Transthyretin amyloid polyneuropathy in France: A cross-sectional study with 413 patients and real-world tafamidis meglumine use (2009-2019).

OBJECTIVE: We aimed to describe characteristics of patients with ATTR variant polyneuropathy (ATTRv-PN) and ATTRv-mixed and assess the real-world use and safety profile of tafamidis meglumine 20mg. METHODS: Thirty-eight French hospitals were invited. Patient files were reviewed to identify clinical manifestations, diagnostic methods, and treatment compliance. RESULTS: Four hundred and thirteen patients (296 ATTRv-PN, 117 ATTRv-mixed) were analyzed. Patients were predominantly male (68.0%) with a mean age of 57.2±17.2 years. Interval between first symptom(s) and diagnosis was 3.4±4.3 years. First symptoms included sensory complaints (85.9%), dysautonomia (38.5%), motor deficits (26.4%), carpal tunnel syndrome (31.5%), shortness of breath (13.3%), and unexplained weight loss (16.0%). Mini-invasive accessory salivary gland or punch skin and nerve biopsies were most common, with a performance of 78.8-100%. TTR genetic sequencing, performed in all patients, revealed 31 TTR variants. Tafamidis meglumine was initiated in 156/214 (72.9%) ATTRv-PN patients at an early disease stage. Median treatment duration was 6.00 years in ATTRv-PN and 3.42 years in ATTRv-mixed patients. Tafamidis was well tolerated, with 20 adverse events likely related to study drug among the 336 patients. CONCLUSION: In France, ATTRv patients are usually identified early thanks to the national network and the help of diagnosis combining genetic testing and mini-invasive biopsies.

Upper limb onset of hereditary transthyretin amyloidosis is common in non-endemic areas.

BACKGROUND AND PURPOSE: The aim is to describe an uncommon phenotype of hereditary ATTR neuropathy with upper limb onset. METHODS: The French TTR Familial Amyloid Polyneuropathy database was used for a retrospective evaluation of 32 consecutive patients with upper limb onset of the neuropathy (study group) and they were compared to 31 Portuguese early-onset patients and 99 late-onset patients without upper limb onset. RESULTS: Initial upper limb symptoms were mostly sensory. Lower limb symptoms began 2.3 ± 3 years after upper limb symptoms. Twenty-four (75%) patients were initially misdiagnosed, with 15 different diagnoses. More patients in the study group had a Neuropathy Impairment Score upper limb/lower limb ratio > 1 compared to the late-onset patient group. The study group had significantly more pronounced axonal loss in the median and ulnar motor nerves and the ulnar sensory and sural nerves. On radial nerve biopsies (n = 11), epineurial vessels were abnormal in six cases, including amyloid deposits in vessel walls (3/11), with vessel occlusion in two cases. CONCLUSION: Upper limb onset of hereditary ATTR neuropathy is not rare in non-endemic areas. It is important to propose early TTR sequencing of patients with idiopathic upper limb neuropathies, as specific management and treatment are required.

Multimodality Imaging of Cardiac Transthyretin Amyloidosis 16 Years After a Domino Liver Transplantation.

We report the case of a 62-year-old man hospitalized in May 2015 for symptomatic heart failure. His medical history included two liver transplantations. The first liver transplantation was performed in 1999 for a mixed alcoholic and hepatitis C-related cirrhosis and the patient received the liver of another patient with Val30Met transthyretin amyloidosis using the domino technique. In 2008, he complained of neuropathic pains and an iatrogenic-acquired transthyretin amyloidosis was diagnosed. On cardiac evaluation, amyloidosis was suspected. In March 2010, a second liver transplantation was performed with a deceased donor without complication. In May 2015, a first episode of symptomatic heart failure occurred and cardiac amyloidosis was investigated by a multimodality evaluation. Electrocardiogram, cardiac biomarkers, echocardiography, and cardiac MRI were in favor of the diagnosis of amyloidosis, whereas 99m Tc-dicarboxypropane diphosphonate scintigraphy was not. Endomyocardial biopsy finally confirmed the positive diagnosis of iatrogenic-acquired cardiac amyloidosis. This case is, to the best of our knowledge, the first to report biopsy-proven cardiac amyloidosis induced by domino liver transplantation and progressing heart failure in spite of retransplantation. The diagnostic modalities are discussed. This case should alert physicians to the cardiac risk in domino liver transplanted patients.

Myocardial muscarinic receptor upregulation and normal response to isoproterenol in denervated hearts by familial amyloid polyneuropathy.

BACKGROUND: Patients with familial amyloid polyneuropathy, a rare hereditary form of amyloidosis, have progressive autonomic neuropathy. The disease usually does not induce heart failure but is associated with sudden death, conduction disturbances, and an increased risk of complications during anesthesia. Although cardiac sympathetic denervation has been clearly demonstrated, the postsynaptic status of the cardiac autonomic nervous system remains unelucidated. METHODS AND RESULTS: Twenty-one patients were studied (age, 39+/-11 years; normal coronary arteries; left ventricular ejection fraction 68+/-9%). To evaluate the density and affinity constants of myocardial muscarinic receptors, PET with (11)C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, was used. Cardiac beta-receptor functional efficiency was studied by the heart rate (HR) response to intravenous infusion of isoproterenol (5 minutes after 2 mg of atropine, 5, 10, and 15 ng/kg per minute during 5 minutes per step). The mean muscarinic receptor density was higher in patients than in control subjects (B'(max), 35.5+/-8.9 versus 26.1+/-6.7 pmol/mL, P=0.003), without change in receptor affinity. The increase in HR after injection of atropine as well as of MQNB was lower in patients compared with control subjects despite a similar basal HR (DeltaHR after atropine, 11+/-21% versus 62+/-17%; P<0.001), consistent with parasympathetic denervation. Incremental infusion of isoproterenol induced a similar increase in HR in patients and control subjects. CONCLUSIONS: Cardiac autonomic denervation in familial amyloid polyneuropathy results in an upregulation of myocardial muscarinic receptors but without change in cardiac beta-receptor responsiveness to catecholamines.

Myocarditis in patients with clinical presentation of myocardial infarction and normal coronary angiograms.

OBJECTIVES: The aim of this study was to assess the diagnosis of myocarditis in patients presenting with acute myocardial infarction (MI) and normal coronary angiograms. BACKGROUND: Most often in these patients, the etiologic diagnosis remains unclear once they are found to have normal coronary arteries. The diagnosis of myocarditis mimicking MI is clinically relevant, because numerous arguments suggest a relation between myocarditis and dilated cardiomyopathy. Myocardial indium-111 (111In)-antimyosin antibody (AMA)/rest thallium-201 (201Tl) imaging allows noninvasive detection of myocarditis. METHODS: Forty-five patients admitted to three intensive care units for suspicion of acute MI, with normal coronary angiograms, were investigated. Indium-111-AMA planar images and then a dual-isotope rest AMA/201Tl tomographic study were performed. Six-month echocardiographic follow-up was obtained in 80% of the patients with initial left ventricular (LV) wall motion abnormalities. RESULTS: In eight patients, AMA and 201Tl scintigraphy were negative. In two patients, a matched 201Tl defect and focal AMA uptake suggested acute MI (due to prolonged vasospasm or spontaneously reperfused coronary occlusion). In 17 patients, diffuse AMA uptake over the whole LV suggested diffuse myocarditis. In 18 patients, focal AMA uptake with a normal 201Tl scan suggested diffuse but heterogeneous, or focal myocarditis. Complete functional recovery was observed in 81% of the patients with a pattern of myocarditis. CONCLUSIONS: Among 45 patients presenting with acute MI and normal coronary angiograms, 38% had diffuse myocarditis and 40% had a scintigraphic pattern of heterogeneous or focal myocarditis. Short-term follow-up showed complete LV functional recovery in 81% of these patients.

[Coronary angioplasty in the acute phase of myocardial infarction in a low-volume center]. / Angioplastie coronaire à la phase aiguë de l'infarctus du myocarde dans un centre de faible volume.

The efficacy of coronary angioplasty in the treatment of acute myocardial infarction was assessed in a low volume centre. Between January 1994 and May 1999, 148 consecutive patients (mean age 59 years, 81% men) with acute myocardial infarction, admitted within 12 hours, were included in this retrospective analysis. On admission, 14% of patients were in cardiogenic shock. The average time between the onset of chest pain and arrival at hospital was 244 +/- 183 mins. Reperfusion (TIMI 3 flow) was obtained on average 111 +/- 60 mins after arrival at hospital and 81 mins after informing the on-call team. After angioplasty, residual stenosis < 50% was obtained in 91% of cases. TIMI 3 flow was obtained in 85% of cases (TIMI 2 + 3 in 93% of cases). Over the years, the delay before treatment decreased and the results of angioplasty improved. In the last 79 patients, residual stenosis < 50% was obtained in 95% of cases, TIMI 3 flow in 87% of cases (TIMI 2 + 3 in 97% of cases). The stenting rate increased from 16% before 1997 to 61% thereafter. The hospital mortality was 4%. Direct or salvage angioplasty in the first 12 hours of myocardial infarction in some low volume centres may be carried out safely with intervention times and success rates comparable to those reported in the literature.

Prognostic value of radionuclide angiography in patients with right ventricular arrhythmias.

BACKGROUND: The prognosis of patients with right ventricular (RV) arrhythmias remains uncertain. This study prospectively evaluated the prognostic value of RV and left ventricular (LV) involvement assessed by radionuclide angiography (RNA) as predictors for sudden death. METHODS AND RESULTS: Patients (n=188) with severe arrhythmias originating from the RV were followed up for a mean of 45+/-34 months. Data on clinical presentation, resting and stress ECG, signal-averaged ECG, 24-hour Holter monitoring, and programmed stimulation were collected along with RNA. Patients were classified as group I (n=82) with normal RNA or group II (n=106) with an abnormal RV suggestive of arrhythmogenic RV cardiomyopathy, classified as diffuse or localized disease, with or without associated LV abnormalities. During follow-up, 14 patients died suddenly, all in group II. None of the clinical and electrical data were predictive of death. An abnormal RNA study was a highly predictive factor for death (P<0.005), as well as the presence of LV abnormalities (P<0.01). CONCLUSIONS: The present study confirms that arrhythmogenic RV cardiomyopathy is a severe disease with a high risk for cardiac death. Evidence of RV abnormalities in patients presenting with RV arrhythmias is highly predictive for sudden death, as is its association with LV involvement.

[Psychosocial effects of angina. Results of a cross-sectional survey of 3,654 patients]. / Retentissement psychosocial de l'angor. Résultats d'une enquête transversale sur 3,654 patients.

The consequences of angina were assessed by a questionnaire completed by 1,528 out-hospital doctors (79% of general practitioners, 21% of cardiologists) on 3,654 patients. This population comprised 2,304 men (64%) and 1,282 women (36%) with a mean age of 69.5 years (men: 67.1, women: 73.8 years). Previous myocardial infarction was present in 36.6% of cases and the average number of angina attacks was 3.1 per month. Angina seemed to affect the social behaviour of 25 to 30% of patients, the affective behaviour of 40% of patients and everyday life style in 60% of cases. Sixty per cent of patients had difficulties in their work and 60% also had psychological consequences of the angina. The social consequences of angina were different according to the patient's gender. Women were more affected in family life and men in their affective behaviour. The psychological consequences were also different: women were more likely to be anxious or depressed whereas men were usually more irritable. The incidence of anxio-depressive reactions with age was not studied (the female population was older). The higher incidence of anxio-depressive symptoms in women may be partially explained by their age at the time of diagnosis and the difference in prognosis between men and women when coronary artery disease is established.

Cardiac sympathetic denervation in familial amyloid polyneuropathy assessed by iodine-123 metaiodobenzylguanidine scintigraphy and heart rate variability.

Familial amyloid polyneuropathy (FAP) is a rare and severe hereditary form of amyloidosis, due to nervous deposits of a genetic variant transthyretin produced by the liver and characterized by both sensorimotor and autonomic neuropathy. Left ventricular systolic dysfunction is rare, but conduction disturbances and sudden deaths can occur. The neurological status of the heart has not been elucidated, and an alteration of the sympathetic nerves may be involved. We studied 17 patients (42+/-12 years) before liver transplantation by iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy, heart rate variability analysis, coronary angiography, radionuclide ventriculography, rest thallium single-photon emission tomography (SPET) and echocardiography. Coronary arteries, left ventricular systolic function and rest thallium SPET were normal in all patients. Only mild evidence of amyloid infiltration was found at echocardiographic examination. Cardiac MIBG uptake was dramatically decreased in patients compared with age-matched control subjects (heart-to-mediastinum activity ratio at 4 h: 1.36+/-0.26 versus 1.98+/-0.35, P<0.001), while there was no difference in MIBG washout rate. Heart rate variability analysis showed a considerable scatter of values, with high values in four patients despite cardiac sympathetic denervation as assessed by MIBG imaging. The clinical severity of the polyneuropathy correlated with MIBG uptake at 4 h but not with the heart rate variability indices. Cardiac MIBG uptake and the heart rate variability indices did not differ according to the presence or absence of conduction disturbances. Patients with FAP have sympathetic cardiac denervation as assessed by MIBG imaging despite a preserved left ventricular systolic function and cardiac perfusion, without correlation with conduction disturbances. Results of the heart rate variability analysis were more variable and this technique does not seem to be the best way to evaluate the extent of cardiac sympathetic denervation in FAP patients.

Normal left ventricular volumes and ejection fraction: assessment with quantitative digital cardioangiography.

The aim of this study was to assess the accuracy and precision of a digital angiography system, the General Electric DX system, as compared to conventional left ventricular cineangiography. After a phantom study, sixty patients with normal coronary arteries and normal left ventricles (LV) were studied. The LV contours were manually traced from raw or subtracted digital runs and from the cine films in an independent manner. A regression formula was used to adjust the DX derived data to the cine film results (Vcorrected = 0.693 Vmeasured +8.65 ml). There was an excellent correlation between the two methods in the end-diastolic volume index (r = 0.97, sd = 4.2 ml/m2), the end-systolic volume index (r = 0.95, sd = 2.7 ml/m2), the stroke volume index (r = 0.93, sd = 4.1 ml/m2), and the ejection fraction (r = 0.85, sd = 3.45%). We conclude that manual tracing of LV contours from either raw or subtracted digital images provides reliable and accurate measurement of LV volume and ejection fraction.

Evaluation of radionuclide angiography in diagnosis of arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: The accuracy of Fourier analysis of radionuclide angiography for the diagnosis of arrhythmogenic right ventricular cardiomyopathy was assessed versus X-ray right ventricular angiography. BACKGROUND: In patients with recurrent right ventricular tachycardia, the diagnosis of arrhythmogenic right ventricular cardiomyopathy is based on the presence of right ventricular wall motion abnormalities on conventional X-ray angiography without evidence of other heart disease. METHODS: X-ray and radionuclide angiography were prospectively compared in 73 patients with ventricular tachycardia. We analyzed the presence of a right ventricular enlargement, global hypokinesia and segmental wall motion abnormalities, using visual analysis for both techniques and Fourier analysis for radionuclide angiography. Disease was noted as absent or present and as diffuse or localized. The interobserver reproducibility of both techniques for the diagnosis of right ventricular wall motion abnormalities was tested in 27 randomly selected patients. RESULTS: According to X-ray angiography, 53 patients were considered to have arrhythmogenic right ventricular cardiomyopathy (22 diffuse, 31 localized forms) and 20 patients a normal right ventricle. The sensitivity of radionuclide angiography was 94.3%, specificity 90% and positive and negative predictive values 96% and 85.7%, respectively. Agreement for the location of the wall motion abnormalities was 60% for the apex, 76% for the outflow tract, 82% for the inferior wall and 74% for the free wall. The diagnostic interobserver reproducibility of X-ray and radionuclide angiography was 74% and 96.2%, respectively. CONCLUSIONS: In a selected cohort, Fourier analysis of radionuclide angiography is an accurate and reproducible tool for the diagnosis of arrhythmogenic right ventricular cardiomyopathy.

Percutaneous coronary angioplasty in patients over 75 years old: immediate and mid-term results.

Ninety-five patients 75 years or older (range 75-90, mean 79) underwent PTCA from 1987 to 1991. Forty-two patients were 80 years or older. Forty-four had prior MI, 5% had prior coronary bypass surgery (CBS), 13% had a prior history of recent cardiac failure, and 81% (77/95) presented with unstable angina, refractory to intravenous treatment in 31 cases. The mean left ventricular ejection fraction was 62% (range 34%-80%). Thirty-nine percent had single vessel disease, 41% had two vessel disease, and 20% had three vessel disease. Coronary calcifications were present in 28%. A single vessel was dilated in 81 patients, two vessels in 14 patients; complete revascularization was achieved in 41%. The clinical angiographic primary success rate was 79% (75/95). There were five procedural deaths, five MI, five CBS and, ten hematomas. Follow-up data were obtained in 100% cases, with a mean follow-up duration of 12 months (ranging from 1-36). There were four deaths, one MI, and two CBS. Twenty percent (15/74) of patients had a second PTCA with a 73% success rate. Finally, 70% of the initial population was asymptomatic after first or second PTCA at mid-term follow-up. We conclude that PTCA is safe and effective in elderly patients, with 70% clinical success rate at mid-term follow-up in spite of frequent incomplete revascularization limited to the culprit lesion.

Percutaneous double balloon valvuloplasty for stenosis of porcine bioprostheses in the tricuspid valve position: a report of 2 cases.

The feasibility and results of percutaneous double balloon valvuloplasty were evaluated in 2 patients with stenosis of porcine bioprostheses in the tricuspid valve position. The procedures were performed with a Trefoil 3 x 10 and a 15 mm balloon. Long inflations (4 and 3 minutes) were well tolerated. A significant immediate increase in the valve area, without significant valvular regurgitation, was achieved in both cases, from 0.65 to 1.15 cm2 in case 1 and from 0.9 to 1.65 cm2 in case 2. Both patients required valve replacement during the follow-up, at 14 and 21 months. There was no restenosis, but echocardiography showed right atrial thrombosis in case 1. Progressive restenosis with peripheral edema and increase of the mean doppler gradient occurred in case 2. The procedure is feasible, safe, and well tolerated. It provides significant immediate hemodynamic improvement, but it should be considered as a palliative technique since a normal valve area can not usually be obtained and a restenosis is likely to occur at midterm follow-up.

[Thrombolytic agents in myocardial infarction: results of large mortality studies]. / Les thrombolytiques dans l'infarctus du myocarde: résultats des grandes études de mortalité.

Large studies involving several thousand patients have clearly established the effectiveness of thrombolytic therapy in reducing mortality in the acute phase of myocardial infarction: the earlier the treatment, the greater this reduction. The value of late thrombolysis remains to be determined by further studies. This technique can be extended to the oldest subjects who benefit most from this type of treatment, bearing in mind that they are at a greater risk of neurological complications. The effectiveness of thrombolysis is partially dissociated from its effects on left ventricular function. Since the thrombolytic agents (streptokinase, anistreplase and recombinant tissue plasminogen activator) are equally effective in reducing mortality and neurological complications, it seems reasonable to use the cheapest of these drugs as initial treatment, except in some special cases.

Complete atrioventricular block following mediastinal irradiation: a report of six cases.

Complete atrioventricular block (AVB) following radiotherapy has been reported rarely, usually after high dose mediastinal irradiation for Hodgkin's disease or lung or breast carcinoma. We report six new cases of episodic complete infranodal AVB, requiring permanent pacemaker implantation. The mean age was 48-years old (ranging from 25-60) at the first Adams Stokes attack, mean delay was 12 years after irradiation (10-18), and mean radiation dose was 5,200 rads (4,000-6,500). All patients had abnormal interval electrocardiograms (right bundle branch block in two, left bundle branch block in three, alternating left and right bundle branch block in one). Electrocardiograms during the episode of AVB or Holter recordings were consistent with infranodal block in all patients; electrophysiological study performed in five patients confirmed infranodal AVB in four, and one was normal. Pericardial disease was constant, which included pericardial constriction in four patients. Two patients died after failure of pericardiectomy to improve congestive heart failure, due to epicardial, myocardial, and endocardial involvement. Noncardiac mediastinal lesions were present in four cases. Since this delayed complication may occur in patients of such age that the relation between the AVB and the chest irradiation is questionable, we propose the following etiologic criteria; high radiation dose (over 4,000 rads); delay of 10 years or more; abnormal interval tracings; pericardial involvement; and associated cardiac or mediastinal radiation-induced lesions.