Pulmonary hypertension in connective tissue diseases: What every CTD specialist should know - but is afraid to ask!

Pulmonary hypertension (PH) is a possible complication of connective tissue diseases (CTDs), especially systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). It is defined by an elevation of the mean pulmonary arterial pressure above 20mmHg documented during a right heart catheterization (RHC). Due to their multiorgan involvement, CTDs can induce PH by several mechanisms, that are sometimes intricated: pulmonary vasculopathy (group 1) affecting arterioles (pulmonary arterial hypertension, PAH) and possibly venules (pulmonary veno-occlusive-like disease), left-heart disease (group 2), chronic lung disease (group 3) and/or chronic thromboembolic PH (group 4). PH suspicion is often raised by clinical manifestations (dyspnea, fatigue), echocardiographic data (increased peak tricuspid regurgitation velocity), isolated decrease in DLCO in pulmonary function tests, and/or unexplained elevation of BNP/NT-proBNP. Its formal diagnosis always requires a hemodynamic confirmation by RHC. Strategies for PH screening and RHC referral have been extensively investigated for SSc-PAH but data are lacking in other CTDs. Therapeutic management of PH depends of the underlying mechanism(s): PAH-approved therapies in group 1 PH (with possible use of immunosuppressants, especially in case of SLE or MCTD); management of an underlying left-heart disease in group 2 PH; management of an underlying chronic lung disease in group 3 PH; anticoagulation, pulmonary endartectomy, PAH-approved therapies and/or balloon pulmonary angioplasty in group 4 PH. Regular follow-up is mandatory in all CTD-PH patients.

Diagnosis and management of heart failure from hospital admission to discharge: A practical expert guidance.

Heart failure (HF) has high event rates, mortality, and is challenging to manage in clinical practice. Clinical management is complicated by complex therapeutic strategies in a population with a high prevalence of comorbidity and general frailty. In the last four years, an abundance of research has become available to support multidisciplinary management of heart failure from within the hospital through to discharge and primary care as well as supporting diagnosis and comorbidity management. Within the hospital setting, recent evidence supports sacubitril-valsartan combination in frail, deteriorating or de novo patients with LVEF≤40%. Furthermore, new strategies such as SGLT2 inhibitors and vericiguat provide further benefit for patients with decompensating HF. Studies with tafamidis report major clinical benefits specifically for patients with ATTR cardiac amyloidosis, a remaining underdiagnosed and undertreated disease. New evidence for medical interventions supports his bundle pacing to reduce QRS width and improve haemodynamics as well as ICD defibrillation for non-ischemic cardiomyopathy. The Mitraclip reduces hospitalisations and mortality in patients with symptomatic, secondary mitral regurgitation and ablation reduces mortality and hospitalisations in patients with paroxysmal and persistent atrial fibrillation. In end-stage HF, the 2018 French Heart Allocation policy should improve access to heart transplants for stable, ambulatory patients and, mechanical circulatory support should be considered to avoid deteriorating on the waiting list. In the community, new evidence supports that improving discharge education, treatment and patient support improves outcomes. The authors believe that this review fills the gap between the guidelines and clinical practice and provides practical recommendations to improve HF management.

Cardiometabolic assessment of lamin A/C gene mutation carriers: a phenotype-genotype correlation.

AIMS: Mutations of the LMNA gene encoding lamin A/C induce heterogeneous phenotypes ranging from cardiopathies and myopathies to lipodystrophies. The aim of this study was to compare cardiometabolic complications in patients with heterozygous LMNA mutations at the 482nd codon, the 'hotspot' for partial lipodystrophy, with carriers of other, non-R482 LMNA mutations. METHODS AND RESULTS: This study included 29 patients with R482 LMNA mutations, 29 carriers of non-R482 LMNA mutation and 19 control subjects. Cardiac and metabolic phenotypes were compared between groups. A family history of either cardiac implantable electronic devices (CIEDs; P < 0.001) or sudden death (P < 0.01) was more frequent in non-R482 than R482 carriers. The non-R482 carriers also had more abnormalities on electrocardiography and received CIEDs more often than R482 carriers (P < 0.001). On cardiac ultrasound, non-R482 patients had greater frequencies of left atrial enlargement (P < 0.05) and lower left ventricular ejection fractions (P < 0.01) than R482 carriers. In contrast, R482 carriers had lower BMI (P < 0.05), leptin (P < 0.01) and fat mass (P < 0.001), but higher intra-/total abdominal fat-mass ratios (P < 0.001) and prevalences of diabetes (P < 0.01) and hypertriglyceridaemia (P < 0.05) than non-R482 carriers, with a trend towards more coronary artery disease. However, non-R482 carriers had higher intra-/total abdominal fat-mass ratios (P < 0.02) and prevalences of diabetes (P < 0.001) and hypertriglyceridaemia (P < 0.05) than the controls. CONCLUSION: Non-R482 carriers present more frequently with arrhythmias than R482 carriers, who twice as often have diabetes, suggesting that follow-up for laminopathies could be adjusted for genotype. Non-R482 mutations require ultra-specialized cardiac follow-up, and coronary artery disease should not be overlooked. Although overlapping phenotypes are found, LMNA mutations essentially lead to tissue-specific diseases, favouring genotype-specific pathophysiological mechanisms.

[Tolerance of bevacizumab therapy in systemic sclerosis-associated pulmonary arterial hypertension: A case report]. / Tolérance du bévacizumab au cours de l'hypertension artérielle pulmonaire associée à la sclérodermie systémique : à propos d'une observation.

INTRODUCTION: No data is available regarding the safety of bevacizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, in patients with pulmonary arterial hypertension (PAH), a condition in which VEGF seems to play a significant and probably protective role. CASE REPORT: We report a patient with a history of systemic sclerosis-associated PAH, stable under bosentan therapy. She was diagnosed with metastatic cervical epidermoid carcinoma and treated by two successive cytotoxic chemotherapy regimens. As these treatments failed to control disease progression, she was started on anti-angiogenic therapy: 3 infusions of bevacizumab 15 mg/kg were administered. Over the course of this treatment, no change in the clinical status or echocardiography parameters was noted. CONCLUSION: This observation suggests that, under careful clinical and echocardiographic follow-up, bevacizumab therapy can be well tolerated in case of stable and moderate PAH. Decision of treatment should be taken cautiously, as the possibility of PAH worsening is not excluded.

Imaging and modern assessment of the right ventricle.

The right ventricular function is difficult to assess owing to its complex morphology, structure and function. The right ventricle (RV) comprises three compartments, the inlet, the apex, and the outlet contracting with a peristaltic motion from the inflow to the outflow chamber and is tightly linked to left ventricular (LV) function through the pulmonary circulation, the interventricular septum and the myocardium inside the pericardial envelop. The relation of RV function to symptom occurrence, exercise capacity and prognosis in a wide variety of cardiac diseases emphasizes the usefulness of its routine assessment. The evaluation of the RV is largely carried out by echocardiography in daily clinical practice despite important limitations inherent to two-dimensional imaging. Multiple views and numerous parameters allow clinicians to integrate the RV function in the clinical decision-making process. Recent modalities of echocardiography such as myocardial deformation and three-dimensional imaging or exercise echocardiography are promising tools for the assessment of the RV. Cardiac magnetic resonance imaging provides the unique opportunity to image the RV in motion and in three dimensions without the limitation of echogenicity. Therefore, cardiac magnetic resonance imaging is taking a growing place in the assessment of the RV in a wide variety of cardio-pulmonary diseases as pulmonary hypertension, ischemia, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, heart failure or congenital heart diseases. Integrating the complex interplay between both ventricles and the pulmonary circulation, this review will discuss the latest results of standard and novel techniques allowing the assessment of RV function by echocardiography and cardiac magnetic resonance imaging, and will provide to the clinicians, facing therapeutic challenges, a comprehensive overview of right heart function.

Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients.

OBJECTIVES: To assess the prevalence and patterns of cardiac abnormalities as detected by cardiac magnetic resonance imaging (MRI) in systemic sclerosis (SSc). METHODS: Fifty-two consecutive patients with SSc underwent cardiac MRI to determine morphological, functional, perfusion at rest and delayed enhancement abnormalities. RESULTS: At least one abnormality on cardiac MRI was observed in 39/52 patients (75%). Increased myocardial signal intensity in T2 was observed in 6 patients (12%), thinning of left ventricle (LV) myocardium in 15 patients (29%) and pericardial effusion in 10 patients (19%). LV and right ventricle (RV) ejection fractions were altered in 12 patients (23%) and 11 patients (21%), respectively. LV diastolic dysfunction was found in 15/43 patients (35%). LV kinetic abnormalities were found in 16/52 patients (31%) and myocardial delayed contrast enhancement was detected in 11/52 patients (21%). No perfusion defects at rest were found. Patients with limited SSc had similar MRI abnormalities to patients with diffuse SSc. Seven of 40 patients (17%) without pulmonary arterial hypertension had RV dilatation. CONCLUSIONS: This study shows that MRI is a reliable and sensitive technique for diagnosing heart involvement in SSc and for analysing its mechanisms, including its inflammatory, microvascular and fibrotic components. Compared with echocardiography, MRI appears to provide additional information by visualising myocardial fibrosis and inflammation. RV dilatation appeared to be non-specific for pulmonary arterial hypertension but could also reflect myocardial involvement related to SSc. Further studies are needed to determine whether cardiac MRI abnormalities have an impact on the prognosis and treatment strategy.

No gender survival difference in a population of patients with chronic heart failure related to left ventricular systolic dysfunction and receiving optimal medical therapy.

INTRODUCTION: Controversial results have been published concerning a possible gender survival difference in patients with chronic heart failure (CHF). METHODS: We analysed data from consecutive patients with stable CHF admitted to our department for prognostic evaluation. Patients underwent coronary angiography, echo-cardiography, radionuclide angiography and a cardiopulmonary exercise test. RESULTS: We included 613 consecutive patients of whom 115 (19%) were women. The major difference in clinical characteristics was a higher proportion of ischaemic cardiomyopathy in men compared to women (51% vs 28%, p<0.0001) and a lower left ventricular ejection fraction (35+/-9 vs 38+/-9%, p=0.001). Therapeutic management was similar in men and women. A total of 140 cardiovascular-related deaths and 4 urgent transplantations occurred during a median follow-up of 1.234 days. There was no gender difference in cardiac survival. Cardiovascular mortality rates at 2 years were 11% in men and 13% in women. CONCLUSIONS: Despite a lower percentage of ischaemic cardiopathy in women, no gender survival benefit was found in our population of CHF patients receiving optimal medical therapy.

Proteomic analysis in cardiovascular diseases.

1. Cardiovascular diseases are a major cause of morbidity and mortality in western countries. The molecular mechanisms responsible for heart dysfunction are still largely unknown, except in cases of genetic defects or alteration of genes and proteins. 2. The publication of genome sequences from humans and other species has demonstrated the complexity of biology, including the finding that one gene does not encode for only one protein but for several, due to mRNA splicing and post-translational modifications. 3. Proteomic analysis can provide an overall understanding of changes in the levels of protein expression. Differential proteomics is a powerful tool for improving our understanding of integrated biochemical responses. The main techniques used are two-dimensional electrophoresis (2D-gel) and Surface-Enhanced Laser Desorption/Ionization Time of Flight (SELDI-TOF) to separate proteins associated with mass spectrometry. Bioinformatic tools make it possible to compare protein profiles obtained from diverse biological samples. 4. The combination of these approaches has proved to be particularly interesting for studying cardiovascular diseases and thereby improving our understanding of the mechanisms involved and identifying new biochemical factors and biomarkers involved in these diseases.

Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis.

OBJECTIVES: There is increasing concern about heart and pulmonary vascular involvement in systemic sclerosis (SSc). One of the most severe complications of SSc is pulmonary arterial hypertension (PAH). There has been an increased awareness of left ventricular (LV) diastolic abnormalities in SSc patients. However, previous studies have generally been conducted in small populations. The aims of this study were to prospectively screen for PAH and to describe echocardiographic parameters in a large group of SSc patients. METHODS: This prospective study was conducted in 21 centres for SSc in France. Patients without severe pulmonary function abnormalities, severe cardiac disease and known PAH underwent Doppler echocardiography performed by a reference cardiologist. RESULTS: Of the 570 patients evaluated, PAH was suspected in 33 patients and was confirmed in 18 by right heart catheterisation. LV systolic dysfunction was rare (1.4%). LV hypertrophy was found in 22.6%, with LV diastolic dysfunction in 17.7%. These LV abnormalities were influenced by age, gender and blood pressure. We identified a small group of 21 patients with a restrictive mitral flow pattern in the absence of any other cardiopulmonary diseases, suggesting a specific cardiac involvement in SSc. CONCLUSIONS: Left and right heart diseases, including PAH, LV hypertrophy and diastolic dysfunction, are common in SSc. However, a small subset of patients without any cardiac or pulmonary diseases have a restrictive mitral flow pattern that could be due to primary cardiac involvement of SSc. The prognostic implications of the LV abnormalities will be evaluated in the 3-year follow-up of this cohort.

Effects of bisoprolol in patients with stable congestive heart failure.

AIM OF THE STUDY: To analyze the effect of bisoprolol in patients with stable congestive heart failure and who tolerated beta-blockers. MATERIAL AND METHODS: Two hundred and one patients performed before and 3 months after maximal tolerated doses of bisoprolol have been reached, a clinical evaluation, an echocardiography, a radionuclide angiography, a cardiopulmonary exercise test and hormonal determinations. RESULTS: Mean dose of bisoprolol was 8.8 +/- 2.4 mg/d. Patients had a significant improvement in NYHA classification. Heart rate at rest decreased from 87 +/- 17 to 66 +/- 12 beats/min (P < 0.0001) without any effect on electrocardiographic parameters. Left ventricular ejection fraction improved from 31 +/- 11 to 41 +/- 13% (P < 0.0001), with a significant decrease in end-diastolic and end-systolic left ventricle diameters and volumes. Mitral profile improved. Peak VO2 increased from 16.1 +/- 5 to 16.8 +/- 5.5 ml/min/kg (P = 0.001) with a significant increase in O2 pulse (from 8.52 +/- 2.7 to 11.2 +/- 3.5 ml/min/beats, P < 0.0001). Plasma levels of A-type and of B-type natriuretic peptides and of norepinephrine significantly decreased after bisoprolol. CONCLUSIONS: Bisoprolol significantly improved left ventricle ejection fraction with a reverse remodeling of the left ventricle, a decrease in hormonal activation and a modest improvement in exercise capacity.

[The genetics of multifactorial cardiovascular disease. How significant for the cardiologist?]. / La génétique des maladies cardiovasculaires multifactorielles. Quel intérêt pour le cardiologue?

Cardiovascular disease represents the prime cause of mortality and morbidity in many countries. The occurrence is affected by pre-existing risk factors of which the best known at the moment are the environmental risk factors. However, for the same level of environmental risk, two individuals do not necessarily have the same probabilities of developing a cardiovascular event. In effect, the constitutional component, accounted for by details in everyone's genetic makeup, can significantly alter this risk. The characterisation and identification of the mutations responsible for this variation in individual susceptibility are complex in the case of multifactorial diseases such as cardiovascular disease. Several studies now allow a glimpse at the expected benefits of understanding this genetic component, as far as diagnosis, prognosis and pharmacogenetics are concerned. The current explosion in high capacity genome techniques will herald new therapeutic approaches likely to further improve the survival and quality of life for our patients.

[Endothelin-1 receptor antagonists in heart failure]. / Antagonistes des récepteurs de l'endothéline-1 dans l'insuffisance cardiaque.

Endothelin-1 is a vasoconstrictor peptide playing an important role in the pathophysiology of heart failure. Endothelin-1 acts after fixation to 2 specific receptors: type A, responsible for vasoconstriction and type B, at the start of transient vasodilation and participating in clearance of the hormone. The experimental results in various animal models have demonstrated beneficial haemodynamic and clinical effects of the mixed or specific antagonists of the type A receptor. The preliminary results of studies conducted in man have confirmed the beneficial haemodynamic effects with lowering of pulmonary pressures, lowering of vascular resistance, and increase in cardiac output. On the other hand, the results of clinical studies have been disappointing, with a neutral effect of an oral mixed antagonist, bosentan, compared to placebo in the only study of morbidity and mortality. These results have put a brake on the development of this therapeutic class in heart failure.

[Aspirin, angiotensin converting enzyme inhibitors and cardiac insufficiency]. / Aspirine, inhibiteur de l'enzyme de conversion de l'angiotensine et insuffisance cardiaque.

The possible negative therapeutic interaction between aspirin and angiotensin converting enzyme inhibitors arose from the conclusions of several experimental studies and retrospective analysis of large scale mortality trials with converting enzyme inhibitors. Some experimental results show inhibition of the vasodilatation of converting enzyme inhibitors, increase in pulmonary pressures, vascular resistances and blood pressure, and degradation of renal function and exercise capacity. However, other studies did not confirm these results. In large scale therapeutic trials, some retrospective analyses, but not all of them, have shown less benefit on morbi-mortality of converting enzyme inhibitors in patients on aspirin. The differences between the doses of aspirin, the type and dosage of the converting enzyme inhibitors and neuro-hormonal activation of the patients could explain the discordant results. The results of randomised trials are awaited but, in the meantime, it is logical to propose small doses of aspirin (< or = 100 mg/day) for patients with cardiac failure and atherosclerosis and to avoid the association in all the other patients.

[Systemic manifestations and development of GPIIbIIIa antibodies in the course of staphylococcal endocarditis. Report of a case]. / Manifestations systémiques et développement d'anticorps anti-GPIIbIIIa au cours d'une endocardite staphylococcique. A propos d'un cas.

Immunological complications of staphylococcal endocarditis are rare but represent a serious event in this condition. The authors report the case of acute tricuspid valve endocarditis in a 38 year old drug addict. The diagnosis was suggested by the presentation of bilateral bacterial lung abscesses with a murmur of tricuspid regurgitation, and confirmed by transthoracic and transoesophageal echocardiography. Bacteriological cultures isolated a methicillin-sensitive staphylococcal aureus. The outcome was complicated by a nephrotic syndrome associated with a glomerulonephritis by deposition of immune complexes and an autoimmune thrombocytopaenic purpura due to acquired anti-glycoprotein IIb IIIa antibodies. Antibiotic therapy led to cure without sequellae of the endocarditis, the nephrotic syndrome and the thrombocytopaenia. This case illustrates the risk of immunological complications during acute staphylococcal tricuspid valve endocarditis and also illustrates the possibility of a favourable outcome with antibiotic therapy alone. However, the potential severity of these complications indicates the need for early diagnosis and strict surveillance of this condition.

[Non-invasive management of a serious acute pulmonary embolism]. / Gestion non invasive d'une embolie pulmonaire aiguë grave.

Prompt diagnosis of a large pulmonary embolus is essential in order to initiate appropriate treatment early. We report a case of a large pulmonary embolus in which management was aided solely by noninvasive investigations. Transthoracic echocardiogram showed elevated right heart pressures which together with the patient symptoms suggested a major pulmonary embolus. Spiral computed tomography of the chest confirmed the diagnosis. The source of the embolus was shown by echodoppler. This case illustrates that a diagnosis of a major pulmonary embolus can be made using noninvasive techniques. Pulmonary angiography should be reserved for those rare cases in which diagnostic uncertainty remains rather than being used as a routine examination prior to consideration of therapeutic decision.