 0.02) LV early diastolic peak filling rate and the ratio of early diastole (68% vs. 78%, p = 0.001). The amount of epicardial and pericardial fat correlated inversely with LV diastolic function. However, myocardial TG content was not independently associated with LV diastolic dysfunction. CONCLUSIONS: In MetS, accumulation of epicardial and pericardial fat is linked to the severity of structural and functional alterations of the heart. The role of increased intramyocardial TG in MetS is more complex and merits further study.