Iron deficiency in myocardial ischaemia: molecular mechanisms and therapeutic perspectives.

Systemic iron deficiency (SID), even in the absence of anaemia, worsens the prognosis and increases mortality in heart failure (HF). Recent clinical-epidemiological studies, however, have shown that a myocardial iron deficiency (MID) is frequently present in cases of severe HF, even in the absence of SID and without anaemia. In addition, experimental studies have shown a poor correlation between the state of systemic and myocardial iron. MID in animal models leads to severe mitochondrial dysfunction, alterations of mitophagy, and mitochondrial biogenesis, with profound alterations in cardiac mechanics and the occurrence of a fatal cardiomyopathy, all effects prevented by intravenous administration of iron. This shifts the focus to the myocardial state of iron, in the absence of anaemia, as an important factor in prognostic worsening and mortality in HF. There is now epidemiological evidence that SID worsens prognosis and mortality also in patients with acute and chronic coronary heart disease and experimental evidence that MID aggravates acute myocardial ischaemia as well as post-ischaemic remodelling. Intravenous administration of ferric carboxymaltose (FCM) or ferric dextrane improves post-ischaemic adverse remodelling. We here review such evidence, propose that MID worsens ischaemia/reperfusion injury, and discuss possible molecular mechanisms, such as chronic hyperactivation of HIF1-α, exacerbation of cytosolic and mitochondrial calcium overload, amplified increase of mitochondrial [NADH]/[NAD+] ratio, and depletion of energy status and NAD+ content with inhibition of sirtuin 1-3 activity. Such evidence now portrays iron metabolism as a core factor not only in HF but also in myocardial ischaemia.

Influence of serum transferrin concentration on diagnostic criteria for iron deficiency in chronic heart failure.

AIMS: Transferrin saturation (TSAT), a marker of iron deficiency, reflects both serum concentrations of iron (SIC) and transferrin (STC). TSAT is susceptible to changes in each of these biomarkers. Little is known about determinants of STC and its influence on TSAT and mortality in patients with heart failure. Accordingly, we studied the relationship of STC to clinical characteristics, to markers of iron deficiency and inflammation and to mortality in chronic heart failure (CHF). METHODS AND RESULTS: Prospective cohort of patients with CHF attending a clinic serving a large local population. A total of 4422 patients were included (median age 75 (68-82) years; 40% women; 32% with left ventricular ejection fraction ≤40%). STC ≤ 2.3 g/L (lowest quartile) was associated with older age, lower SIC and haemoglobin and higher high-sensitivity C-reactive protein, ferritin and N-terminal pro-brain natriuretic peptide compared with those with STC > 2.3 g/L. In the lowest STC quartile, 624 (52%) patients had SIC ≤13 µmol/L, of whom 38% had TSAT ≥20%. For patients in the highest STC quartile, TSAT was <20% when SIC was >13 µmol/L in 185 (17%) patients. STC correlated inversely with ferritin (r = -0.52) and high-sensitivity C-reactive protein (r = -0.17) and directly with albumin (r = 0.29); all P < 0.001. In models adjusted for age, N-terminal pro-brain natriuretic peptide and haemoglobin, both higher SIC (hazard ratio 0.87 [95% CI: 0.81-0.95]) and STC (hazard ratio 0.82 [95% CI: 0.73-0.91]) were associated with lower mortality. SIC was more strongly associated with both anaemia and mortality than either STC or TSAT. CONCLUSIONS: Many patients with CHF and a low STC have low SIC even when TSAT is >20% and serum ferritin >100 µg/L; such patients have a high prevalence of anaemia and a poor prognosis and might have iron deficiency but are currently excluded from clinical trials of iron repletion.

Congestion and Use of Diuretics in Heart Failure and Cardiomyopathies: a Practical Guide.

PURPOSE OF REVIEW: Heart failure is a highly prevalent condition caused by many different aetiologies and characterised by cardiac dysfunction and congestion. Once developed, congestion leads to signs (peripheral oedema) and symptoms (breathlessness on exertion), adverse cardiac remodelling, and an increased risk of hospitalisation and premature death. This review summarises strategies that could enable early identification and a more objective management of congestion in patients with heart failure. RECENT FINDINGS: For patients with suspected or diagnosed heart failure, combining an echocardiogram with assessment of great veins, lungs, and kidneys by ultrasound might facilitate recognition and quantification of congestion, the management of which is still difficult and highly subjective. Congestion is a one of the key drivers of morbidity and mortality in patients with heart failure and is often under-recognised. The use of ultrasound allows for a timely, simultaneous identification of cardiac dysfunction and multiorgan congestion; ongoing and future studies will clarify how to tailor diuretic treatments in those with or at risk of heart failure.

Detecting the vulnerable carotid plaque: the Carotid Artery Multimodality imaging Prognostic study design.

BACKGROUND: Carotid artery disease is highly prevalent and a main cause of ischemic stroke and vascular dementia. There is a paucity of information on predictors of serious vascular events. Besides percentage diameter stenosis, international guidelines also recommend the evaluation of qualitative characteristics of carotid artery disease as a guide to treatment, but with no agreement on which qualitative features to assess. This inadequate knowledge leads to a poor ability to identify patients at risk, dispersion of medical resources, and unproven use of expensive and resource-consuming techniques, such as magnetic resonance imaging, positron emission tomography, and computed tomography. OBJECTIVES: The Carotid Artery Multimodality imaging Prognostic (CAMP) study will: prospectively determine the best predictors of silent and overt ischemic stroke and vascular dementia in patients with asymptomatic subcritical carotid artery disease by identifying the noninvasive diagnostic features of the 'vulnerable carotid plaque'; assess whether 'smart' use of low-cost diagnostic methods such as ultrasound-based evaluations may yield at least the same level of prospective information as more expensive techniques. STUDY DESIGN: We will compare the prognostic/predictive value of all proposed techniques with regard to silent or clinically manifest ischemic stroke and vascular dementia. The study will include ≥300 patients with asymptomatic, unilateral, intermediate degree (40-60% diameter) common or internal carotid artery stenosis detected at carotid ultrasound, with a 2-year follow-up. The study design has been registered on Clinicaltrial.gov on December 17, 2020 (ID number NCT04679727).

Criteria for Iron Deficiency in Patients With Heart Failure.

BACKGROUND: Guidelines on heart failure (HF) define iron deficiency (ID) as a serum ferritin <100 ng/mL or, when 100-299 ng/mL, a transferrin saturation (TSAT) <20%. Inflammation (common in HF) may hinder interpretation of serum ferritin. OBJECTIVES: This study sought to investigate how different definitions of ID affect its prevalence and relationship to prognosis in ambulatory patients with chronic HF. METHODS: Prevalence, relationship with patients' characteristics, and outcomes of various ID definitions were evaluated among patients with HF referred to a regional clinic (Hull LifeLab) from 2001 to 2019. RESULTS: Of 4,422 patients with HF (median age 75 years [range: 68-82 years], 60% men, 32% with reduced left ventricular ejection fraction), 46% had TSAT <20%, 48% had serum iron ≤13 µmol/L, 57% had serum ferritin <100 ng/mL, and 68% fulfilled current guideline criteria for ID, of whom 35% had a TSAT >20%. Irrespective of definition, ID was more common in women and those with more severe symptoms, anemia, or preserved ejection fraction. TSAT <20% and serum iron ≤13 µmol/L, but not guideline criteria, were associated with higher 5-year mortality (HR: 1.27; 95% CI: 1.14-1.43; P < 0.001; and HR: 1.37; 95% CI: 1.22-1.54; P < 0.001, respectively). Serum ferritin <100 ng/mL tended to be associated with lower mortality (HR: 0.91; 95% CI: 0.81-1.01; P = 0.09). CONCLUSIONS: Different definitions of ID provide discordant results for prevalence and prognosis. Definitions lacking specificity may attenuate the benefits of intravenous iron observed in trials while definitions lacking sensitivity may exclude patients who should receive intravenous iron. Prespecified subgroup analyses of ongoing randomized trials should address this issue.

Natural history and prognostic significance of iron deficiency and anaemia in ambulatory patients with chronic heart failure.

AIMS: Iron deficiency (ID) and anaemia are common in heart failure; less is known about changes over time. METHODS AND RESULTS: We investigated prevalence, incidence and resolution of ID and anaemia in 906 patients with chronic heart failure (median age 73 (65-79) years, 70% men, 51% with heart failure with reduced ejection fraction) 1 year apart. ID was defined as serum iron ≤13 µmol/L and anaemia as haemoglobin <13.0 g/dL for men or <12.0 g/dL for women. FAIR-HF criteria for ID were also considered. At baseline, 10% had anaemia without ID, 23% had ID without anaemia, 20% had both, and 47% had neither. Percentages changed little over 1 year, but 157 (30%) patients had new-onset ID, 104 (16%) new-onset anaemia, whilst ID resolved in 173 (44%) and anaemia in 63 (23%). Compared to those who remained iron replete (iron >13 µmol/L), mortality was higher in those with persistent or incident ID at 1 year [hazard ratio (HR) 1.81 (1.23-2.67), and HR 1.40 (0.91-2.14), respectively] in multivariable models (P = 0.02). Compared to persistent ID, resolution of ID was associated with a lower mortality [HR 0.61 (0.44-0.86); P = 0.004]. Changes in ID defined by FAIR-HF criteria were not similarly associated with mortality. Anaemia was associated with a poor outcome even if it resolved. CONCLUSIONS: The prevalence and incidence of ID and anaemia are high in chronic heart failure but so is the rate of resolution. Persistent or incident ID, defined by a serum iron ≤13 µmol/L, is associated with higher mortality and resolution of ID with lower mortality.

Rate of venous thromboembolism and atrial fibrillation in a real-world case series of advanced cancer patients: the CaTEV Study.

BACKGROUND: Venous thromboembolism is the second leading cause of death in cancer patients and its incidence seems underestimated. In addition, cancer patients have an increased risk of developing atrial fibrillation, which may be the first presentation of cancer itself. The primary aim of this study was to define the incidence of venous thromboembolism (VTE) and atrial fibrillation in a real-word series of advanced cancer patients. METHODS: We performed a retrospective single-institution study on patients diagnosed with stage IV solid neoplasia at the outpatient clinic of the Medical Oncology Unit (Spedali Civili Brescia, Italy), from January to December 2018. RESULTS: A total of 403 patients were enrolled, with a mean age at presentation of 63 years (range 18-85 years). A VTE was observed in 24% of cases, half of which occurred after diagnosis of metastatic neoplasia, with a median time of onset of 5.5 months (range 0-84). About 3% of patients developed atrial fibrillation after cancer diagnosis. In this patient series, no statistically significant differences were found when comparing Khorana and PROTECHT thromboembolic risk scores, both before and after the start of chemotherapy. Overall, about 25% of the patients received anticoagulant therapy; in most cases, the drug of choice was low-molecular-weight heparin (LMWH). CONCLUSION: This study showed for cancer patients a considerably higher incidence of VTE and a comparable incidence of atrial fibrillation than reported in literature. Validated thromboembolic risk scores appear to be poorly predictive, and LMWH remains the most widely used anticoagulant drug.

T wave abnormalities identify patients with previous lateral wall myocardial infarction and circumflex artery disease.

BACKGROUND: The diagnosis of previous lateral myocardial infarction is based on QRS morphology. OBJECTIVES: To explore the diagnostic role of T wave abnormalities. METHODS: We studied 166 patients with known or suspected ischemic heart disease who underwent a 12-lead electrocardiogram, myocardial perfusion scintigraphy, and coronary arteriography within 90days. We excluded patients with bundle-branch block, hypertrophy, or paced rhythm. RESULTS: Only one patient had a prominent R wave in V1, no patient showed lateral Q waves of necrosis. T wave amplitude in V2-V6 ≥0.6mV, and T wave amplitude in lead 1+V6 ≤0mV detected a lateral infarction (sensitivity 33 and 44%, specificity 83 and 80%). T wave amplitude in lead 1+V6 ≤0mV was the only independent predictor of infarction or LCx occlusion (AUC 0.72 and 0.74). Serum potassium values were not associated with T wave abnormalities. CONCLUSION: T wave abnormalities identify previous lateral infarction and LCx disease.