Dimitrios Farmakis

Cardiac status in well-treated patients with thalassemia major.

Abstract:  Objective: To assess cardiac status in a large group of patients with thalassemia major who had been treated in a standard way since their early infancy with intensive transfusions and deferoxamine chelation therapy and who had good compliance with this regimen. Methods and Results: We assessed clinically and echocardiographically 202 thalassemia major patients aged 27.3 ± 6.3 yr and 75 age and sex‐matched healthy controls. Overt cardiac disease was encountered in 14 patients (6.9%), including 5 (2.5%) with congestive heart failure, aged 26–37 yr, and 9 with systolic left ventricular (LV) dysfunction, aged 23–37 yr. Ten patients (5.0%) had a history of pericarditis. Left atrial and LV diameters, LV mass and cardiac output were significantly higher in patients than in controls, while peripheral resistance and LV afterload were significantly lower. Relative LV wall thickness did not differ between patients and controls, but it was significantly lower in patients with overt cardiac disease compared to those without (P < 0.05). Restrictive LV filling was observed in 37.6% of patients and was significantly more frequent in cases with overt cardiac disease (P < 0.01). Pulmonary hypertension was practically absent. Hematological parameters and pulmonary artery pressure levels were not independently associated with the presence of overt cardiac disease. Conclusion: Strict lifelong adherence to the standard transfusion and deferoxamine therapy reduces considerably the occurrence of heart failure, LV dysfunction and pericarditis, prevents early heart failure and pulmonary hypertension, but does not eliminate completely cardiac disease in patients with thalassemia major.

Iron Overload Cardiomyopathy in Clinical Practice

The cardiomyopathies are heart muscle diseases of primary or secondary origin. Primary cardiomyopathies are often of unknown cause, hence their treatment is limited to general heart failure management. In secondary cardiomyopathies, in contrast, the identification of the underlying cause allows for a more specific, hence effective, approach that, when applied early, may prevent the development of heart failure. The term iron overload cardiomyopathy (IOC) recently has been introduced to describe a secondary form of cardiomyopathy resulting from the accumulation of iron in the myocardium mainly because of genetically determined disorders of iron metabolism or multiple transfusions.1,2 This condition, although previously overlooked, has lately attracted the attention of investigators because iron overload is, on one hand, a frequently encountered condition, especially in association with certain hematologic conditions, and on the other hand, its accurate identification and effective management have now become possible. IOC has been recently described as a dilated cardiomyopathy, characterized by left ventricular (LV) remodeling with chamber dilatation and reduced LV ejection fraction (LVEF).1 However, primary hemochromatosis, a genetically determined condition leading to iron overload, is classically categorized as an infiltrative cause of restrictive cardiomyopathy.3 Moreover, secondary hemochromatosis may lead to severe diastolic LV dysfunction in the early stages of the disease, before LVEF is affected.4,5 In the present review, we describe the forms, pathophysiology, and phenotypic expression of IOC, focusing on ventricular geometry and function and describing the early diastolic abnormalities that lead ultimately to heart muscle dysfunction and heart failure. The clinical implications of the condition are also discussed. Iron overload is the accumulation of excess body iron in different organs as a result of increased intestinal absorption, parenteral administration, or increased dietary intake.6 Besides being a crucial component of hemoglobin with a key role in erythropoiesis, oxygen …

Insights Into Onco-Cardiology: Atrial Fibrillation in Cancer

Atrial fibrillation (AF) has been found to occur with an increased frequency in patients with malignancies, particularly in those undergoing cancer surgery. The occurrence of AF in cancer may be related to comorbid states or a direct tumor effect or may represent a complication of cancer surgical or medical therapy, whereas inflammation may be a common denominator for both conditions. Treating AF in patients with malignancies is a challenge, especially in terms of antithrombotic therapy, because cancer may result in an increased risk of either thrombosis or hemorrhage and an unpredictable anticoagulation response, whereas thromboembolic risk prediction scores such as CHADS2 (Cardiac Failure, Hypertension, Age, Diabetes, and Stroke [doubled]) may not be applicable. The general lack of evidence imposes an individualized approach to the management of AF in those patients, although some general recommendations based on current guidelines in noncancer patients and the existing evidence in cancer patients, where available, may be outlined.

Pulmonary Hypertension in β‐Thalassemia

Abstract: Cardiac involvement represents the leading cause of mortality in both forms of β‐thalassemia, namely, thalassemia major (TM) and thalassemia intermedia (TI), and pulmonary hypertension (PHT) is part of the cardiopulmonary complications of the disease. PHT was initially documented in a small group of TI patients with right heart failure. In a subsequent study of a large 110‐patient series, aged 32.5 ± 11.4 years, age‐related PHT was encountered in nearly 60% of cases, having caused right heart failure in six of them; interestingly, all patients had preserved left ventricular systolic function. Conflicted evidence, however, existed with respect to the development of PHT in heterogeneously treated and young TM populations. To resolve this discrepancy, a recent study compared cardiac disease between two large aged‐matched groups of TM (n= 131) and TI (n= 74) patients, both treated uniformly in the currently accepted manner (regular transfusion and chelation therapy in TM, absence of any particular treatment in TI); well‐treated TM patients, in contrast to TI patients, did not develop PHT, while systolic left ventricular dysfunction was present only in TM cases. PHT in β‐thalassemia results from a rather complex pathophysiology, in which chronic tissue hypoxia seems to hold a key role. Although both forms of the disease share a common molecular background, the diverse severity of the genetic defect and of the resulting clinical phenotype require a different therapeutic approach. Regular lifelong therapy in TM patients eliminates chronic hypoxia, thereby preventing PHT, whereas the absence of systematic treatment in TI leads to a cascade of reactions that compensate for chronic anemia, but at the same time allow the development of PHT.

Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial

Aims Serelaxin is effective in relieving dyspnoea and improving multiple outcomes in acute heart failure (AHF). Many AHF patients have preserved ejection fraction (HFpEF). Given the lack of evidence-based therapies in this population, we evaluated the effects of serelaxin according to EF in RELAX-AHF trial. Methods and results RELAX-AHF randomized 1161 AHF patients to 48-h serelaxin (30 μg/kg/day) or placebo within 16 h from presentation. We compared the effects of serelaxin on efficacy endpoints, safety endpoints, and biomarkers of organ damage between preserved (≥50%) and reduced (<50%, HFrEF) EF. HFpEF was present in 26% of patients. Serelaxin induced a similar dyspnoea relief in HFpEF vs. HFrEF patients by visual analogue scale-area under the curve (VAS-AUC) through Day 5 [mean change, 461 (−195, 1117) vs. 397 (10, 783) mm h, P = 0.87], but had possibly different effects on the proportion of patients with moderately or markedly dyspnoea improvement by Likert scale at 6, 12, and 24 h [odds ratio for favourable response, 1.70 (0.98, 2.95) vs. 0.85 (0.62, 1.15), interaction P = 0.030]. No differences were encountered in the effect of serelaxin on short- or long-term outcome between HFpEF and HFrEF patients including cardiovascular death or hospitalization for heart/renal failure through Day 60, cardiovascular death through Day 180, and all-cause death through Day 180. Similar safety and changes in biomarkers (high-sensitivity troponin T, cystatin-C, and alanine/aspartate aminotransferases) were found in both groups. Conclusions In AHF patients with HFpEF compared with those with HFrEF, serelaxin was well tolerated and effective in relieving dyspnoea and had a similar effect on short- and long-term outcome, including survival improvement.

Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial

Therapy with i.v. iron in patients with chronic heart failure (CHF) and iron deficiency (ID) improves symptoms, functional capacity, and quality of life. We sought to investigate whether these beneficial outcomes are independent of anaemia.

Pulmonary Hypertension Associated With Hemoglobinopathies Prevalent But Overlooked

Hemoglobinopathies constitute a heterogeneous group of hereditary hemoglobin disorders characterized by either reduced (thalassemias) or defective (sickle cell disease) globin chain synthesis that results in chronic hemolytic anemia. They represent the most common monogenetic disorders in humans, and although traditionally confined to specific geographic areas and populations (the Mediterranean Basin and the Middle and Far East in the case of β-thalassemia; Sub-Saharan Africa and African-Americans in the case of sickle cell disease), they have currently expanded to a global distribution because of the immigration of those populations to the Western world.1 Although their clinical severity is variable, the hemoglobinopathies are generally demanding conditions, particularly in the homozygous state, characterized by reduced survival, multiorgan complications, frequent hospitalizations, and need for lifelong management, thus posing a significant medical and socioeconomic burden. Cardiovascular complications are among the leading causes of mortality and morbidity in hemoglobinopathies.1 In the wide spectrum of cardiovascular manifestations of these patients, pulmonary hypertension (PH) holds a prominent place. It has been postulated that hemoglobinopathies, along with HIV infection and schistosomiasis, may be the most common causes of PH worldwide given the high prevalence of PH in those populations.2 ### β-Thalassemia PH is a frequent finding in patients with hemoglobinopathies, but the reported prevalence varies in the different conditions and according to the method used for screening (Table 1). In thalassemia intermedia, a form of β-thalassemia that accounts for 20% to 25% of cases, PH has been recognized as the most striking cardiovascular finding and the main cause of heart failure. In a preliminary report, all 7 patients with thalassemia intermedia with heart failure had preserved systolic left ventricular (LV) function and severe PH as shown by right-sided heart catheterization.8 This initial report was followed by a systematic study of 110 patients with thalassemia intermedia with a mean …

Evaluation of left atrial longitudinal function in patients with hypertrophic cardiomyopathy: a tissue Doppler imaging and two-dimensional strain study

Objective: We sought to quantify left atrial longitudinal function by tissue Doppler (TDI) and two-dimensional (2D) strain in patients with hypertrophic cardiomyopathy (HCM). Design: Case-control study. Setting: Tertiary university hospital. Patients: 43 consecutive patients with familial HCM, aged 49 (SD 18) years, along with 21 patients with non-HCM left ventricular hypertrophy (LVH, aged 52 (12) years) and 27 healthy volunteers (aged 42 (13) years). Interventions: Subjects were studied by both TDI and 2D left atrial strain during all three atrial phases (reservoir, conduit, contractile), as well as by left ventricular systolic strain; total atrial deformation (TAD) was defined as the sum of maximum positive and maximum negative strain during a cardiac cycle. Main outcome measures: Left atrial longitudinal function. Results: Both TDI and 2D atrial strain and TAD were significantly reduced in HCM, compared to the other two groups in all atrial phases (p<0.001 in most cases); left ventricular systolic strain was also significantly reduced in HCM (p<0.001). Adding 2D contractile atrial strain to a model of conventional echo measurements (including left atrial diameter and volume index, interventricular septal thickness and E/A ratio and E/e′ ratios) increased its prognostic value in differentiating HCM from non-HCM LVH (p value of the change <0.001), while addition of TDI atrial strain or left ventricular strain did not. A cut-off for 2D contractile strain of −10.82% discriminated HCM from non-HCM LVH with a sensitivity of 82% and a specificity of 81%. Intra-observer and inter-observer variabilities for atrial strain in HCM were 16% and 17.5% for TDI and 8% and 9.5% for 2D, respectively. Processing time per case in HCM was 12.5 (2.6) minutes for TDI versus 3.8 (1.2) minutes for 2D strain (p<0.001). Conclusion: Left atrial longitudinal function is reduced in HCM compared to non-HCM LVH and healthy controls. In addition, 2D atrial strain has an additive value in differentiating HCM from non-HCM LVH and it is more reproducible and less time consuming than TDI strain.

Functional electrical stimulation improves endothelial function and reduces peripheral immune responses in patients with chronic heart failure

Background Previous studies have shown beneficial effects of functional electrical stimulation (FES) on muscle performance and exercise capacity of patients with chronic heart failure. This study evaluates the impact of FES on endothelial function and peripheral markers of immune activation in patients with moderate to severe heart failure. Methods Twenty-four patients with a left ventricular ejection fraction of less than 40% and New York Heart Association class II-III symptoms, undergoing optimized drug therapy, were randomly assigned (2:1) to a 6-week training programme of FES (n = 16) or served as controls (n = 8). Endothelial function was assessed by Doppler flow-mediated dilatation (FMD) of the brachial artery before and after the training programme. Peripheral pro-inflammatory/anti-inflammatory markers such as tumour necrosis factor (TNF)-α, interleukin (IL)-6, soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1 and IL-10 were also measured before and after training. Results A significant improvement on the 6-min walk test (7.5 ± L3.3%), Minnesota Living Score (18.2 ± 8.6%) and FMD (38.5 ± 15.1%) was observed only in the FES-treated group. FES also causes a significant reduction of TNF-α (−11.5 ± 8.9%), sICAM-1 (−13.1 ± 9.8%), and sVCAM-1 (−10.6 ± 6.6%), as well as a respective increase in the ratio IL-10/TNF-α (37.1 ± 29.4%). In the FES group, the percentage improvement in the Minnesota Living Score was significantly correlated with respective changes in circulating TNF-α (r = 0.624, P<0.01), sVCAM-1 (r = 0.665, P<0.001) and the ratio IL-10/TNF-α (r = −0.641, P<0.01). Conclusion FES is an exercise training programme that improves endothelial function in patients with chronic heart failure, and also has anti-inflammatory effects.

Pregnancy in patients with well-treated β-thalassemia: Outcome for mothers and newborn infants

OBJECTIVE Our purpose was to investigate the course and outcome of pregnancy in women with well-treated beta-thalassemia. STUDY DESIGN Twenty-two pregnancies, including one twin pregnancy, in 19 women were studied. Pregnancy was advised when patients had received a prolonged intensive treatment with hypertransfusions and iron chelation and had echocardiographically normal resting left ventricular performance. All conceptions were spontaneous. Cardiac function, along with hematologic, endocrinologic, and hepatic parameters were initially assessed and monitored throughout pregnancy and for 2 to 9 years post partum. Babies were delivered by elective cesarean section. RESULTS Twenty-one healthy newborn infants were delivered. A spontaneous abortion and a case of exomphalos also occurred. Gestation, delivery, and recovery were surprisingly uneventful, and no significant cardiac complications were encountered. CONCLUSION Pregnancy can be safe for mothers and babies, provided that women with thalassemia have been started early on intensive treatment and have a normal resting cardiac performance.