Laennecs' mediate auscultation: Child's play.

Before Laennec, respiratory diseases that we recognize today were often confused, because the heart and lung are locked inside the rib cage. Impressed by the autopsies performed by Xavier Bichat (1771-1802), Laennec maintained the importance of the anatomoclinical method. But he indicated in his early 1820s lectures at the Collège de France that the discovery of auscultation was fortuitous and empirical. Duffin demonstrates that medical discoveries hardly obey an implacable logic, they arise outside of pre-established projects. In this paper, we retrace the chronology and antecedents at the origin of the important medical invention that is the stethoscope.

Home-Based Care Evolution in Chronic Respiratory Failure between 2001 and 2015 (Antadir Federation Observatory).

BACKGROUND: The aetiologies of chronic respiratory failure (CRF) are moving in many western countries. Obesity-Hypoventilation syndrome (OHS) has become one of the most common indications of non-invasive ventilation (NIV) with Chronic Obstructive Pulmonary Diseases (COPD). Long-Term Oxygen Therapy (LTOT) technology is the treatment plan for CRF patients in the new era. OBJECTIVES: This study aimed to assess home-based care evolution in CRF patients on LTOT (LTOT) and/or NIV from the ANTADIR observatory. METHODS: A computerized database from 14 regional facilities was analysed (30% of French home-treated patients). Patient age, sex, aetiology, home respiratory devices were recorded between 2001 and 2015. RESULTS: By the end of 2015, 12,147 CRF patients received LTOT (40%), NIV (24%), LTOT + NIV (23%), continuous positive airway pressure (CPAP; 11%) or LTOT + CPAP (3%). Between 2001 and 2015, we observed a decrease of LTOT (63-40%) in the benefit of NVI ± LTOT (25-47%). Regarding the aetiology, we note a slight decrease in obstructive disease and a significant increase in restrictive disease, mainly due to OHS. The 10-year survival was better on NIV ± LTOT than on LTOT, for overall patients and for both obstructive and restrictive patients. The 10-year survival was better on NIV ± LTOT than on LTOT (35 vs. 10%, p < 0.05). In COPD patients on LTOT, a switch from conventional to new home devices was observed. Stationary LTOT systems were less prescribed, while portable/transportable -system, liquid oxygen and self-filling oxygen were increasingly prescribed. CONCLUSION: Our study confirmed changes in CRF aetiologies and home devices. OHS is now an important indication of NIV. Using new LTOT technologies changed home prescriptions in COPD patients.

Combined measurement of carbon monoxide and nitric oxide lung transfer does not improve the identification of pulmonary hypertension in systemic sclerosis.

Screening is important to determine whether patients with systemic sclerosis (SSc) have pulmonary hypertension because earlier pulmonary hypertension treatment can improve survival in these patients. Although decreased transfer factor of the lung for carbon monoxide (TLCO) is currently considered the best pulmonary function test for screening for pulmonary hypertension in SSc, small series have suggested that partitioning TLCO into membrane conductance (diffusing capacity) for carbon monoxide (DMCO) and alveolar capillary blood volume (VC) through combined measurement of TLCO and transfer factor of the lung for nitric oxide (TLNO) is more effective to identify pulmonary hypertension in SSc patients compared with TLCO alone. Here, the objective was to determine whether combined TLCO-TLNO partitioned with recently refined equations could more accurately detect pulmonary hypertension than TLCO alone in SSc.For that purpose, 572 unselected consecutive SSc patients were retrospectively recruited in seven French centres.Pulmonary hypertension was diagnosed with right heart catheterisation in 58 patients. TLCO, TLNO and VC were all lower in SSc patients with pulmonary hypertension than in SSc patients without pulmonary hypertension. The area under the receiver operating characteristic curve for the presence of pulmonary hypertension was equivalent for TLCO (0.82, 95% CI 0.79-0.85) and TLNO (0.80, 95% CI 0.76-0.83), but lower for VC (0.75, 95% CI 0.71-0.78) and DMCO (0.66, 95% CI 0.62-0.70).Compared with TLCO alone, combined TLCO-TLNO does not add capability to detect pulmonary hypertension in unselected SSc patients.

Assessing Functional Capacity in Directly and Remotely Monitored Home-Based Settings in Individuals With Chronic Respiratory Diseases: Protocol for a Multinational Validation Study.

BACKGROUND: Pulmonary rehabilitation is widely recommended to improve functional status and as secondary and tertiary prevention in individuals with chronic pulmonary diseases. Unfortunately, access to timely and appropriate rehabilitation remains limited. To help close this inaccessibility gap, telerehabilitation has been proposed. However, exercise testing is necessary for effective and safe exercise prescription. Current gold-standard tests, such as maximal cardiopulmonary exercise testing (CPET) and the 6-minute walk test (6MWT), are poorly adapted to home-based or telerehabilitation settings. This was an obstacle to the continuity of services during the COVID-19 pandemic. It is essential to validate tests adapted to these new realities, such as the 6-minute stepper test (6MST). This test, strongly inspired by 6MWT, consists of taking as many steps as possible on a "stepper" for 6 minutes. OBJECTIVE: This study aims to evaluate the metrological qualities of 6MST by (1) establishing concurrent validity and agreement between the 6MST and CPET, as well as with the 6MWT; (2) determining test-retest reliability in a home-based setting with direct and remote (videoconferencing) monitoring; and (3) documenting adverse events and participant perspectives when performing the 6MST in home-based settings. METHODS: Three centers (Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec in Québec, Groupement des Hôpitaux de l'Institut Catholique de Lille in France, and FormAction Santé in France) will be involved in this multinational project, which is divided into 2 studies. For study 1 (objective 1), 30 participants (Québec, n=15; France, n=15) will be recruited. Two laboratory visits will be performed to assess anthropometric data, pulmonary function, and the 3 exercise tolerance tests (CPET, 6MWT, and 6MST). Concurrent validity (paired sample t tests and Pearson correlations) and agreement (Bland-Altman plots with 95% agreement limits) will be evaluated. For study 2 (objectives 2 and 3), 52 participants (Québec, n=26; France, n=26) will be recruited. Following a familiarization trial (trial 1), the 6MST will be conducted on 2 separate occasions (trials 2 and 3), once under direct supervision and once under remote supervision, in a randomized order. Paired sample t test, Bland-Altman plots, and intraclass correlations will be used to compare trials 2 and 3. A semistructured interview will be conducted after the third trial to collect participants' perspectives. RESULTS: Ethical approval was received for this project (October 12, 2023, in Québec and September 25, 2023, in France) and the first participant was recruited in February 2024. CONCLUSIONS: This study innovates by validating a new clinical test necessary for the development and implementation of new models of rehabilitation adapted to home and telerehabilitation contexts. This study also aligns with the United Nations Sustainable Development Goals by contributing to augmenting health care service delivery (goal 3) and reducing health care access inequalities (goal 11). TRIAL REGISTRATION: ClinicalTrials.gov NCT06447831; https://clinicaltrials.gov/study/NCT06447831. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57404.

Evaluation of the Post-COVID-19 Functional Status (PCFS) Scale in a cohort of patients recovering from hypoxemic SARS-CoV-2 pneumonia.

INTRODUCTION: COVID-19 sequelae are numerous and multisystemic, and how to evaluate those symptomatic patients is a timely issue. Klok et al proposed the Post-COVID-19 Functional Status (PCFS) Scale as an easy tool to evaluate limitations related to persistent symptoms. Our aim was to analyse PCFS Scale ability to detect functional limitations and its correlation with quality of life in a cohort of patients, 2-9 months after hospitalisation for COVID-19 hypoxemic pneumonia. METHODS: PCFS Scale was evaluated in 121 patients together with quality of life and dyspnoea questionnaires, pulmonary function tests and CT scans. RESULTS: We observed a high correlation with multiple questionnaires (Short Form-36, Hospital Anxiety and Depression Scale, modified Medical Research Council, end Borg Six-Minute Walk Test), making the PCFS Scale a quick and global tool to evaluate functional limitations related to various persistent symptoms following COVID-19 pneumonia. DISCUSSION: The PCFS Scale seems to be a suitable instrument to screen for patients who will require careful follow-up after COVID-19 hypoxemic pneumonia even in the absence of pulmonary sequelae.

Impulse oscillometry and spirometry measurements relative to personal best values at the time of acute exacerbations of cystic fibrosis in adults.

BACKGROUND: Diagnosis of acute exacerbation (AE) of cystic fibrosis (CF) must be precise because both under- and over-prescription of antibiotics may be detrimental. How lung function tests contribute to diagnose AE is unclear. We aimed to describe variation of spirometry and oscillometry measurements, at Stable state and at AE in adults with CF. METHODS: Patients were included in a retrospective single-centre study when both spirometry (FEV1, FVC) and oscillometry (X5, R5, R5-R20 and AX) data were available for at least one Stable and one AE visit between December 2016 and July 2019. For each visit, we calculated variation (Δ) in spirometry and oscillometry indices in comparison with personal best values. Measurements were expressed as % of predicted values and Z-scores when applicable. Areas under ROC curves (AUC) were computed. RESULTS: Forty-two patients (28 ± 9 years, FEV1 64 ± 21%) were included; 80 AE and 104 Stable visits were analysed. FEV1 (L, %pred and Z-score) and FVC (%pred and Z-score) varied significantly between AE and Stable visits (p < .05), although differences were small (80 ml/2.7%pred for FEV1). Among oscillometry indices, X5 (kPa.s.L-1 ), R5-R20 (kPa.s.L-1 ) and AX (kPa/L) varied significantly. The AUCs for the variation in spirometry indices ranged from 0.601 (ΔFVC L) to 0.635 (ΔFEV1%pred). They were not significantly different from the AUCs for ΔX5 (0.589), ΔR5-R20 (0.649) and ΔAX (0.598). CONCLUSIONS: Performance of both spirometry and oscillometry to discriminate AE from Stable state was poor. Variation of oscillometry indices (X5, R5-R20, AX) may be helpful when spirometry is unreliable or uncomfortable.

Translation and Cultural Adaptation of PROactive Instruments for COPD in French and Influence of Weather and Pollution on Its Difficulty Score.

Introduction: The recently developed daily and clinical visit PROactive physical activity in COPD (PPAC) instruments are hybrid tools to objectively quantify the level of physical activity and the difficulties experienced in everyday life. Our aim was to translate these instruments for the French-speaking chronic obstructive pulmonary disease (COPD) community worldwide and evaluate the influence of weather and pollution on difficulty score. Methods: The translation procedure was conducted following the guidelines for cross-cultural adaptation process. The translated clinical visit (C-PPAC) was tested among COPD patients in France. A retest was conducted after an interval of at least 2 weeks. The C-PPAC difficulty score was then tested to see how sensitive it was to the influence of weather and outdoor pollution. Results: One hundred and seventeen COPD patients (age 65±9 years; FEV1: 51±20%) from 9 regions in France were included. The French version of C-PPAC was found comprehensible by the patients with an average score of 4.8/5 on a Likert-scale. It showed good internal consistency with Cronbach's α>0.90 and a good test retest reliability with an intraclass correlation coefficient of ≥0.80. The difficulty score was negatively correlated with duration of daylight (ρ=-0.266; p<0.01) and influenced by the intensity of rainfall (light vs. heavy rainfall: 68±16 vs. 76±14 respectively, p=0.045). The score was lower in patients receiving long term oxygen therapy (60±15 vs. 71±15, p<0.01), but not correlated with the pollution indices. Conclusion: The French versions of the questionnaires of the PPAC instruments are accepted and comprehensible to COPD patients. The difficulty score of C-PPAC is sensitive to duration of daylight and rainfall. Such weather factors must be taken into consideration when evaluating the physical activity behavior using these tools in COPD.

Pivotal role of c-Fos in nitric oxide synthase 2 expression in airway epithelial cells.

The regulation of nitric oxide synthase 2 (NOS2) in airway epithelial cells plays a key role in the innate host response to a wide variety of microbial agents and also participates in the generation of pathologic airway inflammation. Among the important signalling cascades that direct NOS2 gene expression are nuclear factor kappaB (NFkappaB) and interferon-gamma (IFNgamma)/signal transducer and activator of transcription 1 (STAT-1). Previous studies suggest activator protein-1 (AP-1), in particular c-Fos component of AP-1, influences NOS2 expression. We investigated the effect of c-Fos modulation using RNA interference siRNA on NOS2 gene expression. A549 cells stably transfected with a plasmid overexpressing a c-Fos siRNA construct (FOSi) resulted in a decrease of NOS2 protein inducibility by IFN gamma. In contrast, classical IFN gamma inducible signal transduction pathways interferon regulated factor-1 (IRF-1) and pSTAT-1 were activated at a similar magnitude in FOSi and control cells. DNA-protein binding assays showed that c-Fos binding was present in wild type cells, but reduced in FOSi clones. FOSi clones had activation of NFkappaB detectable by DNA-protein binding assays, which may have contributed to a decrease of NOS2 expression. Overall, these studies indicate that c-Fos is a requisite and specific component for inducible NOS2 expression.

Determining the minimally important difference in quadriceps strength in individuals with COPD using a fixed dynamometer.

Background: Measurement of quadriceps muscular force is recommended in individuals with COPD, notably during a pulmonary rehabilitation program (PRP). However, the tools used to measure quadriceps maximal voluntary contraction (QMVC) and the clinical relevance of the results, as well as their interpretation for a given patient, remain a matter of debate. The objective of this study was to estimate the minimally important difference (MID) of QMVC using a fixed dynamometer in individuals with COPD undergoing a PRP. Methods: Individuals with COPD undergoing a PRP were included in this study. QMVC was measured using a dynamometer (MicroFET2) fixed on a rigid support according to a standard-ized methodology. Exercise capacity was measured by 6-minute walk distance (6MWD) and evaluation of quality of life with St George's respiratory questionnaire (SGRQ) and Hospital Anxiety and Depression Scale (HADS) total scores. All measures were obtained at baseline and the end of the PRP. The MID was calculated using distribution-based methods. Results: A total of 157 individuals with COPD (age 62.9±9.0 years, forced expiratory volume in 1 second 47.3%±18.6% predicted) were included in this study. At the end of the PRP, the patients had improved their quadriceps force significantly by 8.9±15.6 Nm (P<0.001), as well as 6MWD by 42±50 m (P<0.001), SGRQ total score by -9±17 (P<0.001) and HADS total score by -3±6 (P<0.001). MID estimation using distribution-based analysis was 7.5 Nm by empirical rule effect size and 7.8 Nm by Cohen's effect size. Conclusion: Measurement of QMVC using a fixed dynamometer is a simple and valuable tool capable of assessing improvement in quadriceps muscle force after a PRP. We suggest an MID of 7.5 Nm to identify beneficial changes after a PRP intervention.

One minute sit-to-stand test is an alternative to 6MWT to measure functional exercise performance in COPD patients.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is frequently associated with a reduced functional exercise performance. Even if this parameter is routinely evaluated using 6-minute walking test (6MWT), new field tests are regularly investigated as alternative tests. The aim of this study was to compare functional exercise performance evaluation by sit-to-stand test (STST) and 6MWT and to evaluate reliability and repeatability of the STST in COPD patients. METHOD: Forty-two COPD patients performed randomly two tests: 6MWT and STST. Each test was repeated two times. Distance (6MWD) and number of repetitions were measured. Cardiorespiratory parameters, dyspnea and lower limb fatigue (Borg) were recorded before and after the tests. RESULTS: Sit-to-stand repetitions (19 ± 6) and 6MWD (441 ± 104 m) were correlated (r = .716; P < .001). Good repeatability was found for STST and 6MWT. Good reliability was observed for STST (ICC = 0.902). Variations of heart rate and pulsed oxygen saturation were significantly different between these two tests (23% ± 17% vs 13% ± 11%; P = .022 and -7.6% ± 4.6% vs -0.7% ± 2.7%; P < .001 for 6MWT and STST, respectively). Variations of dyspnea and lower limb fatigue were similar between both tests (P = .827 and P = .467). CONCLUSION: The one minute sit-to-stand test is a valuable alternative to 6MWT to estimate functional exercise performance in COPD patients. The cardiorespiratory demand is different between both tests although the variation of dypsnea is similar. No learning effect was observed for STST.

Deconditioning, fatigue and impaired quality of life in long-term survivors after allogeneic hematopoietic stem cell transplantation.

Long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at high risk for treatment-related adverse events, that may worsen physical capacity and may induce fatigue and disability. The aims of this prospective study were to evaluate exercise capacity in allotransplant survivors and its relationship with fatigue and disability. Patient-reported outcomes and exercise capacity were evaluated in 71 non-relapse patients 1 year after allo-HSCT, using validated questionnaires, cardiopulmonary exercise testing (CPET) with measure of peak oxygen uptake (peakVO2) and deconditioning, pulmonary function testing, echocardiography and 6-min walk test. A high proportion (75.4%) of allo-HSCT survivors showed abnormal cardiopulmonary exercise testing parameters as compared to predicted normal values, including 49.3% patients who exhibited moderate to severe impairment in exercise capacity and 37.7% patients with physical deconditioning. PeakVO2 values were not accurately predicted by 6-min walk distances (r = 0.53). Disability and fatigue were strongly associated with decreased peakVO2 values (p = 0.002 and p = 0.008, respectively). Exercise capacity was reduced in most allo-HSCT long-term survivors. Because reduced exercise capacity was associated with fatigue, disability and a decrease in quality of life, cardiopulmonary exercise testing should be performed in every patient who reports fatigue and disability.

Sit-to-stand tests for COPD: A literature review.

BACKGROUND: Sit-to-stand tests (STST) have recently been developed as easy-to-use field tests to evaluate exercise tolerance in COPD patients. As several modalities of the test exist, this review presents a synthesis of the advantages and limitations of these tools with the objective of helping health professionals to identify the STST modality most appropriate for their patients. METHOD: Seventeen original articles dealing with STST in COPD patients have been identified and analysed including eleven on 1min-STST and four other versions of the test (ranging from 5 to 10 repetitions and from 30 s to 3 min). In these studies the results obtained in sit-to-stand tests and the recorded physiological variables have been correlated with the results reported in other functional tests. RESULTS: A good set of correlations was achieved between STST performances and the results reported in other functional tests, as well as quality of life scores and prognostic index. According to the different STST versions the processes involved in performance are different and consistent with more or less pronounced associations with various physical qualities. These tests are easy to use in a home environment, with excellent metrological properties and responsiveness to pulmonary rehabilitation, even though repetition of the same movement remains a fragmented and restrictive approach to overall physical evaluation. CONCLUSIONS: The STST appears to be a relevant and valid tool to assess functional status in COPD patients. While all versions of STST have been tested in COPD patients, they should not be considered as equivalent or interchangeable.

Microarray analysis reveals complex remodeling of cardiac ion channel expression with altered thyroid status: relation to cellular and integrated electrophysiology.

Although electrophysiological remodeling occurs in various myocardial diseases, the underlying molecular mechanisms are poorly understood. cDNA microarrays containing probes for a large population of mouse genes encoding ion channel subunits ("IonChips") were developed and exploited to investigate remodeling of ion channel transcripts associated with altered thyroid status in adult mouse ventricle. Functional consequences of hypo- and hyperthyroidism were evaluated with patch-clamp and ECG recordings. Hypothyroidism decreased heart rate and prolonged QTc duration. Opposite changes were observed in hyperthyroidism. Microarray analysis revealed that hypothyroidism induces significant reductions in KCNA5, KCNB1, KCND2, and KCNK2 transcripts, whereas KCNQ1 and KCNE1 expression is increased. In hyperthyroidism, in contrast, KCNA5 and KCNB1 expression is increased and KCNQ1 and KCNE1 expression is decreased. Real-time RT-PCR validated these results. Consistent with microarray analysis, Western blot experiments confirmed those modifications at the protein level. Patch-clamp recordings revealed significant reductions in I(to,f) and I(K,slow) densities, and increased I(Ks) density in hypothyroid myocytes. In addition to effects on K+ channel transcripts, transcripts for the pacemaker channel HCN2 were decreased and those encoding the alpha1C Ca2+ channel (CaCNA1C) were increased in hypothyroid animals. The expression of Na+, Cl-, and inwardly rectifying K+ channel subunits, in contrast, were unaffected by thyroid hormone status. Taken together, these data demonstrate that thyroid hormone levels selectively and differentially regulate transcript expression for at least nine ion channel alpha- and beta-subunits. Our results also document the potential of cDNA microarray analysis for the simultaneous examination of ion channel transcript expression levels in the diseased/remodeled myocardium.

Effects of diesel particles on the control of intracellular mycobacterial growth by human macrophages in vitro.

Changes that may modify the capacity of macrophages to control mycobacterial growth could favour the reactivation of bacillary proliferation within protective granulomas developed in response to mycobacterial infection. There is increasing evidence that diesel exhaust particles (DEPs) could suppress some macrophage functions, but it is not known whether DEPs may alter macrophage mycobactericidal activity. The aim of this study was to assess the effect of DEPs on the mycobactericidal activity of human mononuclear phagocytes in vitro. Human monocytes from healthy donors were cultured for 3 days in the presence or absence of DEPs or carbon black particles (CBPs), and then infected with a Mycobacterium bovis bacillus Calmette-Guérin reporter strain expressing luciferase activity. DEPs were rapidly internalized by monocyte-derived macrophages without cytotoxic effect. Mycobactericidal activity of cells exposed to DEPs was not different from that of cells cultured in their absence or in the presence of CBPs. Although our study was restricted to the mycobactericidal activity of human macrophages in vitro, the results indicate that DEPs do not directly influence the first line of defence against microorganisms. Whether exposure to DEPs influences the adaptive immune response against mycobacterial infections remains to be determined.

Acute respiratory failure revealing adult-onset Still's disease: diagnostic value of low glycosylated ferritin level.

The authors report three cases of adult-onset Still's disease with severe hypoxemic pulmonary involvement, mimicking severe pulmonary sepsis. Clinicians must be aware of this rare form of such disease. Low (<20%) glycosylated ferritin level in the presence of unexplained prolonged fever with leukocytosis can help in the diagnosis.

Is the 1-minute sit-to-stand test a good tool for the evaluation of the impact of pulmonary rehabilitation? Determination of the minimal important difference in COPD.

BACKGROUND: The 1-minute sit-to-stand (STS) test could be valuable to assess the level of exercise tolerance in chronic obstructive pulmonary disease (COPD). There is a need to provide the minimal important difference (MID) of this test in pulmonary rehabilitation (PR). METHODS: COPD patients undergoing the 1-minute STS test before PR were included. The test was performed at baseline and the end of PR, as well as the 6-minute walk test, and the quadriceps maximum voluntary contraction (QMVC). Home and community-based programs were conducted as recommended. Responsiveness to PR was determined by the difference in the 1-minute STS test between baseline and the end of PR. The MID was evaluated using distribution and anchor-based methods. RESULTS: Forty-eight COPD patients were included. At baseline, the significant predictors of the number of 1-minute STS repetitions were the 6-minute walk distance (6MWD) (r=0.574; P<10-3), age (r=-0.453; P=0.001), being on long-term oxygen treatment (r=-0.454; P=0.017), and the QMVC (r=0.424; P=0.031). The multivariate analysis explained 75.8% of the variance of 1-minute STS repetitions. The improvement of the 1-minute STS repetitions at the end of PR was 3.8±4.2 (P<10-3). It was mainly correlated with the change in QMVC (r=0.572; P=0.004) and 6MWD (r=0.428; P=0.006). Using the distribution-based analysis, an MID of 1.9 (standard error of measurement method) or 3.1 (standard deviation method) was found. With the 6MWD as anchor, the receiver operating characteristic curve identified the MID for the change in 1-minute STS repetitions at 2.5 (sensibility: 80%, specificity: 60%) with area under curve of 0.716. CONCLUSION: The 1-minute STS test is simple and sensitive to measure the efficiency of PR. An improvement of at least three repetitions is consistent with physical benefits after PR.

Long-term amiodarone administration remodels expression of ion channel transcripts in the mouse heart.

BACKGROUND: The basis for the unique effectiveness of long-term amiodarone treatment on cardiac arrhythmias is incompletely understood. The present study investigated the pharmacogenomic profile of amiodarone on genes encoding ion-channel subunits. METHODS AND RESULTS: Adult male mice were treated for 6 weeks with vehicle or oral amiodarone at 30, 90, or 180 mg x kg(-1) x d(-1). Plasma and myocardial levels of amiodarone and N-desethylamiodarone increased dose-dependently, reaching therapeutic ranges observed in human. Plasma triiodothyronine levels decreased, whereas reverse triiodothyronine levels increased in amiodarone-treated animals. In ECG recordings, amiodarone dose-dependently prolonged the RR, PR, QRS, and corrected QT intervals. Specific microarrays containing probes for the complete ion-channel repertoire (IonChips) and real-time reverse transcription-polymerase chain reaction experiments demonstrated that amiodarone induced a dose-dependent remodeling in multiple ion-channel subunits. Genes encoding Na+ (SCN4A, SCN5A, SCN1B), connexin (GJA1), Ca2+ (CaCNA1C), and K+ channels (KCNA5, KCNB1, KCND2) were downregulated. In patch-clamp experiments, lower expression of K+ and Na+ channel genes was associated with decreased I(to,f), I(K,slow), and I(Na) currents. Inversely, other K+ channel alpha- and beta-subunits, such as KCNA4, KCNK1, KCNAB1, and KCNE3, were upregulated. CONCLUSIONS: Long-term amiodarone treatment induces a dose-dependent remodeling of ion-channel expression that is correlated with the cardiac electrophysiologic effects of the drug. This profile cannot be attributed solely to the amiodarone-induced cardiac hypothyroidism syndrome. Thus, in addition to the direct effect of the drug on membrane proteins, part of the therapeutic action of long-term amiodarone treatment is likely related to its effect on ion-channel transcripts.