Iron therapy and severe arrhythmias in HFrEF: rationale, study design, and baseline results of the RESAFE-HF trial.

AIMS: The Iron Intravenous Therapy in Reducing the burden of Severe Arrhythmias in HFrEF (RESAFE-HF) registry study aims to provide real-word evidence on the impact of intravenous ferric carboxymaltose (FCM) on the arrhythmic burden of patients with heart failure with reduced ejection fraction (HFrEF), iron deficiency (ID), and implanted cardiac implantable electronic devices (CIEDs). METHODS AND RESULTS: The RESAFE-HF (NCT04974021) study was designed as a prospective, single-centre, and open-label registry study with baseline, 3, 6, and 12 month visits. Adult patients with HFrEF and CIEDs scheduled to receive IV FCM as treatment for ID as part of clinical practice were eligible to participate. The primary endpoint is the composite iron-related endpoint of haemoglobin ≥ 12 g/dL, ferritin ≥ 50 ng/L, and transferrin saturation > 20%. Secondary endpoints include unplanned HF-related hospitalizations, ventricular tachyarrhythmias detected by CIEDs and Holter monitors, echocardiographic markers, functional status (VO2 max and 6 min walk test), blood biomarkers, and quality of life. In total, 106 patients with a median age of 72 years (14.4) were included. The majority were male (84.9%), whereas 92.5% of patients were categorized to New York Heart Association II/III. Patients' arrhythmic burden prior to FCM administration was significant-19 patients (17.9%) received appropriate CIED therapy for termination of ventricular tachyarrhythmia in the preceding 12 months, and 75.5% of patients have frequent, repetitive multiform premature ventricular contractions. CONCLUSIONS: The RESAFE-HF trial is expected to provide evidence on the effect of treating ID with FCM in HFrEF based on real-world data. Special focus will be given on the arrhythmic burden post-FCM administration.

The impact of atrial mechanical function on age-dependent presentation of neurocardiogenic syncope.

BACKGROUND: The contribution of atrial and ventricular function in neurocardiogenic syncope (NCS) pathophysiology is elusive. HYPOTHESIS: We assessed the influence of echocardiographic properties to the age of presentation and NCS recurrences. METHODS: We assigned 124 patients with symptoms suggesting NCS, to those with syncope initiation at age <35 (group A, n = 56) and >35 years (group B, n = 68). Echocardiographic indices were measured before head-up tilt test (HUTT). RESULTS: A total of 55 had positive HUTT (44%) with a trend favoring group A (p = .08). Group A exhibited lower left atrial (LA) volume index (17 ± 6 vs. 22 ± 11 ml/m2 , p = .015), higher LA ejection fraction (69 ± 10 vs. 63 ± 11%, p = .008), LA peak strain (reservoir phase 41 ± 13 vs. 31 ± 14%, p = .001, contraction phase 27 ± 11 vs. 15 ± 10%, p < .001) and LA peak strain rate (reservoir phase 1.83 ± 1.04 vs. 1.36 ± 0.96 1/s, p = .012, conduit phase 2.36 ± 1.25 vs. 1.36 ± 0.78 1/s, p = .001). Group A showed smaller minimum right atrial (RA) volume, better RA systolic function, superior left ventricular diastolic indices, and lower filling pressures. Group A patients were more likely to have >3 recurrences (82.0% vs. 50.1%, p < .05). CONCLUSIONS: Patients with younger age of NCS onset and more syncopal recurrences manifest smaller LA and RA dimensions with distinct patterns of systolic and diastolic function and better LA reservoir and contraction properties. These findings may indicate an increased susceptibility to preload reduction, thereby triggering the NCS mechanism.

Free Cortisol Is a More Accurate Marker for Adrenal Function and Does Not Correlate with Renal Function in Cirrhosis.

BACKGROUND: The accuracy of diagnosis and clinical implications of the hepatoadrenal syndrome, as currently diagnosed using total cortisol, remain to be validated. AIM: The aim of this study was to assess adrenal function using free cortisol in stable cirrhosis and study the potential implications of any abnormalities for renal and/or cardiac function. METHODS: Sixty-one stable consecutively enrolled patients with cirrhosis underwent assessment of adrenal function using the low-dose short Synacthen test, renal function by 51Cr-EDTA glomerular filtration rate (GFR), and cardiac function by two-dimensional echocardiography. RESULTS: Eleven patients (18%) had total peak cortisol (PC) < 500 nmol/L, but no patient had free PC < 33 nmol/L indicating that diagnosis of AI using total cortisol is not confirmed using free cortisol. Free cortisol did not correlate with GFR or parameters of cardiac function. Patients with higher Child-Pugh class had progressively lower free cortisol. Patients with low GFR < 60 mL/min (N = 22) had more frequently grade II-III diastolic dysfunction (66.7% vs. 17.6%; p = 0.005) and had higher Child-Pugh and MELD score compared to those with normal GFR. CONCLUSIONS: Diagnosis of AI using total cortisol is not confirmed using free cortisol and is thus considered unreliable in cirrhosis. Free cortisol is not associated with renal or cardiac dysfunction. Lower free cortisol in more advanced stages of liver disease might be secondary to decreased synthesis due to lower cholesterol levels. Irrespective of free cortisol, parameters of cardiac dysfunction are associated with renal impairment supporting the cardio-renal hypothesis.

Relation of regional myocardial structure and function in hypertrophic cardiomyopathy and amyloidois: a combined two-dimensional speckle tracking and cardiovascular magnetic resonance analysis.

AIMS: We aimed at investigating the relationship between segmental morphology [wall thickness (WT) and WT location (LT: base-mid-apex)], loading conditions and underlying pathological substrate [histology (H), hypertrophy vs. infiltration] with segmental longitudinal (SLS) and circumferential (SCS) strain in a group of patients with hypertrophic cardiomyopathy (HCM) and cardiac amyloidosis (CA). METHODS AND RESULTS: We included 30 patients with biopsy-proven CA (65.4 ± 10.7 years, 66% male, 76.7% AL type) and 50 patients with HCM matched for maximum WT (60 ± 16 years, 80% male). SLS and SCS were assessed with speckle-tracking echocardiography in an 18-segment model of left ventricle, while morphological parameters were measured in short-axis cardiovascular magnetic resonance cine loops which corresponded with echo segments. In total, 1440 segments were evaluated of which 198 (36.7%) in CA and 252 (28%) in HCM had WT >12 mm (maximum WT 18.1 ± 3.7 mm in CA vs. 18.6 ± 4.1 in HCM, P = 0.59). SLS showed association with WT [beta 0.49, 95% confidence interval (CI) 0.37-0.6; P < 0.0005], LT and H (P < 0.0005 for both), with CA segments demonstrating 5.94% more impaired SLS compared with HCM segments with the same WT and LT. On the other hand, there was no linear association between SCS and WT, with SCS being dependent on LT, H (P < 0.0005) and preload (P < 0.002). CONCLUSION: Our study indicates that regional myocardial mechanics are differentially influenced by local morphological parameters. While SLS is dominated by WT, SCS is more determined by LT and H. These findings may have an important role in diagnosis and prognosis of patients with thickened hearts.

Left atrial deformation as a potent predictor for paroxysmal atrial fibrillation in patients with end-stage renal disease.

It is widely known that various factors contribute to left atrial (LA) mechanical dysfunction in patients with end stage renal disease (ESRD). However, the connection between atrial dysfunction and arrhythmic events such as paroxysmal atrial fibrillation (PAF), in this group of patients, remains unclear. The purpose of our study was to evaluate prospectively the association between LA deformation indices and PAF in ESRD patients. 79 patients (41 men, mean age 57 ± 17) with ESRD and preserved left ventricular systolic function comprised the study population. All patients underwent a baseline comprehensive echocardiography study and were followed for a mean period of 16 ± 5 months. PAF episodes, first and the following events, were reported. LA longitudinal strain reflecting LA reservoir function and LA longitudinal strain rate reflecting LA pump function were specifically evaluated as LA deformation indices of interest, using 2D speckle tracking echocardiography. At the end of follow up period nine patients died. 15 of the rest 70 reported one or more episodes of PAF. LA indexed volumes were significantly higher in patients with PAF (32 ± 26 vs. 21.5 ± 9 ml/m2, p = 0.002), mean LA strain was significantly reduced (17 ± 7 vs. 27 ± 9%, p < 0.001) as well as mean LA stain rate (- 1.19 ± 0.5 vs. - 1.95 ± 0.5 1/s, p < 0.001). Multivariate analysis showed that LA strain rate when adjusted with age together with PAF history remained the single most significant echocardiographic parameter for PAF prediction. Impaired LA strain and LA strain rate are associated with PAF in ESRD patients. LA strain rate might be a better independent predictor of PAF, compared to standard echocardiographic indices. Further prospective studies are needed to validate its relevance in routine clinical practice.

Echo Parameters for Differential Diagnosis in Cardiac Amyloidosis: A Head-to-Head Comparison of Deformation and Nondeformation Parameters.

BACKGROUND: A plethora of echo parameters has been suggested for distinguishing cardiac amyloidosis (CA) from other causes of myocardial thickening with, however, scarce data on their head-to-head comparison. This study aimed at comparing the diagnostic accuracy of various deformation and conventional echo parameters in differentiating CA from other hypertrophic substrates, especially in the gray zone of mild hypertrophy (maximum wall thickness ≤16 mm) or normal ejection fraction (EF). METHODS AND RESULTS: We included 100 subjects, of which 40 were patients with newly diagnosed, biopsy-proven CA (65.5±10.8 years, 65% male, 62.5% amyloidosis light chain [AL] type), 40 patients with hypertrophic cardiomyopathy matched for demographics and maximum wall thickness (60.1±14.8 years, 85% male), and 20 hypertensives with prominent myocardial remodeling. Quantifiable conventional morphological and functional parameters along with multidimensional strain and strain-derived ratios indices, previously suggested to diagnose CA, were analyzed. EF global longitudinal strain ratio showed the best performance to discriminate CA (area under the curve, 0.95; 95% confidence intervals, 0.89-0.98; P<0.00005). Traditional echo indices showed overall low sensitivities and high specificities (among them myocardial contraction fraction ratio had the highest area under the curve, 0.80; 95% confidence intervals, 0.7-0.87; P<0.0001). In the challenging subgroups (maximum wall thickness ≤16 mm and EF>55%), EF global longitudinal strain ratio remained the best predicting parameter of CA diagnosis (multiple logistic regression models P<0.00005 and P=0.0002, respectively) independent of the CA type. CONCLUSIONS: Our study demonstrated that in patients with thickened hearts, EF global longitudinal strain ratio has the best accuracy in detecting CA, even among the most "challenging" patient subgroups as those with mild hypertrophy and normal EF.

Diastolic dysfunction is associated with low urinary sodium excretion in patients with decompensated cirrhosis.

BACKGROUND/AIM: The pathogenesis and the clinical impact of diastolic dysfunction (DD) in cirrhosis remain unclear. Our aim was to investigate the factors significantly associated with the presence of DD in patients with decompensated cirrhosis on the waiting list for liver transplantation. MATERIAL AND METHODS: consecutive patients with decompensated cirrhosis, who admitted for transplant assessment, were prospectively evaluated. We assessed the independent factors associated with the presence of DD, while their discriminative ability was evaluated by AUC curve. The diagnosis of DD was based on Doppler echocardiography and classified into three categories according to the current guidelines. RESULTS: we evaluated 115 consecutive patients. Sixty six patients (57.3%-group 1) had DD and 49 (42.7%-group 2) had not DD. The 2 groups had similar Child-Pugh/MELD scores and survival. In multivariable logistic regression analysis, pulse rate (OR: 1.082, 95% CI: 1.03-1.15, p = 0.004), and UNa24h (OR: 0.98, 95% CI: 0.97- 0.99, p = 0.004) were the only variables independently associated with the presence of DD. In the subgroup of consecutive patients (n = 31) with evaluation of cytokines, those (n = 22) with DD, compared to those (n = 9) without DD, had significantly higher levels of inteleukin-6 [145 (45-2000) vs. 56 (10-149)pg/mL, p = 0.043]. CONCLUSIONS: We found that DD was independently associated with lower 24-hour urine sodium. Although no correlation was found between DD and severity of liver disease or survival, further studies are needed for final conclusions.

The impact of smoking on cardiovascular outcomes and comorbidities in statin-treated patients with coronary artery disease: a post hoc analysis of the GREACE study.

BACKGROUND: Smoking adversely affects cardiovascular disease (CVD) morbidity and mortality; however the effect of long-term statin treatment in high risk smokers is not entirely clear. The primary endpoint of this post hoc analysis of the GREek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study (n=1,600 patients with established coronary heart disease, mean follow-up 3-years) was the incidence of major CVD events, a composite of death, myocardial infarction, revascularization, unstable angina, heart failure, and stroke in statin-treated patients (n=880) who continued to smoke (n=129) compared with ex-smokers (n=309) and never smokers (n=442) as well as on patients not treated with a statin (n=720) of all smoking categories. Secondary endpoints were the effect of smoking on chronic kidney disease (CKD) and on non-alcoholic fatty liver disease (NAFLD), two major and common independent CVD risk factors. RESULTS: Among statin treated patients the hazard ratio (HR) for current smokers compared with never smokers was 1.86 [95% confidence interval-(CI) 1.19-2.10); similar was the HR for current smokers compared with ex-smokers. Absolute (16.3%) and relative (45.6%) CVD risk reduction was great in current smokers on statins compared with those not on a statin; however they still had the highest absolute CVD event incidence (19.4%). Low high density lipoprotein cholesterol and higher triglycerides may account, at least in part, for this. The highest risk of CVD events in any of the 6 groups was in the smokers not on a statin (35.7%). CKD and NAFLD were not negatively affected by smoking and they do not appear to be implicated in the adverse effect of smoking on CVD event rate in patients on a statin. CONCLUSIONS: Statins reduce CVD morbidity and mortality in current smokers with CVD, but these remain high in terms of absolute incidence compared with ex- and never smokers. CKD and NAFLD are not affected by smoking and do not seem to contribute to this high CVD event incidence. These make smoking cessation imperative in high risk patients even if they are on statins.

Aortic root replacement in case of isolated aortitis and previous coronary artery bypass.

The surgical management of aortic regurgitation in a patient with aortitis is potentially of high risk, especially if it is a reoperation. We present the case of a 59-year-old man for whom coronary artery bypass surgery was not feasible due to structural abnormalities of the aorta and hybrid management was applied. The histopathological examination showed aortitis. One year later, the same patient developed severe aortic regurgitation. In order to minimize the surgical risk of the reoperation we considered all the surgical options. The modified Bentall procedure still seems to be the gold standard in these cases.

Atypical atrial myxomas in two asymptomatic patients: a case report.

BACKGROUND: Atypical cardiac myxomas are a rare occurrence and may present with a variety of clinical manifestations depending on the morphology and location. CASE PRESENTATION: Two cases of cardiac myxomas atypically located in asymptomatic patients, diagnosed by transthoracic and transoesophageal echocardiography, are presented. In the first case a myxoma is located under the anterior mitral valve leaflet and in the second case a myxoma is located in the right atrium. CONCLUSION: We emphasize the leading role of transthoracic and transoesophageal echocardiography in the diagnosis of intracavitary cardiac tumours.

Cardiorenal anemia syndrome: do erythropoietin and iron therapy have a place in the treatment of heart failure?

The cardiorenal anemia syndrome in congestive heart failure (CHF) is an independent risk factor for vascular morbidity and mortality. Several factors play a role in the pathogenesis of anemia in CHF, including inflammation, impaired renal function, use of certain antihypertensive or cardioprotective agents, and gastrointestinal or urinary losses of essential hemopoietic factors. Several trials evaluated the effects of administering erythropoietin (EPO) and/or iron to patients with CHF. Even though most of them were uncontrolled studies, their results suggest that EPO treatment might be beneficial in CHF. Nevertheless, more studies are needed and certain issues should be resolved, particularly the optimal hemoglobin level, before EPO can become part of the treatment of patients with CHF.

Spironolactone versus eplerenone for the treatment of idiopathic hyperaldosteronism.

The aim of this prospective, randomised, open-label, blinded-end point study was to compare the efficacy and safety of eplerenone versus spironolactone in patients with bilateral idiopathic hyperaldosteronism (IHA). After a 2-week washout period, 34 patients with IHA were assigned to receive either spironolactone 25 mg b.i.d. (n = 17) or eplerenone 25 mg b.i.d. (n = 17) for 24 weeks. If the patients' blood pressure (BP) was not < 140/90 mmHg, the doses were gradually increased up to 400 mg for spironolactone and 200 mg for eplerenone. If the patients' BP remained uncontrolled, a daily dose of hydrochlorothiazide 12.5 mg was added at week 16. The primary outcome was the percentage of patients with BP < 140/90 mmHg at 16 weeks (i.e., with aldosterone antagonist monotherapy). The patients' BP was normalised in 13 out of 17 (76.5%) and 14 out of 17 (82.4%) patients in the spironolactone and eplerenone groups, respectively (p = 1.00). Systolic BP decreased more rapidly with eplerenone. Serum potassium levels were normalised (> 3.5 mmol/l) in all patients at 4 weeks. Mild hyperkalaemia was observed in two patients receiving 400 mg of spironolactone and in three patients receiving 150 mg of eplerenone. Two patients presented with bilateral painful gynaecomastia at the end of week 16 while receiving 400 mg of spironolactone. Switching spironolactone to 150 mg of eplerenone daily resulted in resolution of gynaecomastia and also maintained BP control. At the end of the study, 19 patients were on eplerenone and 15 were on spironolactone. However, this did not affect the primary end point, because the switch from spironolactone to eplerenone (in two patients) occurred at the end of week 16. It was concluded that eplerenone was as effective as spironolactone in reducing BP in patients with IHA. The risk of mild hyperkalaemia was similar with both drugs.

Do we need a statin-nicotinic acid-aspirin mini-polypill to treat combined hyperlipidaemia?

This review considers the treatment for combined hyperlipidaemia (CH) with a combination formulation of three drugs: a statin, nicotinic acid (NA) and aspirin--a mini-polypill. CH is a highly atherogenic dyslipidaemia manifested either as familial combined hyperlipidaemia or dyslipidaemia related to the metabolic syndrome or Type 2 diabetes mellitus. These types of dyslipidaemia are highly prevalent in the general population. Statin plus extended-release NA is a promising treatment option for the normalisation of these atherogenic lipid alterations, regression of atherosclerosis, as well as for primary or secondary prevention of cardiovascular disease (CVD) events. The addition of aspirin might prove a useful adjunct that might reduce the cutaneous side effects of NA while also acting as an antiplatelet agent in high-CVD-risk patients. However, the effective dose of aspirin may need to be at least 160 mg/day. This triple combination might improve patient compliance when compared with the three drugs administered separately.

Coronary calcification in patients with end-stage renal disease: a novel endocrine disorder?

Cardiovascular mortality is significantly increased among patients with end-stage renal disease. The commonly observed vascular calcification in such patients has been considered as one of the causative factors. In patients undergoing dialysis, the incidence of coronary artery calcification is 2-5 times higher compared to patients with normal renal function and angiographically demonstrated coronary artery disease. Moreover, epidemiological studies have revealed a significant correlation of the extent of coronary artery calcification with the severity of underlying atherosclerotic lesions. Vascular calcification was initially considered as a passive process of hydroxyapatite deposition due to elevated plasma concentrations of calcium and phosphate. Nevertheless, there is a growing body of evidence that vascular calcification is an actively regulated and cell-mediated process. This phenomenon includes phenotypic alterations of vascular smooth muscle cells mainly resulting from an imbalance between promoters (such as increased Ca x P product) and inhibitors (fetuin-A, GLA protein, osteoprotegerin) of mineral deposition. With regard to the therapeutic approach, despite the evident effectiveness of both traditional and innovative remedies in the management of metabolic and electrolytic abnormalities of patients with end-stage renal disease, an individualized intervention based on etiopathogenesis is really required.