Summary
Background
Cardiac amyloidosis due to familial amyloid polyneuropathy (FAP) includes restrictive cardiomyopathy, thickened cardiac walls, conduction disorders and cardiac denervation. Impaired blood pressure variability has been documented in FAP related to the Val30Met mutation.
Aims
To document blood pressure variability in FAP patients with various mutation types and its relationship to the severity of cardiac involvement.
Methods
Blood pressure variability was analysed in 49 consecutive FAP patients and was compared with a matched control population. Cardiac evaluation included echocardiography, right heart catheterization, electrophysiological study, Holter electrocardiogram and metaiodobenzylguanidine (MIBG) scintigraphy.
Results
A non-dipping pattern was found in 80% of FAP patients and in 35% of control patients ( P < 0.0001); this was due to a significantly lower diurnal blood pressure in FAP patients (FAP group, 113 ± 21 mmHg; control group, 124 ± 8 mmHg; P < 0.0001), whereas nocturnal blood pressures were similar. Among FAP patients, a non-dipping pattern was significantly associated with haemodynamic involvement, cardiac thickening or conduction disorders. These associations did not depend on the average blood pressure levels. Impaired blood pressure variability was more frequent and more pronounced in patients with multiple criteria for severe cardiac amyloidosis.
Conclusion
Low blood pressure variability is common in cardiac amyloidosis due to FAP. A non-dipping pattern was more frequently observed in FAP patients with haemodynamic impairment, cardiac thickening or conduction disorders. It is suggested that impairment of circadian rhythm of blood pressure reflects the severity of cardiac amyloidosis due to FAP.
Résumé
Contexte
L’amylose cardiaque due à la polyneuropathie familiale amyloïde (FAP) est caractérisée par une cardiopathie restrictive, des troubles conductifs et une dénervation cardiaque. L’altération de la variabilité de la pression artérielle (VPA) a été observée chez les patients présentant une FAP secondaire à la mutation Val30Met.
Objectifs
Nous avons testé l’hypothèse qu’une variabilité tensionnelle basse serait associée à la sévérité de l’atteinte amyloïde cardiaque dans la FAP.
Méthodes
La VPA a été analysée chez 49 patients consécutifs atteints de FAP et comparée à un groupe témoin. L’atteinte cardiaque a été évaluée par échocardiographie, cathétérisme droit, étude électrophysiologique Holter-ECG et scintigraphie cardiaque à la MIBG.
Résultats
La VPA était altérée chez 80 % des patients FAP contre 35 % dans le groupe témoin ( p < 0,0001) et était due à une pression artérielle diurne plus basse dans la FAP (FAP 113 ± 21 mmHg ; témoin 124 ± 8 mmHg ; p < 0,0001), alors que les pressions nocturnes étaient équivalentes. Dans le groupe FAP, le profil « non-dipper » était associé à une atteinte hémodynamique, un épaississement myocardique, ou des troubles conductifs sans différence significative concernant la dénervation cardiaque. L’altération de la VPA était plus fréquente et plus prononcée chez les patients présentant plusieurs critères d’atteinte cardiaque amyloïde.
Conclusion
La FAP est associée à une faible VPA. Les patients présentant une atteinte hémodynamique, un épaississement myocardique ou des troubles conductifs présentent plus fréquemment une VPA altérée. Il semble que l’altération de la VPA reflète la sévérité de l’amylose cardiaque dans la FAP.
Background
Blood pressure (BP) is characterized by a circadian pattern, with higher pressure during the diurnal period than during the nocturnal period . This circadian BP variability (BPV) is related to the imbalance between cardiac output and systemic resistance and is influenced by the autonomic nervous system . A non-dipping profile is defined by a blunted fall in BP (less than 10%) during the nocturnal period and has been observed in various clinical conditions, including systemic hypertension, diabetes and renal failure . The non-dipping profile is also associated with poor prognosis in hypertensive or diabetic patients but also in the general population . In systemic hypertension, non-dipper patients display a worse haemodynamic profile, a higher left ventricular (LV) mass index and greater peripheral organ damage compared with dipper patients .
Familial amyloid polyneuropathy (FAP) is an autonomic dominant disease induced by the misfolding of a mutated protein, transthyretin (TTR) . More than 100 different TTR mutations are currently described, with various clinical presentations . In Europe, several geographical foci are reported (Portugal, Sweden) and the most common mutation is the Val30Met mutation . Polyneuropathy due to FAP includes autonomic nervous system impairment and cardiac denervation . This cardiac autonomic denervation is associated with lower circadian BPV at the early stages of FAP . However, cardiopathy due to FAP includes not only cardiac denervation, but also conduction disorders, increased wall thickness and, later in the course of the disease, haemodynamic impairment with restrictive pattern . The precise relationship between these various components of cardiac involvement and BPV is still unknown.
The aim of our study was to document BPV in FAP patients with various mutation types. We tested the hypothesis that low BPV reflects the severity of cardiac disease in FAP, namely haemodynamic impairment, wall thickening due to amyloid infiltration, conduction disorders and cardiac denervation.
Methods
Our retrospective, single-centre study included consecutive FAP patients hospitalized from September 2009 to April 2011. Patients were recruited through the French Reference Centre for Familial Amyloid Polyneuropathy and other Rare Peripheral Neuropathies. One patient with arterial hypertension was excluded from the study and 49 FAP patients entered the final analysis. All patients had high quality ambulatory BP monitoring, which is part of our routine protocol in FAP. The FAP diagnosis was confirmed by TTR genotyping. Eleven different TTR mutations were documented and the TTR mutation type was Val30Met in 28 over 49 patients (57%). Ambulatory BP data were also obtained in 49 age- and sex-matched control subjects. Control subjects were patients who were referred for suspicion of arterial hypertension but in whom this diagnosis was ruled out; the subjects were also free from antihypertensive treatment. The study complied with the Declaration of Helsinki and informed consent was obtained from all patients.
Clinical status was evaluated by the polyneuropathy disability (PND) score as previously described . Briefly, a PND score I indicates preserved walking ability; II indicates that walking is impaired but that the patient is able to walk without a stick or crutch; III means that the patient walks with the help of one (or two) stick(s) or crutch(es); and IV means that patient is unable to walk even with help.
Ambulatory BP monitoring was performed in all FAP patients according to the European Society of Cardiology guidelines . The BP monitor (Spacelabs Healthcare, Issaquah, WA, USA) was set to obtain BP readings at 30-minute intervals during the day and 60-minute intervals during the night. The following data were collected for each patient: heart rate, systolic BP (SBP), diastolic BP (DBP), mean BP (MBP) and pulse pressure. The dipping of SBP, DBP and MBP during the nocturnal period compared with the diurnal period was calculated as follows: dipping (%) = (diurnal BP − nocturnal BP)/diurnal BP × 100. A non-dipper pattern was diagnosed if the nocturnal decrease in SBP was inferior to 10% compared with the diurnal period. The standard deviation (SD) of BP was collected for each patient and the coefficient of variation (cVar) of BP was calculated.
Echocardiography included M-mode, two-dimensional, pulsed Doppler and tissue Doppler imaging recordings. M-mode allowed the measurement of LV dimensions. LV ejection fraction (LVEF) was assessed using Simpson’s modified biplane method. Pulsed Doppler was used to measure peak early (E) and late (A) diastolic velocities of the mitral flow. Pulsed tissue Doppler imaging of the lateral LV wall allowed the measurement of systolic (S) and early diastolic (Ea) velocities. Right heart catheterization using a Swan-Ganz catheter allowed the recording of pressure from the right atrium, right ventricle and pulmonary artery, and pulmonary capillary wedge pressure. Cardiac output was measured in triplicate using the thermodilution method.
FAP-related haemodynamic impairment was diagnosed if at least one of the following criteria was observed: LVEF less or equal to 50%; pulmonary capillary wedge pressure greater than 12 mmHg; E/Ea ratio greater than 8; E/A ratio greater than 2.
Cardiac infiltration was quantified by measuring interventricular septum thickness and calculating relative wall thickness (RWT); RWT = (2*PWTd)/LVIDd, where PWTd is posterior wall thickness and LVIDd is LV internal diameter at end-diastole. Patients with arterial hypertension had been excluded at entry (see above) and no patient had aortic stenosis. Cardiac thickening was confirmed if: the interventricular septum thickness was greater than 12 mm; the RWT was greater than 0.42.
Conduction disorders were evaluated by surface electrocardiogram and electrophysiological study. The His bundle potential was recorded by a quadripolar lead and the time between the His bundle potential and ventricular depolarization was measured (HV interval). Conduction disorders were defined by one of the following criteria: PR interval greater or equal to 200 ms; complete bundle branch block (QRS duration ≥ 120 ms); HV interval greater than 70 ms; patients implanted with a pacemaker.
The autonomic nervous system was evaluated in a subgroup of 32 over 49 patients according to our routine protocol, based on: 24-hour Holter electrocardiogram with measurement of SD of normal-to-normal RR intervals (abnormal if < 100 ms); and 123-metaiodobenzylguanidine (123-MIBG) cardiac scintigraphy (heart/mediastinum ratio at 4 hours; normal value > 1.6) .
Statistical analysis
Continuous variables are presented as mean ± SD. Categorical variables are presented as frequencies and percentages. Analysis of BPV included circadian BPV (dipping status, level of dipping), SD of BP and cVar. The cVar was calculated as follows: (SD × 100)/mean. To comply with the mathematical formula for cVar and the level of dipping, the relationship between these two variables used the absolute value of dipping. Comparisons between normal continuous variables were performed using the Mann-Whitney test. Categorical unpaired variables were compared using Fisher’s exact test. Correlation between continuous variables was measured by Spearman’s test. In order to assess BP level as a potential confounding factor, the relationship between the dipping level and the presence/absence of conditions was analysed by a multiple logistic regression. Levels of SBP and dipping entered the analysis as independent variables and the presence/absence of condition entered the analysis as the dependent variable. Results of the multiple logistic regression are expressed as coefficient ± standard error (Coeff) and P value. A value of P < 0.05 was considered statistically significant. The statistical software used was Statview (version 5.0; SAS Institute, Inc., Cary, NC, USA).
Results
Comparison between familial amyloid polyneuropathy and control groups
A non-dipping pattern was documented in 39 over 49 FAP patients (80%) and in 17 over 49 controls (35%; P < 0.0001) ( Tables 1 and 2 ; Fig. 1 ). Compared with controls, FAP patients displayed significantly lower BP values during the diurnal period, whereas nocturnal BP values were similar. Over 24 hours, FAP patients also displayed a lower cVar of BP than control subjects. If diurnal and nocturnal periods were considered separately, no statistically significant differences were found between FAP patients and controls. In order to identify the level of BP as a potential confounding factor, the level of dipping was correlated to the average value of SBP and to a variable independent of average BP level (cVar of SBP), in the overall population (control + FAP, n = 98) and in both subgroups. There was a weak positive relationship between SBP and percentage of dipping in the overall population ( r = 0.2, P = 0.03), thus explaining 4% of the percentage of dipping ( r 2 = 0.04). This correlation was not statistically significant if FAP patients ( r = 0.16; P = 0.27) and controls ( r = −0.03; P = 0.8) were considered separately. The absolute level of dipping was strongly correlated with the cVar of SBP, not only in the overall population ( n = 98, r = 0.69; P < 0.0001) but also in the FAP group ( n = 49, r = 0.58; P < 0.0001) and the control group ( r = 0.73; P < 0.0001) ( Fig. 2 ).
| Control ( n = 49) | FAP ( n = 49) | P | |
|---|---|---|---|
| General characteristics | |||
| Age (years) | 55 ± 13 | 55 ± 12 | 0.9 |
| Men | 33 (67.3) | 33 (67.3) | 1 |
| % of successful measures | 89 ± 10 | 93 ± 7 | 0.05 |
| Ambulatory blood pressure monitoring | |||
| SBP (mmHg) | 120 ± 8 | 114 ± 13 | 0.007 |
| DBP (mmHg) | 74 ± 6 | 72 ± 9 | 0.15 |
| MBP (mmHg) | 89 ± 6 | 86 ± 9 | 0.02 |
| PP (mmHg) | 46 ± 7 | 43 ± 8 | 0.01 |
| Heart rate (bpm) | 71 ± 9 | 74 ± 12 | 0.4 |
| Ambulatory blood pressure monitoring: diurnal period | |||
| SBP (mmHg) | 124 ± 8 | 113 ± 21 | < 0.0001 |
| DBP (mmHg) | 78 ± 7 | 72 ± 13 | 0.004 |
| MBP (mmHg) | 94 ± 7 | 86 ± 15 | 0.0003 |
| PP (mmHg) | 47 ± 7 | 42 ± 10 | 0.003 |
| Heart rate (bpm) | 74 ± 9 | 75 ± 16 | 0.8 |
| Ambulatory blood pressure monitoring: nocturnal period | |||
| SBP (mmHg) | 110 ± 9 | 110 ± 20 | 0.8 |
| DBP (mmHg) | 65 ± 6.3 | 68 ± 13 | 0.047 |
| MBP (mmHg) | 81 ± 7 | 82 ± 15 | 0.3 |
| PP (mmHg) | 45 ± 7 | 42 ± 9 | 0.048 |
| Heart rate (bpm) | 66 ± 10 | 70 ± 15 | 0.1 |
| Control ( n = 49) | FAP ( n = 9) | P | |
|---|---|---|---|
| Blood pressure dipping | |||
| Non-dipper patients n (%) | 17 (35) | 39 (80) | < 0.0001 |
| Dipping SBP (%) | 11 ± 6 | 3 ± 8 | < 0.0001 |
| Dipping DBP (%) | 16 ± 7 | 5 ± 9 | < 0.0001 |
| Dipping MBP (%) | 14 ± 7 | 4 ± 8 | < 0.0001 |
| Blood pressure variability: diurnal and nocturnal periods | |||
| SBP | |||
| SD (mmHg) | 12 ± 9 | 10 ± 10 | 0.0009 |
| cVar (%) | 10 ± 3 | 9 ± 3 | 0.01 |
| DBP | |||
| SD (mmHg) | 10 ± 5 | 8 ± 4 | 0.0001 |
| cVar (%) | 14 ± 3 | 12 ± 3 | 0.0003 |
| MBP | |||
| SD (mmHg) | 11 ± 2 | 9 ± 2 | 0.0004 |
| cVar (%) | 12 ± 3 | 10 ± 3 | 0.003 |
| PP | |||
| SD (mmHg) | 8 ± 3 | 7 ± 2 | 0.0004 |
| cVar (%) | 17 ± 4 | 16 ± 4 | 0.02 |
| Heart rate | |||
| SD (mmHg) | 10 ± 3 | 7 ± 4 | < 0.0001 |
| cVar (%) | 13 ± 5 | 9 ± 5 | < 0.0001 |
| Blood pressure variability: diurnal period | |||
| SBP | |||
| SD (mmHg) | 11 ± 3 | 10 ± 3 | 0.03 |
| cVar (%) | 9 ± 2 | 11 ± 14 | 0.7 |
| DBP | |||
| SD (mmHg) | 9 ± 2 | 8 ± 2 | 0.02 |
| cVar (%) | 11 ± 3 | 13 ± 12 | 0.5 |
| MBP | |||
| SD (mmHg) | 10 ± 2 | 9 ± 2 | 0.02 |
| cVar (%) | 10 ± 2 | 12 ± 13 | 0.6 |
| PP | |||
| SD (mmHg) | 8 ± 2 | 7 ± 2 | 0.0004 |
| cVar (%) | 17 ± 4 | 18 ± 13 | 0.2 |
| Heart rate | |||
| SD (mmHg) | 9 ± 3 | 7 ± 4 | < 0.0001 |
| cVar (%) | 13 ± 5 | 11 ± 13 | < 0.0001 |
| Blood pressure variability: nocturnal period | |||
| SBP | |||
| SD (mmHg) | 9 ± 4 | 9 ± 3 | 0.5 |
| cVar (%) | 9 ± 4 | 9 ± 3 | 0.5 |
| DBP | |||
| SD (mmHg) | 8 ± 2 | 8 ± 3 | 0.1 |
| cVar (%) | 8 ± 2 | 8 ± 3 | 0.1 |
| MBP | |||
| SD (mmHg) | 8 ± 3 | 8 ± 3 | 0.5 |
| cVar (%) | 8 ± 3 | 8 ± 3 | 0.5 |
| PP | |||
| SD (mmHg) | 6 ± 2 | 5 ± 2 | 0.045 |
| cVar (%) | 6 ± 2 | 5 ± 2 | 0.045 |
| Heart rate | |||
| SD (mmHg) | 6 ± 2 | 4 ± 3 | 0.01 |
| cVar (%) | 6 ± 2 | 4 ± 3 | 0.01 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
