Cardiac light chain amyloidosis (AL-CA) patients often die within three months of starting chemotherapy. Chemotherapy for non-immunoglobulin M gammopathy with AL-CA frequently includes bortezomib ...(Bor), cyclophosphamide (Cy), and dexamethasone (D). We previously reported that NT-ProBNP levels can double within 24h of dexamethasone administration, suggesting a deleterious impact on cardiac function. In this study, we evaluate the role of dexamethasone in early cardiovascular mortality during treatment.
We retrospectively assessed 100 de novo cardiac AL patients (62% male, mean age 68 years) treated at our institute between 2009 and 2018 following three chemotherapy regimens: CyBorDComb (all initiated on day 1; 34 patients), DCyBorSeq (D, day 1; Cy, day 8; Bor, day 15; 17 patients), and CyBorDSeq (Cy, day 1; Bor, day 8; D, day 15; 49 patients). The primary endpoint was cardiovascular mortality and cardiac transplantation at days 22 and 455. At day 22, mortality was 20.6% with CyBorDComb, 23.5% with DCyBorSeq, and 0% with CyBorDSeq (p = 0.003). At day 455, mortality was not significantly different between regimens (p = 0.195). Acute toxicity of dexamethasone was evaluated on myocardial function using a rat model of isolated perfused heart. Administration of dexamethasone induced a decrease in left ventricular myocardium contractility and relaxation (p<0.05), supporting a potential negative inotropic effect of dexamethasone in AL-CA patients with severe cardiac involvement.
Delaying dexamethasone during the first chemotherapy cycle reduces the number of early deaths without extending survival. It is clear that dexamethasone is beneficial in the long-term treatment of patients with AL-CA. However, the initial introduction of dexamethasone during treatment is critical, but may be associated with early cardiac deaths in severe CA. Thus, it is important to consider the dosage and timing of dexamethasone introduction on a patient-severity basis. The impact of dexamethasone in the treatment of AL-CA needs further investigation.
Purpose
Increased cardiac uptake (CU) on early-phase
99m
Tc-HMDP scintigraphy has demonstrated diagnostic and prognostic values in amyloid transthyretin (ATTR) cardiac amyloidosis (CA). Extracardiac ...uptake (ECU) has been poorly studied. We assessed the clinical value of ECU, in combination with CU, on
99m
Tc-HMDP scintigraphy using a novel Methodological Amyloidosis Diagnostic Index (MADI).
Methods
We reviewed all patients referred for suspicion of CA, who underwent
99m
Tc-HMDP scintigraphy over an 8-year period. ECU, CU, and MADI were determined: MADI0 = neither ECU or CU, MADI1 = ECU alone, MADI2 = CU alone, and MADI3 = ECU + CU.
Results
Of 308 eligible patients, 247 had CA, including 75 ATTRv, 107 ATTRwt, and 65 light-chain (AL), while 61 had another cardiopathy (controls). ECU was observed in 29% of CA and 3% of controls. Most frequent sites of ECU were pleuropulmonary (16% of CA, 3% of controls) followed by the digestive tract and subcutaneous tissues. The liver and spleen ECU was only observed in AL-CA (
n
= 8). CU was only observed in CA patients (
n
= 187), of whom 182 had ATTR-CA vs. 5 AL-CA,
P
< 0.001. MADI0 was only observed in controls (97%) and in AL-CA (60%). MADI1 was mainly observed in AL-CA (positive predictive value, PPV = 91%) while MADI2/3 were more frequent in ATTR-CA (PPV = 97%),
P
< 0.0001. MADI > 0 vs. MADI0 in AL and MADI3 vs. MADI2 in ATTR were associated with a worse prognosis (
P
= 0.03 and
P
= 0.002, respectively).
Conclusions
ECU combined with CU demonstrates high diagnostic and prognostic values in CA patients. MADI seems an easy and reliable score in clinical practice.
Aims
Atrial fibrillation (AF)/atrial flutter is common during cardiac amyloidosis (CA). Electrical cardioversion (EC) is a strategy to restore sinus rhythm (SR). However, left atrial thrombus (LAT) ...represents a contraindication for EC. CA patients with AF/atrial flutter have a high prevalence of LAT. We aimed to evaluate EC characteristics, LAT prevalence and risk factors, and AF/atrial flutter outcome in CA patients undergoing EC, predominantly treated with direct oral anticoagulants (DOACs).
Methods and results
All patients with CA and AF/atrial flutter referred for the first time to our national referral centre of amyloidosis for EC from June 2017 to February 2021 were included in this study. In total, 66 patients (median age 74.5 70;80.75 years, 67% male) were included with anticoagulation consisted of DOAC in 74% of cases. All patients underwent cardiac imaging before EC to rule out LAT. EC was cancelled due to LAT in 14% of cases. Complete thrombus resolution was observed in only 17% of cases. The two independent parameters associated with LAT were creatinine hazard ratio (HR) = 1.01; confidence interval (CI) = 1.00–1.03, P = 0.036 and the use of antiplatelet agents (HR = 13.47; CI = 1.85–98.02). EC acute success rate was 88%, and we observed no complication after EC. With 64% of patients under amiodarone, AF/atrial flutter recurrence rate following EC was 51% after a mean follow‐up of 30 ± 27 months.
Conclusions
Left atrial thrombus was observed in 14% of CA patients listed for EC and mainly treated with DOAC. The acute EC success rate was high with no complication. The long‐term EC success rate was acceptable (49%).
Aims
Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage.
Methods and results
This ...prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision‐making regarding therapy. Over the 12‐year study period, among the 233 patients included, 133 were NYHA III‐IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT‐proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut‐off values for Stage 1: hsTnT ≤ 107 ng/L and NT‐proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT‐proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT‐proBNP then CB 4 μmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 μmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI 2–24. At 1 year, 102 (44%) patients died and the Kaplan–Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI 11–18) and stage 3, 6.6 months (95% CI 1–13). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2.
Conclusions
The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.
Background: We assesse the evolution and prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (cTnT-HS) in transthyretin amyloid cardiomyopathy ...(ATTR-CA) before and after tafamidis treatment. Methods and Results: 454 ATTR-CA patients without tafamidis (Cohort A) and 248 ATTR-CA with tafamidis (Cohort B) were enrolled. Event-free survival (EFS) events were death, heart transplant, or acute heart failure. In Cohort A, 27% of patients maintained NT-proBNP < 3000 ng/L and 14% cTnT-HS < 50 ng/L at 12 months relative to baseline levels. In Cohort B, the proportions were 49% and 29%, respectively. In Cohort A, among the 333 patients without an increased NT-proBNP > 50% relative to baseline EFS was extended compared to the 121 patients with an increased NT-proBNP > 50% (HR: 0.75 0.57; 0.98; p = 0.032). In Cohort A, baseline NT-proBNP > 3000 ng/L and cTnT-HS > 50 ng/L and a relative increase of NT-proBNP > 50% during follow-up were independent prognostic factors of EFS. The slopes of logs NT-proBNP and cTnT-HS increased with time before and stabilized after tafamidis. Conclusion: ATTR-CA patients with increasing NT-proBNP had an increased risk of EFS. Tafamidis stabilize NT-proBNP and cTnT-HS increasing, even if initial NT-proBNP levels were >3000 ng/L. Thus suggesting that all patients, irrespective of baseline NT-proBNP levels, may benefit from tafamidis.
ATTRwt-CA occurs in elderly patients and leads to severe heart failure. The disease mechanism involves cardiac and extracardiac infiltration by amyloid fibrils. The objectives of this study are to ...describe the frailty phenotype in patients with ATTRwt-CA and to assess the associations between frailty parameters, the severity of cardiac involvement, and the course of amyloid disease. We used multidimensional geriatric tools to prospectively assess frailty in patients with ATTRwt-CA consulting (in 2018–2019) in the French National Reference Center for Cardiac Amyloidosis. We included 36 patients (35 males; median age: 82 years (76–86). A third of the patients were categorized as NYHA class III or IV, and 39% had an LVEF below 45%. The median serum NTproBNP was 3188 (1341–8883) pg/mL. The median duration of amyloidosis was 146 months (73–216). The frequency of frailty was 50% and 33% according to the physical frailty phenotype and the Short Emergency Geriatric Assessment questionnaire, respectively. Frailty affected a large number of domains, namely autonomy (69%), balance (58%), muscle weakness (74%), malnutrition (39%), dysexecutive syndrome (72%), and depression (49%). The severity of CA was significantly associated with many frailty parameters independently of age. Balance disorders and poor mobility were also significantly associated with a longer course of amyloid disease. Frailty is frequent in patients with ATTRwt-CA. Some frailty parameters were significantly associated with a longer course of amyloid disease and CA severity. Taking into account frailty in the assessment and management of ATTRwt should improve patients’ quality of life.
Aims
The prevalence of autonomic neuropathy (AN) is high in patients with hereditary transthyretin amyloidosis but remains unknown in transthyretin wild‐type cardiac amyloidosis (ATTRwt‐CA). This ...study aimed to determine the prevalence of AN in patients with ATTRwt‐CA using Sudoscan®, a non‐invasive method used to provide evidence of AN in clinical practice and based on measurement of electrochemical skin conductance at the hands and feet (fESC).
Methods and results
A series of 62 non‐diabetic patients with ATTRwt‐CA was prospectively included over 2 years and compared with healthy elderly subjects, matched by age, gender, and body mass index. The presence of AN was defined as electrochemical skin conductance at the hands <60 μS and/or fESC <70 μS, and conductances were analysed according to clinical, biological, and echocardiographic data. Mean fESC was significantly lower in patients with ATTRwt‐CA compared with elderly controls: 68.3 (64.1–72.5) vs. 76.9 (75.6–78.1) μS (P < 0.0001), respectively. Prevalence of fESC <70 μS was higher in ATTRwt‐CA patients than in controls: 48.4% vs. 19.9%, P < 0.05. Univariate analysis showed that fESC, N‐terminal pro‐B‐type natriuretic peptide, creatinine plasma levels, and echocardiographic global longitudinal strain were associated with decompensated cardiac failure and death. Multivariate analysis revealed that fESC was an independent prognostic factor, and Kaplan–Meier estimator evidenced a greater occurrence of cardiac decompensation and death in patients with fESC <70 μS, P = 0.046.
Conclusions
Reduced fESC was observed in almost 50% of patients with ATTRwt‐CA and was associated with a worse prognosis. Sudoscan® could easily be used to screen ATTRwt‐CA patients for the presence of AN and identify patients at higher risk for a poor outcome.
Aims: Multimodal imaging has allowed cardiac amyloidosis (CA) to be increasingly recognised as a treatable cause of heart failure with preserved ejection fraction, but its prognosis remains poor due ...to late diagnosis. To assess the left ventricular diastolic function (LVDF) patterns in a large contemporary CA cohort according to the current recommendations and to identify their determinants. Methods and Results: We conducted a monocentric, observational study on a cohort of CA patients from a tertiary CA referral centre. Diastolic function was analysed using standard echocardiography and clinical, laboratory and survival parameters were collected. Four hundred and sixty-four patients with one of the three main type of CA were included: 41% had grade III diastolic dysfunction (restrictive mitral pattern), 25% had grade II diastolic dysfunction, and 25% had grade I diastolic dysfunction; 9% were unclassified. No difference was found between the main CA types. After multivariate analyses, grades II and III were independently associated with dyspnoea, elevated NT-proBNP, cardiac infiltration and systolic dysfunction (global longitudinal strain). Grade I patients had a better prognosis. Conclusions: All LVDF patterns can be observed in CA. One quarter of CA patients have grade I LVDF, reflecting the emergence of earlier stage-related phenotypes with a better prognosis.
Aims
Cardiac amyloidosis (CA) has a poor prognosis which is aggravated by diagnostic delay. Amyloidosis extracardiac and cardiac events (AECE and ACE) may help improve CA diagnosis and typing. The ...aim of this study was to compare AECE and ACE between different CA types and assess their relationship with survival.
Methods and results
This retrospective cohort study conducted in France from June 2008 to May 2019, at the Henry Mondor Hospital. This cohort included 983 patients with CA. Mean age at inclusion was 73.1 ± 11.4 years, 726 (75.1%) were male and the mean body mass index was 24.5 ± 4.1 kg/m2. Among them, 321 had immunoglobulin light chain (AL) amyloidosis, 434 had wild‐type transthyretin (ATTRwt), and 212 had hereditary transthyretin (ATTRv). The first AECE and/or ACE occurred at a mean age of 63 ± 11 years for AL and ATTRv, and 70 ± 12 years for ATTRwt (P < 0.01). The median (Q1–Q3) delay between declaration of the first events and diagnosis varied from 11.1 (5.9; 34.8) months for AL to 92.2 (39.0; 174.7) months for ATTRwt (P < 0.01). The nature of the onset of AECE or ACE varied based on amyloidosis type, heart failure symptoms for AL (26%) and integumentary symptoms for ATTRv with cardiologic or mixed phenotype (39%) and ATTRwt (42%). In AL and ATTRwt, a short delay between the onset of the first AECE or ACE and diagnosis was associated with reduced survival rate (log‐rank test P‐value <0.01).
Conclusions
This study highlights the impact of amyloidosis type and evolution on diagnostic delay and on prognosis. Physicians must be aware and vigilant in front of extracardiac and cardiac events to considerably improve early diagnosis of amyloidosis.
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