Transthyretin Amyloidosis Cardiomyopathy in Greece: Clinical Insights from the National Referral Center.

BACKGROUND: Clinical characteristics and outcomes of patients with transthyretin amyloidosis cardiomyopathy (ATTR-CM) vary by region, necessitating the acquisition of country-specific evidence for proper management. METHODS: This is an observational study including sequential patients presenting in the Amyloidosis Reference Center of Greece, from 01/2014 to 12/2022. ATTR-CM was diagnosed by positive scintigraphy and exclusion of light-chain amyloidosis or positive biopsy typing. Genetic testing was performed in all cases. RESULTS: One-hundred and nine ATTR-CM patients were included (median age, 81 years) of which 15 carried TTR mutations (27% Val30Met). Most patients (82%) presented with heart failure and 59% with atrial fibrillation, while 10% had aortic stenosis. Importantly, 78 (71.6%) had clinically significant extracardiac manifestations (45% musculoskeletal disorder, 40% peripheral neuropathy and 33% gastrointestinal symptoms). Sixty-five (60%) received disease-specific treatment with tafamidis. Estimated median survival was 48 months; advanced NYHA class, National Amyloidosis Center stage, eGFR<45 ml/kg/1.73m2, NT-pro-BNP>5000 pg/mL were associated with worse survival, while tafamidis treatment was associated with improved survival in patients with IVS≥ 12 mm. DISCUSSION: These are the first data describing the characteristics, management, and outcomes of patients with ATTR-CM in Greece, which could influence local guidelines. SHORT TITLE: Transthyretin cardiomyopathy in Greece.

Arrhythmias in Patients with Cardiac Amyloidosis: A Comprehensive Review on Clinical Management and Devices.

Cardiac amyloidosis (CA) is a rare but potentially life-threatening disease in which misfolded proteins accumulate in the cardiac wall tissue. Heart rhythm disorders in CA, including supraventricular arrhythmias, conduction system disturbances, or ventricular arrhythmias, play a major role in CA morbidity and mortality, and thus require supplementary management. Among them, AF is the most frequent arrhythmia during CA hospitalizations and is associated with significantly higher mortality, while ventricular arrhythmias are also common and are usually associated with poor prognosis. Early diagnosis of potential arrythmias could be performed through ECG, Holter monitoring, and/or electrophysiology study. Clinical management of these patients is quite significant, and it usually includes initiation of amiodarone and/or digoxin in patients with AF, potential electrical cardioversion, or ablation in specific patients with indication, as well as initiation of anticoagulants in all patients, independent of AF and CHADS-VASc score, for potential intracardiac thrombus. Moreover, identification of patients with conduction disorders that could benefit from prophylactic pacemaker implantation and/or CRT as well as identification of patients with life-threatening ventricular arrythmias that could benefit from ICD could both increase the survival rates of these patients and improve their quality of life.

Outcomes for patients with systemic light chain amyloidosis and Mayo stage 3B disease.

Patients with cardiac light chain amyloidosis and Mayo stage 3b disease define a high-risk population with very poor prognosis. Here, we report treatment outcomes of 80 consecutive patients with newly diagnosed AL and Mayo 3b who received novel regimens. Early mortality (<1 month) rate was 12.5%. On intention-to-treat, overall hematologic response rate was 40%, with complete response (CR)/very good partial response (VGPR) in 25% and partial response (PR) in 15%. At 1- and 3- month landmark analysis CR or VGPR/PR rates were 25%/23.5% and 34%/25.5%, respectively. Among patients that were treated with daratumumab-based therapies, 52.6% and 85.7% achieved at least VGPR within one 1 and 3 months, respectively. Three-month cardiac response rate was 11.3% and 6-month was 18.8%. At least hemVGPR at 3 months was associated with cardiac response at 6 months (p = 0.034). Median overall survival (OS) was 6.3 months. At 1-month landmark at least hemPR was associated with better median OS (24.1 vs. 4.9 months, p = 0.017) and at 3-month landmark, at least hemVGPR was associated with a median OS of 40.7 versus 17 months for hemPR and 7.4 months for those without hematologic response (p = 0.028). Cardiac response at 3 months was associated with longer median OS (59.7 vs. 10.9 months, p = 0.044). Factors associated with poorer survival were κ-light chain amyloidosis (median OS 2.9 vs. 7.4 months, p = 0.028), peripheral nerve involvement (3.4 vs. 10.45 months, p = 0.024), systolic blood pressure <90 mmHg (2 vs. 8 months, p = 0.002), baseline LVEF <55% (median OS 3.4 vs. 32 months, p = 0.29) and New York Heart Association (NYHA) class (2.7 months for NYHA 3B-4 vs. 8 months for NYHA 2-3A, p = 0.02). Twenty-one patients (26.3%) received salvage therapy and ORR was 57.1%. Median OS for patients who received second line therapy was 24 months. In conclusion, patients with Mayo 3b disease benefit from early hematologic response but cardiac response rates remain low.

Late T-wave inversion following resolution of non-ischemic acute pulmonary edema.

Electrocardiographic (ECG) changes occurring several hours after the onset of acute cardiogenic pulmonary edema have been seldom described. The proposed explanatory mechanisms are various and not fairly established. In the absence of significant coronary artery disease, these ECG abnormalities could be attributed to mechanisms implicated in coronary microcirculatory dysfunction.

Cardio-oncology: A Focus on Cardiotoxicity.

Cardio-oncology is a recently developed field in cardiology aimed at significantly reducing cardiovascular morbidity and mortality and improving quality of life in cancer survivors. Cancer survival rates have been constantly increasing, mainly because of the advent of new, more potent and targeted therapies. However, many of the new therapies - along with some of the older chemotherapeutic regimens such as anthracyclines - are potentially cardiotoxic, which is reflected increasingly frequently in the published literature. Cardiotoxicity adversely affects prognosis in cancer patients, thus its prevention and treatment are crucial to improve quality and standards of care. This review aims to explore the existing literature relating to chemotherapy- and radiotherapy-induced cardiotoxicity. An overview of the imaging modalities for the identification of cardiotoxicity and therapies for its prevention and management is also provided.

Repetitive-incessant electrical storm triggered by early repolarization.

Early repolarization syndrome (ERS) was originally considered a normal variant with benign outcome. However, recent studies have demonstrated that it can be linked to a considerable risk of life-threatening arrhythmias and sudden cardiac death. We report a case with an extraordinary, extremely malignant clinical expression of ERS refractory to all antiarrhythmic drugs including quinidine. This case demonstrates real-time changes of dynamic electrocardiogram (ECG) preceding a polymorphic ventricular tachycardia (VT)-ventricular fibrillation (VF) and possible external factors triggering arrhythmia onset. Implantable cardioverter-defibrillator (ICD) function was terminated 6 months after implantation due to multiple-incessant electrical storm (ES). Catheter ablation was the definite treatment of this malignant entity.

Arteriovenous renal replacement therapy in end-stage left-sided heart failure patients has a detrimental effect on patients with impaired right ventricular function.

OBJECTIVE: Chronic intermittent renal replacement therapy(RRT) is an alternate method of decongestion for patients presenting with diuretic-resistant, end-stage heart failure(HF) and cardiorenal syndrome. The optimal method of vascular access has not been confirmed. This study investigated the 6-month outcomes of patients with end-stage HF after the creation of arteriovenous communications (AVC) compared with other means of RRT. METHODS: We treated 40 patients with chronic, intermittent, ambulatory RRT, of whom 15 (37.5%; Group A) underwent creation of AVC, and 25 (62.5%; Group B) received intraperitoneal (n=6) or internal jugular catheters (n=19) with the goal of achieving body weight stabilization and relief from congestion. RESULTS: The characteristics of the two groups were similar. According to Cox regression analysis, the 6-month rate of death or re-hospitalization for HF was significantly higher in Group A (73%) than in Group B (44%); hazard ratio (HR): 2.58; 95% confidence interval (CI) 1.2-6.2; P=0.02. Over a 6-month follow-up, the cumulative survival was significantly shorter (P=0.03) in Group A (13.8±10 weeks) than in Group B (20.7±7 weeks). In the 15 patients who received AVC, the only independent predictor of adverse outcome at 6 months was serum total bilirubin concentration (HR 2.5; 95% CI 1.1-5.7, p=0.02), whereas in the 25 patients who underwent other means of RRT, pulmonary vascular resistance (PVR) was identified as a risk factor for hospitalization or death at 1-year follow-up (HR 1.26; 95% CI 1.1-1.57, p=0.04). CONCLUSION: In patients with end-stage HF, the creation of AVC for intermittent RRT was followed by a significant increase in morbidity and mortality in comparison to the safe and effective placement of permanent central venous catheters. Patients with elevated PVR seem to comprise a group at high risk for adverse outcomes after central catheter insertion.

Fluoxetine vs. placebo for the treatment of recurrent vasovagal syncope with anxiety sensitivity.

AIMS: The optimal medical therapy of patients with vasovagal syncope (VVS) remains controversial. Fluoxetine is effective against anxiety and panic disorders, while its use has shown promising results for VVS. Anxiety sensitivity is a personality trait observed in a considerable proportion of patients with VVS, associated with predisposition to anxiety and panic disorders. Our aim was to examine whether fluoxetine exerts beneficial effects regarding VVS prevention in the subset of patients with anxiety sensitivity. METHODS AND RESULTS: We assessed 106 patients with typical history of recurrent VVS, without other comorbidities, and a diagnostic, positive head-up tilt test. A psychiatric examination ruled out clinical psychiatric disease. Their psychological, stress-related profile was assessed by the Anxiety Sensitivity Index (ASI) questionnaire, a 16-item questionnaire, assessing fear of anxiety-related sensations, previously studied in VVS. Patients scoring positive for ASI (n = 60, 57% of the population) were randomized in a 2:1 fashion to receive either 10-40 mg fluoxetine daily (n = 40) or placebo (n = 20), and were followed-up for 1 year. A significant difference was observed between patients receiving fluoxetine and those with placebo, regarding the distribution of syncope-free time during the study (P < 0.05). A significant difference was also observed between the two groups regarding presyncopal events and the total number of patients who experienced syncope or presyncope during follow-up. CONCLUSION: Sensitivity to anxiety is a common personality trait in recurrent VVS. Fluoxetine is superior to placebo against syncope in these patients. This drug may be a first-line pharmacological treatment for this difficult-to-treat group.

Late-onset right ventricular dysfunction after mechanical support by a continuous-flow left ventricular assist device.

BACKGROUND: Right heart failure (RHF) is a serious post-operative complication of left ventricular assist device (LVAD) implantation, with significant morbidity and mortality. Many clinical, hemodynamic and laboratory variables have been shown to have prognostic value for appearance of RHF. We sought to investigate the incidence of new-onset right ventricular dysfunction (RVD) complicating the long-term use of LVADs. METHODS: We retrospectively examined all patients supported with a continuous-flow LVAD for >1 year at our center. RESULTS: Twenty patients (mean age 54 ± 10 years, 95% men, 60% with ischemic cardiomyopathy, left ventricular ejection fraction 22 ± 6%, pulmonary capillary wedge pressure 23.5 ± 7.5 mm Hg, brain natriuretic peptide [BNP] 1,566 ± 1,536 pg/ml, serum creatinine 1.6 ± 0.64 mg/dl, furosemide dose 643 ± 410 mg/day) underwent long-term mechanical support as destination therapy support with a continuous-flow LVAD (HeartMate II) at our center. During follow-up (1,219 ± 692 days), 9 patients (45%) manifested symptoms and signs of RVD (increase in right atrial pressure [RAP], BNP and daily furosemide dose compared with the early post-operative period). In these patients, RAP was increased by 6.6 ± 2.6 mm Hg and BNP by 526 ± 477 pg/ml, whereas furosemide dose increased by 145 ± 119 mg. The mean and median times of RVD onset were 2.3 ± 1.5 and 2.1 years, respectively, after LVAD implantation (range 0.4 to 4.8 years). Four of these patients (44.4%) demonstrated further deterioration of RV function and died 73 ± 106 days (median 25 days, range 9 to 231 days) after first manifestation of RVD. Comparisons of baseline variables regarding medical history and clinical status did not demonstrate significant differences between the patients with or without RVD, including parameters related to RV function at the time of implantation. CONCLUSIONS: Late-onset RVD is a complication of LVAD support, which can manifest several months to years from device implantation. This complication has significant adverse implications with regard to patient outcome. Prognostic factors need to be identified to follow and treat high-risk patients more efficiently.

Prolonged intra-aortic balloon pump support in biventricular heart failure induces right ventricular reverse remodeling.

BACKGROUND: Right ventricular dysfunction is associated with high morbidity and mortality in candidates for left ventricular assist device (LVAD) implantation or cardiac transplantation. METHODS: We examined the effects of prolonged intra-aortic balloon pump (IABP) support on right ventricular, renal and hepatic functions in patients presenting with end-stage heart failure. RESULTS: Between March 2008 and June 2013, fifteen patients (mean age = 49.5 years; 14 men) with end-stage systolic heart failure (HF), contraindications for any life saving procedure (conventional cardiac surgery, heart transplantation, LVAD implantation) and right ventricular dysfunction were supported with the IABP. The patients remained on IABP support for a mean of 73 ± 50 days (median 72, range of 13-155). We measured the echocardiographic and hemodynamic changes in right ventricular function, and the changes in serum creatinine and bilirubin concentrations before and during IABP support. Mean right atrial pressure decreased from 12.7 ± 6.5 to 3.8 ± 3.3 (P < 0.001) and pulmonary artery pressure decreased from 35.7 ± 10.6 to 25 ± 8.4 mmHg (P = 0.001), while cardiac index increased from 1.5 ± 0.4 to 2.2 ± 0.7 l/m(2)/min (P = 0.003) and right ventricular stroke work index from 485 ± 228 to 688 ± 237 mmHg × ml/m(2) (P = 0.043). Right ventricular end-diastolic diameter decreased from 34.0 ± 6.5 mm to 27.8 ± 6.2 mm (P < 0.001) and tricuspid annular systolic tissue Doppler velocity increased from 9.6 ± 2.4 cm/s to 11.1 ± 2.3 cm/s (P = 0.029). Serum creatinine and bilirubin decreased from 2.1 ± 1.3 to 1.4 ± 0.6 mg/dl and 2.0 ± 1.0 to 0.9 ± 0.5 mg/dl, respectively (P = 0.002 and P < 0.001, respectively). CONCLUSIONS: Prolonged IABP support of patients presenting with end-stage heart failure and right ventricular dysfunction induced significant improvement in right ventricular and peripheral organ function.

High furosemide dose has detrimental effects on survival of patients with stable heart failure.

INTRODUCTION: High doses of furosemide for heart failure (HF) have been correlated with an increased mortality, though whether they are a marker of disease severity or an independent predictor is unknown. We hypothesized that, in patients presenting with stable HF, the likelihood of long-term major adverse clinical events is increased by higher furosemide doses. METHODS: We retrospectively recorded the doses of furosemide prescribed to 173 consecutive, clinically stable patients during a first ambulatory HF department visit. The low-dose group included 103 patients treated with 80 mg and the high-dose group included 70 patients treated with >80 mg of furosemide daily. Proportional hazard regression analyses were performed with single and multiple variables in search of correlates of long-term adverse clinical events. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. RESULTS: The baseline characteristics of the 2 groups were similar, except for estimated glomerular filtration rate, which was higher in the low- than the high-dose group (72.9 ± 19.4 vs. 60.8 ± 22.0 mL/min/ m2, p<0.001). The 3-year survival free from the composite endpoint was significantly higher in the lowdose group than in the high-dose group (93.1% vs. 60.0%, p<0.001). By multiple variable analysis, highdose furosemide was an independent predictor of an adverse outcome at 3 years (adjusted HR: 15.25; 95% CI:1.06-219.39, p=0.045). The incidence of deterioration of renal function and episodes of hypokalemia during follow up was also higher in the high furosemide dose (73.2% vs. 48.3, p=0.003, and 43.1% vs. 6.5%, p<0.001, respectively). CONCLUSIONS: High doses of furosemide administered in order to stabilize HF patients and continued thereafter are associated with an adverse clinical outcome.

Counterpulsation: a concept with a remarkable past, an established present and a challenging future.

The intra-aortic balloon pump (IABP), which is the main representative of the counterpulsation technique, has been an invaluable tool in cardiologists' and cardiac surgeons' armamentarium for approximately half a century. The IABP confers a wide variety of vaguely understood effects on cardiac physiology and mechano-energetics. Although, the recommendations for its use are multiple, most are not substantially evidence-based. Indicatively, the results of recently performed prospective studies have put IABP's utility in the setting of post-infarction cardiogenic shock into question. However, the particular issue remains open to further research. IABP support in high-risk patients undergoing PCI is associated with favorable long-term clinical outcome. In cardiac surgery, the use of IABP in cases of peri-operative low-output syndrome, refractory angina or ischemia-related mechanical complications is a usual, but poorly justified strategy. Anecdotal cases of treatment of incessant ventricular arrhythmias, reversal of right ventricular dysfunction and partial myocardial recovery have also been reported with its use. Converging data demonstrate the potential of safe long-term IABP support as a bridge to decision making or a bridge to transplantation modality in patients with heart failure. The feasibility of IABP insertion via other than the femoral artery sites enhances this potential. Despite the fact that several other counterpulsation devices have been developed and tested overtime none has managed to substitute the IABP, which continues to be most frequently used mechanical assist device.

Respiratory drive and breathing pattern abnormalities are related to exercise intolerance in chronic heart failure patients.

BACKGROUND: Patients with chronic heart failure (CHF) are characterized by exercise intolerance and ventilatory abnormalities that are related to poor prognosis. We hypothesized that CHF patients have increased respiratory drive and abnormal breathing pattern during exercise in relation to disease severity. MATERIALS AND METHODS: The study population consisted of 219 stable CHF patients and 30 healthy control subjects. All subjects underwent a symptom-limited cardiopulmonary exercise testing (CPET), pulmonary function tests, measurement of the maximal inspiratory pressure (PImax) and respiratory drive (P0.1). Measurements included peak oxygen uptake ( [Formula: see text] peak, ml/kg/min). Respiratory drive was measured by mouth occlusion pressure P0.1 and P0.1/PImax ratio at rest, and by mean inspiratory flow (VT/TI) at rest and during exercise. CHF patients were divided into 3 groups according to [Formula: see text] peak (Group A: >20, Group B: 20-16 and Group C: <16ml/kg/min). RESULTS: CHF patients presented higher P0.1/PImax (4.1±3.6 vs 3.0±1.5, p=0.007) and VT/TI at rest (0.48±0.14 vs 0.41±0.10, L/s respectively, p=0.004) and lower VT/TI at peak exercise (2.17±0.66 vs 2.56±0.73, L/s, p=0.009) compared to controls. P0.1/PImax was higher in CHF Group C vs B vs A (4.9±2.9 vs 3.6±1.8 vs 3.1±1.8, respectively, p<0.001), while VT/TI at peak exercise was lower (1.71±0.43 vs 2.15±0.52 vs 2.65±0.64, L/s, respectively, p<0.001). CONCLUSIONS: CHF patients present increased respiratory drive at rest and abnormal breathing pattern during exercise in relation to CHF severity.