Damien Logeart

Human Cardiac Troponin T: Cloning and Expression of New Isoforms in the Normal and Failing Heart

Troponin T, like many myofibrillar proteins, exists as multiple isoforms encoded by distinct genes or generated by splicing of the same primary RNA transcript. We have previously cloned the first human cardiac troponin T (cTnT) cDNA and showed the differential expression of cTnT in cardiac and skeletal muscle during ontogenic development. In this work we located the human cTnT gene by means of fluorescent in situ hybridization to 1q32 and, by sequencing thirteen cDNAs isolated from a human fetal heart cDNA library, identified three new isoforms resulting from specific combinations of three variable regions in human cTnT cDNA. The first variable region is a 30-bp box located at the 5 end of the cDNA, which can be excised either totally or only from the first 3 bp onwards; the second is a codon which can be completely excised; and the third is a 9-bp box in the 3 half of the cDNA, which can also be excised either totally or only from the first 3 bp. The existence of the corresponding RNAs in fetal and adult ventricles was confirmed by RNase protection studies. No accumulation of the fetal isoforms was found in failing ventricles compared with controls.

Impact of Ivabradine on Central Aortic Blood Pressure and Myocardial Perfusion in Patients With Stable Coronary Artery Disease.

Abstract—Treatment of hypertensive patients with &bgr;-blockers reduces heart rate and decreases central blood pressure less than other antihypertensive drugs, implying that reducing heart rate without altering brachial blood pressure could increase central blood pressure, explaining the increased cardiovascular risk reported with &bgr;-blocker. We describe a randomized, double-blind study to explore whether heart rate reduction with the If inhibitor ivabradine had an impact on central blood pressure. We included 12 normotensive patients with stable coronary artery disease, heart rate ≥70 bpm (sinus rhythm), and stable background &bgr;-blocker therapy. Patients received ivabradine 7.5 mg BID or matched placebo for two 3-week periods with a crossover design and evaluation by aplanation tonometry. Treatment with ivabradine was associated with a significant reduction in resting heart rate after 3 weeks versus no change with placebo (−15.8±7.7 versus +0.3±5.8 bpm; P=0.0010). There was no relevant between-group difference in change in central aortic systolic blood pressure (−4.0±9.6 versus +2.4±12.0 mm Hg; P=0.13) or augmentation index (−0.8±10.0% versus +0.3±7.6%; P=0.87). Treatment with ivabradine was associated with a modest increase in left ventricular ejection time (+18.5±17.8 versus +2.8±19.3 ms; P=0.074) and a prolongation of diastolic perfusion time (+215.6±105.3 versus −3.0±55.8 ms with placebo; P=0.0005). Consequently, ivabradine induced a pronounced increase in Buckberg index, an index of myocardial viability (+39.3±27.6% versus −2.5±13.5% with placebo; P=0.0015). In conclusion, heart rate reduction with ivabradine does not increase central aortic blood pressure and is associated with a marked prolongation of diastolic perfusion time and an improvement in myocardial perfusion index. Clinical Trial Registration—URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-004779-35.

Myocardial Fractional Flow Reserve Measurement Using Contrast Media as a First-Line Assessment of Coronary Lesions in Current Practice

BACKGROUNDnFractional flow reserve (FFR) measurement requires adenosine injection. However, adenosine can induce conductive and rhythmic complications, or be contraindicated in some patients. Contrast-induced hyperemia could provide a simple first-line method (contrast-enhanced FFR; cFFR) to assess coronary lesions. In this study we evaluated the accuracy of cFFR to predict lesion significance.nnnMETHODSnThis prospective study included 104 patients with 138 coronary lesions. Each stenosis was evaluated using resting distal coronary pressure to aortic pressure ratio (Pd/Pa) measurements using intracoronary iodixanol (cFFR) and adenosine (FFR) injection. An FFR value ≤ 0.8 defined a significant lesion.nnnRESULTSnDose-ranging analysis (nxa0= 12 lesions) showed that 10 mL iodixanol was required to obtain the lowest cFFR value. Intermeasurement reproducibility of cFFR (nxa0= 18 lesions) showed limited variability and small mean estimated bias (0.001 ± 0.014). Values of cFFR and FFR were highly correlated in a first series of nxa0= 36 lesions (rxa0= 0.9; P < 0.001). Receiver-operating characteristic curve analysis showed an excellent accuracy of cFFR cutoff value of ≤ 0.85 in predicting FFR value ≤ 0.80 (area under the curve, 0.94; 95% confidence interval, 0.90-0.98; sensitivity, 95%; specificity, 73%). This threshold was then tested prospectively in an independent cohort of nxa0= 72 lesions. A cFFR value ≤ 0.85 correctly identified hemodynamically significant lesions with a sensitivity of 100%, specificity of 78%, positive predictive value of 78%, and negative predictive value of 100%.nnnCONCLUSIONSncFFR is reproducible and can be achieved with usual volumes of contrast. A cFFR threshold value of 0.85 provides excellent sensitivity and negative predictive value in coronary artery stenosis.

Iron status and inflammatory biomarkers in patients with acutely decompensated heart failure: early in-hospital phase and 30-day follow-up

Iron deficiency (ID) is an important comorbidity in heart failure (HF).1 Its reported prevalence in chronic heart failure (CHF) is 30–50% and it constitutes an independent predictor of morbidity, mortality and cardiac transplantation.2,3 Current European Society of Cardiology (ESC) guidelines for the diagnosis and management of acute and chronic HF recommend assessment of iron parameters in symptomatic HF patients with reduced ejection fraction, with ensuing iron therapy in cases of ID, as defined by the criteria used in the FAIR-HF (Ferinject Assessment in patients with IRon deficiency and chronic Heart Failure) trial.1,4 Data on ID in acutely decompensated HF (ADHF) are scarce, yet in the CardioFer study, conducted in 865 patients in France, ID showed a higher prevalence in ADHF patients (60–80%).5 In this study, we performed serial blood sampling in ADHF patients and assessed the reliability of ID diagnosis during ADHF. In addition, we wanted to evaluate the associations between parameters of iron metabolism and biomarkers of inflammation, cardiovascular stress, fibrosis and renal function. Patients were derived from the Biomarcoeurs cohort (ClinicalTrials.gov: NCT 01374880), detailed previously.6 This substudy included patients with decompensated CHF and de novo HF. Patients with a concomitant infection or myocardial ischaemia were excluded. The protocol of the study was approved by the local ethics committee and patients provided written informed consent. Following admission, blood sampling was performed at day 0 (D0) and day 30 (D30). Iron status was assessed in several ways: we considered absolute and functional ID as defined by the ESC1 thus: ID was considered to be absolute if serum ferritin was <100 μg/L, and functional when serum ferritin was 100–299 μg/L and transferrin saturation (TSAT) was <20%. Furthermore, we assessed plasma levels of hepcidin and soluble transferrin receptor (sTfR) and defined ID as represented by serum hepcidin of <14.5 ng/mL (5th percentile among healthy controls; depleted iron stores) and/or sTfR of ≥1.59 mg/L (95th percentile among healthy controls; depleted intracellular iron content in metabolizing cells).7 Several biomarkers were analysed, including brain natriuretic peptide (BNP), mid-regional–proadrenomedullin (MRproADM), procalcitonin (PCT), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), growth/differentiation factor-15 (GDF15), galectin-2, fibrinogen, soluble ST2, tumour necrosis factor-α (TNF-α) and myeloperoxidase (MPO). Statistical analyses were performed using STATA version 14.2 (StataCorp LLC, College Station, TX, USA). Groups were compared with the Student’s t-test, Wilcoxon matched-pairs signed-rank sum test, Pearson’s χ2 test or McNemar test when appropriate. A P-value of <0.05 was considered to indicate statistical significance. Forty-seven ADHF patients (32 men and 15 women) in whom assessments of ferritin and TSAT had been made at both D0 and D30 were included (data are available in supplementary material online, Tables S1 and S2). Their age (mean± standard deviation) was 70.4±13.7 years. Median BNP was 1004 pg/mL [interquartile range (IQR): 652–1676 pg/mL]. At D0, the median ferritin value was 93 μg/L (IQR: 76–107 μg/L) and median TSAT was 13% (IQR: 6–20%). Twenty-seven (57%) patients fulfilled criteria for absolute ID and 12 (26%) patients did so for functional ID. Thus, 83% of ADHF patients fulfilled the criteria for ID at admission. At D30 of follow-up and guideline-based treatments, the median ferritin value was found to have increased to 159 μg/L (IQR: 134–190 μg/L; P< 0.0001), median TSAT was 17% (IQR: 12–23%; P= 0.0176), and median BNP was 261 pg/mL (IQR: 176–462 pg/mL; P< 0.0001). Frequencies of absolute and functional ID were 11% (five patients) and 57% (27 patients), respectively. The remaining 15 patients (32%) were not ID at D30 of follow-up. Iron status changed significantly between D0 and D30 (P= 0.00001). The difference between the absence and presence of ID is clinically more important than the difference between absolute and functional ID; therefore, absolute and functional ID were combined for the purpose of comparing overall prevalences of ID between D0 and D30, which showed a trend toward statistical significance (P= 0.07) (Figure 1A) and only a moderate association between ID status at D0 and D30 (φ coefficient: 0.26). Circulating levels of hepcidin and sTfR were available for 41 patients at D0; 34 (83%) patients were identified as ID. Comparisons of ID status at D0 using either ferritin/transferrin or hepcidin/sTfR criteria are presented in Figure 1B. Twenty-eight patients (68%) were similarly categorized by both definitions, 13 patients (32%) were considered to be ID according to one but not the other definition. Based on our subsample of 41 patients, there was no difference between these iron parameters in sensitivity to detect ID at admission (P= 0.78); further analysis revealed a weak association between both tests (φ coefficient: 0.04). To explain the variation in ferritin and TSAT in parallel with adequate treatment of ADHF, we correlated the iron parameters studied with several cardiovascular and inflammatory biomarkers. ΔFerritin (ferritin at D30 minus ferritin at D0) correlated with Δsoluble ST2 (Spearman’s ρ=−0.4028; P= 0.0082) and ΔIL-6 (ρ=−0.3569; P= 0.0138), but not with ΔMR-proADM, ΔBNP, ΔPCT, ΔTNF-α, ΔhsCRP, ΔGDF15, Δgalectin-3, Δfibrinogen or ΔMPO. ΔTransferrin saturation correlated only with Δgalectin-3 (ρ=−0.3858; P= 0.0074). We did not detect a correlation between Δhepcidin or ΔsTfR and the other biomarkers studied. In conclusion, biochemical evidence of ID is common at admission for ADHF. Transferrin saturation and ferritin increase significantly over a period of 30 days following ADHF admission, which changes the ID status of patients significantly between D0 and D30 following ADHF. Thus, iron status is not stationary in ADHF patients, even during short periods of follow-up. Changing levels of circulating markers of inflammation weakly correlated with changing circulating iron parameters, which supports the suggestion that systemic inflammation contributes to alterations in iron status between admission and steady state. By contrast, changing iron

HypnosIS to faciLitate trans-Esophageal echocardiograPhy Tolerance: The I-SLEPT study

BACKGROUNDnTrans-oesophageal echocardiography (TOE) is one of the major diagnostic tests in cardiovascular medicine, but the procedure is associated with some discomfort for the patient.nnnAIMnTo determine the additive value of hypnosis as a means of improving patient comfort during TOE.nnnMETHODSnWe randomly assigned 98 patients with non-emergency indications for TOE to a 30-minute hypnosis session combined with topical oropharyngeal anaesthesia (HYP group) or topical oropharyngeal anaesthesia only (CTRL group) before the procedure. The primary efficacy endpoint was the level of patient discomfort assessed using a visual analogue scale (VAS).nnnRESULTSnThe VAS score was significantly reduced in the HYP group compared with the CTRL group (6 [5; 8] vs. 7 [5; 9]; P=0.046). No statistically significant differences were observed in terms of procedure failure (HYP group 2.2% vs. CTRL group 3.9%; P=1.00) and procedure length (HYP group 7 [5; 11] minutes vs. CTRL group 8 [7; 11] minutes; P=0.29). However, the patients subjective estimations of the length of the procedure were significantly shorter in the HYP group than in the CTRL group (8 [5; 10] vs. 10 [10; 20] minutes; P<0.0001). There were no major adverse events in either group. The reported minor events rate was lower in the HYP group (36% vs. 57%; P=0.04).nnnCONCLUSIONnHypnosis is an efficient alternative or complementary method for improving patient comfort during TOE.

Echocardiographic examination: a major role in the management of heart failure.

MOTS CLÉS Insuffisance cardiaque ; Échocardiographie Echocardiographic examination is the main imaging tool for the comprehensive assessment of heart failure, with respect to diagnosis, stratification, and follow-up. Hospitalization for heart failure tends to be associated with worsened prognosis [1]. The pathology is identified in around one-third of hospitalizations for acute heart failure, leading to initial assessment of the underlying cardiomyopathy, usually performed with an echocardiogram. This examination forms part of the diagnosis, looking for systolic and/or diastolic left ventricular dysfunction, evidence of ischaemic disease, hypertrophic cardiomyopathy, valvular disease, pulmonary hypertension, right ventricular dysfunction, and pericardial disease. Identification of any of these abnormalities can be highly clinically relevant, although specific concerns regarding echographic-based diagnosis of heart failure with preserved ejection fraction have been underlined recently [2]. In patients with chronic heart failure, decompensated heart failure may be due to a worsening of the underlying cardiomyopathy or to another factor such as deterioration of an associated valvular disease, presence of atrioventricular or intraventricular asynchronism, intraventricular thrombosis, or significant pulmonary hypertension. Serial echographic examinations can help to guide treatment during hospitalization in difficult cases [3], mainly by monitoring cardiac output and filling pressures [4]. In most intensive care units, echocardiography is now more frequently used than pulmonary artery catheters. Moreover, Doppler analysis-derived filling pressures can predict early outcome after discharge. Although brain natriuretic peptide testing is very useful to rule out the diagnosis on admission and to stratify patient severity [1], this exam cannot replace echocardiography. Therefore, echocardiography should be performed during any hospitalization for heart failure.

Rare Visualization of Entrapped Left Ventricular Thrombi in Noncompacted Myocardium

A 64-year-old man with no significant medical history presented to the emergency department with severe acute heart failure. Initial management was based on oxygen therapy, diuretics, and nitroglycerin. Twenty-four hours after admission, the patient developed aphasia and left arm weakness. Brain MRI showed multiple strokes (Figure A) compatible with cardiac emboli. Echocardiography showed dilated cardiomyopathy with severe left ventricular (LV) dysfunction (ejection …