Thibaud Brunet

Laurent Bonello

Chekrallah Chamandi

Victoria Tea

Olivier Nallet

Thibault Lhermusier

Romain Gallet

Jean-Noel Labèque

Franck Albert

François Schiele

Jean Ferrières

Tabassome Simon

Nicolas Danchin

Etienne Puymirat
email: etienne.puymirat@aphp.fr

Long-term mortality after ST-elevation myocardial infarction in the reperfusion and modern secondary prevention therapy era according to coronary artery disease extent: The FAST-MI registries

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Objectif. -Evaluer la survie à 3 ans des patients avec un SCA ST+ pluri tronculaire comparé à ceux mono tronculaires.

Méthodes. -A partir des registres FAST-MI 2005, 2010 et 2015, 3 enquêtes nationales, nous avons inclus tous les patients avec un SCA ST+ traités par angioplastie primaire dans les 24 heures après l'apparition des symptômes. Les principales caractéristiques, la prise en charge et la survie à 3 ans de ces patients ont été analysées selon le statu coronaire (1, 2 ou 3 vaisseau[x] atteint[s]).

Résultats. -Parmi les 3907 patients inclus (âge moyen 62,4 ± 13,7 ans; 75,9 % d'homme), les patients pluri tronculaires représentaient 47,9 %. Globalement, ils étaient plus âgés avec un profil de risque plus sévère. En analyse multi variée, seuls les patients tri tronculaires avaient un sur risque de mortalité à 3 ans par rapport aux patients mono tronculaires (HR 1,52, IC95 % 1,68-2,26 ; P < 0,001).

Les patients pluri tronculaires revascularisés complétement (avant la sortie) avaient un pronostic similaire à ceux mono tronculaires (HR 1,17, IC95 % 0,84-1,64 ; P = 0,35).

Conclusions. -Les patients pluri tronculaires représentent encore une proportion importante des SCA ST+. Si l'atteinte tri tronculaire reste associée à une surmortalité à 3 ans, les patients pluri tronculaires complétement revascularisés semblent toutefois avoir un pronostic similaire à ceux mono tronculaires avec les traitements de reperfusion et de prévention secondaire modernes.

KEYWORDS

Background

In 40-65% of patients presenting with acute ST-segment elevation myocardial infarction (STEMI), additional angiographic significant lesions (i.e. > 50% diameter stenosis) may exist in non-culprit vessels [START_REF] Corpus | Multivessel percutaneous coronary intervention in patients with multivessel disease and acute myocardial infarction[END_REF][START_REF] Hanratty | Exaggeration of nonculprit stenosis severity during acute myocardial infarction: implications for immediate multivessel revascularization[END_REF][START_REF] Jaski | Outcome of urgent percutaneous transluminal coronary angioplasty in acute myocardial infarction: comparison of single-vessel versus multivessel coronary artery disease[END_REF][START_REF] Meliga | Early angio-guided complete revascularization versus culprit vessel PCI followed by ischemia-guided staged PCI in STEMI patients with multivessel disease[END_REF][START_REF] Windecker | ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI)[END_REF]. The presence of multivessel disease (MVD) in these patients is an important predictor of short-term as well as long-term mortality after primary percutaneous coronary intervention (PCI) compared with patients with single-vessel disease (1-VD) [START_REF] Corpus | Multivessel percutaneous coronary intervention in patients with multivessel disease and acute myocardial infarction[END_REF][START_REF] Hanratty | Exaggeration of nonculprit stenosis severity during acute myocardial infarction: implications for immediate multivessel revascularization[END_REF][START_REF] Jaski | Outcome of urgent percutaneous transluminal coronary angioplasty in acute myocardial infarction: comparison of single-vessel versus multivessel coronary artery disease[END_REF][START_REF] Meliga | Early angio-guided complete revascularization versus culprit vessel PCI followed by ischemia-guided staged PCI in STEMI patients with multivessel disease[END_REF][START_REF] Windecker | ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI)[END_REF].

Several sources, including registries specific to acute myocardial infarction (AMI) and large administrative or billing databases, have shown a decrease in mortality in patients with STEMI over the last 20 years [START_REF] Fox | Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006[END_REF][START_REF] Kostis | Myocardial Infarction Data Acquisition System (MIDAS 14) Study Group. Trends in mortality of acute myocardial infarction after discharge from the hospital[END_REF][START_REF] Movahed | Trends in the age adjusted mortality from acute ST segment elevation myocardial infarction in the United States (1988-2004) based on race, gender, infarct location and comorbidities[END_REF][START_REF] Puymirat | Acute Myocardial Infarction: Changes in Patient Characteristics, Management, and 6-Month Outcomes Over a Period of 20 Years in the FAST-Infarction) 1995 to 2015[END_REF][START_REF] Puymirat | Association of changes in clinical characteristics and management with improvement in survival among patients with ST-elevation myocardial infarction[END_REF][START_REF] Rogers | Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006[END_REF][START_REF] Rosamond | Twenty-two-year trends in incidence of myocardial infarction, coronary heart disease mortality, and case fatality in 4 US communities, 1987-2008[END_REF][START_REF] Steiger | Significant decrease in in-hospital mortality and major adverse cardiac events in Swiss STEMI patients between 2000 and December 2007[END_REF][START_REF] Szummer | Improved outcomes in patients with ST-elevation myocardial infarction during the last 20 years are related to implementation of evidence-based treatments: experiences from the SWEDEHEART registry 1995-2014[END_REF][START_REF] Yeh | Population trends in the incidence and outcomes of acute myocardial infarction[END_REF]. The decline in short-and long-term mortality in these patients is explained by several factors, including: increased use and improved delivery of reperfusion therapy, particularly primary PCI; temporal changes in patient population characteristics; and increased use and improved delivery of recommended secondary prevention [START_REF] Fox | Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006[END_REF][START_REF] Kostis | Myocardial Infarction Data Acquisition System (MIDAS 14) Study Group. Trends in mortality of acute myocardial infarction after discharge from the hospital[END_REF][START_REF] Movahed | Trends in the age adjusted mortality from acute ST segment elevation myocardial infarction in the United States (1988-2004) based on race, gender, infarct location and comorbidities[END_REF][START_REF] Puymirat | Acute Myocardial Infarction: Changes in Patient Characteristics, Management, and 6-Month Outcomes Over a Period of 20 Years in the FAST-Infarction) 1995 to 2015[END_REF][START_REF] Puymirat | Association of changes in clinical characteristics and management with improvement in survival among patients with ST-elevation myocardial infarction[END_REF][START_REF] Rogers | Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006[END_REF][START_REF] Rosamond | Twenty-two-year trends in incidence of myocardial infarction, coronary heart disease mortality, and case fatality in 4 US communities, 1987-2008[END_REF][START_REF] Steiger | Significant decrease in in-hospital mortality and major adverse cardiac events in Swiss STEMI patients between 2000 and December 2007[END_REF][START_REF] Szummer | Improved outcomes in patients with ST-elevation myocardial infarction during the last 20 years are related to implementation of evidence-based treatments: experiences from the SWEDEHEART registry 1995-2014[END_REF][START_REF] Yeh | Population trends in the incidence and outcomes of acute myocardial infarction[END_REF]. To our knowledge, the prognosis of patients with STEMI according to coronary status has not been recently assessed after these changes.

The aim of the present study was to evaluate characteristics, management and survival at 3 years in patients with STEMI undergoing primary PCI within the recommended delay (i.e. within 24 hours of symptoms onset) according to coronary status, in the modern reperfusion era and with optimized secondary prevention medication.

Methods

FAST-MI registries

Three nationwide French registries were conducted 5 years apart over a 10-year period (2005-2015):

French registry of Acute ST-elevation or non-ST-elevation Myocardial Infarction (FAST-MI) 2005 (ClinicalTrials.gov identifier: NCT00673036) [START_REF] Cambou | The French registry of Acute ST elevation or non-ST-elevation Myocardial Infarction (FAST-MI): study design and baseline characteristics[END_REF], FAST-MI 2010 (ClinicalTrials.gov identifier: NCT01237418) [START_REF] Hanssen | French Registry on Acute ST-elevation and non STelevation Myocardial Infarction 2010. FAST-MI 2010[END_REF] and FAST-MI 2015 (ClinicalTrials.gov identifier: NCT02566200) [START_REF] Belle | French Registry on Acute ST-elevation and non-ST-elevation Myocardial Infarction 2015 (FAST-MI 2015). Design and baseline data[END_REF] (Appendix).

The methods used for these registries have been detailed previously [START_REF] Cambou | The French registry of Acute ST elevation or non-ST-elevation Myocardial Infarction (FAST-MI): study design and baseline characteristics[END_REF][START_REF] Hanssen | French Registry on Acute ST-elevation and non STelevation Myocardial Infarction 2010. FAST-MI 2010[END_REF][START_REF] Belle | French Registry on Acute ST-elevation and non-ST-elevation Myocardial Infarction 2015 (FAST-MI 2015). Design and baseline data[END_REF]; briefly, their primary objectives were to evaluate the characteristics, management and outcomes of patients with AMI, as seen in routine clinical practice, on a countrywide scale.

All registries consecutively included patients with STEMI or non-ST-segment elevation myocardial infarction admitted to cardiac intensive care units within 48 hours of symptom onset, during a specified 1-month period (October to December 2005, 2010, and 2015). AMI was defined by increased levels of cardiac biomarkers (troponins, creatine kinase or creatine kinase myocardial band [CK-MB]), together with either compatible symptoms or electrocardiogram changes. Patients who died soon after admission and for whom cardiac markers were not measured were included if they had signs or symptoms associated with typical ST-segment changes. Exclusion criteria were: (1) refusal to participate; (2) iatrogenic myocardial infarction, defined as occurring within 48 hours of any therapeutic procedure; and (3) AMI diagnosis invalidated in favour of another diagnosis. STEMI was diagnosed when ST-segment elevation ≥ 1 mm was seen in at least two contiguous leads in any location on the index or qualifying electrocardiogram, or when presumed new left bundle branch block or documented new Q waves were observed.

Participation in the study was offered to all institutions that received AMI emergencies (including university teaching hospitals, general and regional hospitals and private clinics). Physicians were instructed that the study should not affect clinical care or management. The study was conducted in accordance with the guidelines on good clinical practice and French law. The study protocol for the

Study population

For the present analysis, we enrolled in the three surveys all consecutive patients with STEMI undergoing primary PCI within 24 hours of symptoms onset, with known coronary status (n = 4059).

Patients with previous coronary artery bypass grafting were excluded (n = 115), as were patients with no significant coronary artery disease (CAD) on coronary angiography (n = 37). Finally, 3907 patients were selected for this study ( A non-culprit lesion was defined as ≥ 50% diameter stenosis by visual estimate in at least one non-infarct-related vessel. In addition, non-culprit lesions had to be located in a vessel that was not stented as part of the index culprit lesion PCI. To define CAD extent, all three coronary arteries were assigned one point each, and two points for the left main coronary artery, whatever the status of the left anterior descending and left circumflex arteries, resulting in a maximum score of 3 (i.e. 1-VD versus two-vessel disease [2-VD] versus three-vessel disease ). Multivessel CAD was defined as 2-VD or 3-VD. Procedural success for the culprit lesion was defined as a final Thrombolysis In Myocardial Infarction (TIMI) flow of 2 or 3 after PCI, whereas failure was defined as a final TIMI flow of 0 or 1 (data available in 3576/3907 patients). Finally, complete myocardial revascularization was defined by successful PCI of the culprit lesion and all non-culprit lesions (i.e. restoration of blood supply to the myocardium), achieved before discharge.

Patient characteristics, management and outcomes were analysed according to coronary status (i.e. 1-VD versus 2-VD versus 3-VD). The primary endpoint of the study was survival at 3 years.

Data collection

Data on baseline characteristics, including demographics, risk factors and medical history, were collected as described previously [START_REF] Cambou | The French registry of Acute ST elevation or non-ST-elevation Myocardial Infarction (FAST-MI): study design and baseline characteristics[END_REF][START_REF] Hanssen | French Registry on Acute ST-elevation and non STelevation Myocardial Infarction 2010. FAST-MI 2010[END_REF][START_REF] Belle | French Registry on Acute ST-elevation and non-ST-elevation Myocardial Infarction 2015 (FAST-MI 2015). Design and baseline data[END_REF]. Information on the use of cardiac procedures, including the use of PCI and the use of medications (anticoagulants, antiplatelet agents, diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and lipid-lowering agents) in the first 48 hours and at hospital discharge, was collected. For all surveys, follow-up was centralized at the French Society of Cardiology. Three-year mortality follow-up was > 97% complete.

Statistical analysis

Continuous variables are reported as means ± standard deviations or medians (interquartile ranges), as appropriate. Discrete variables are described as counts and percentages. Groups were compared by analysis of variance for continuous variables and by the χ 2 test (or Fisher's exact test) for discrete variables. Hazard ratios (HRs) are presented with their 95% confidence intervals (CIs). Survival curves were estimated using the Kaplan-Meier estimators and were compared using log-rank tests. One-year and 3-year survival were analysed according to number of vessels involved, and the impact of MVD was compared using a multivariable backward stepwise Cox analysis, with a threshold of 0.10 for variable elimination, among the different risk groups. Variables included in the final models were selected ad hoc, based on their physiological relevance and potential to be associated with outcomes; they comprised age, sex, risk factors, co-morbidities, left ventricular ejection fraction, year of the study and management (medications and interventional). Procedural success and complete myocardial revascularization were added in a second model, including four groups: 1-VD with successful PCI; MVD with complete revascularization before discharge; MVD without complete revascularization before discharge; and primary PCI failure. A sensitivity analysis was performed in the population surviving the index hospitalization. Analyses were repeated using forward stepwise analysis to check the consistency of the results. Statistical analyses were performed using IBM SPSS Statistics, version 26.0 (IBM SPSS Inc., Chicago, IL, USA). For all analyses, two-sided P values < 0.05 were considered significant. Patients with MVD were older, with more risk factors and co-morbidities (i.e. chronic kidney disease, history of stroke, peripheral artery disease and atrial fibrillation); more of these patients had a history of myocardial infarction and myocardial revascularization.

Results

Patient characteristics

Clinical presentation and management

Median time from symptom onset to first call (patient delay) was longer in patients with MVD, whereas no difference was observed in delay from call to primary PCI (system delay) (Table 2).

Clinical presentation on admission was different according to coronary status (Table 2). The proportion of anterior myocardial infarction was higher in patients with 1-VD. Symptoms of heart failure (Killip class ≥ II) were more frequent in patients with MVD (1-VD, 8.7%; 2-VD, 11.5%; 3-VD, 17%; P < 0.001). The Global Registry of Acute Coronary Events (GRACE) score increased gradually from patients with 1-VD to patients with 3-VD (1-VD, 139 ± 32; 2-VD, 145 ± 31; 3-VD, 150 ± 33; P < 0.001).

The rates of TIMI score 0/1 for the culprit lesion before primary PCI were similar in all groups.

Procedural characteristics are detailed in Table 2. Thrombus aspiration was mainly used in patients with 1-VD. Drug-eluting stents were used similarly in all study groups. Proportion of PCI success (i.e. TIMI score 2/3 after PCI) was higher in patients with 1-VD (95.7% in the overall population). In patients with MVD, 41% had complete myocardial revascularization before discharge. The rate of patients with MVD and complete revascularization before discharge increased from 29.9% to 58.9% between 2005 and 2015.

Medications used during the first 48 hours are listed in Table A.1. Ticagrelor and prasugrel were prescribed more frequently in patients with 1-VD, as were glycoprotein IIb/IIIa inhibitors. Finally, no difference was observed for anticoagulant therapies, statins and beta-blockers according to number of vessels involved. Diuretics were mainly used in patients with MVD.

In-hospital complications and mortality at 1 and 3 years

In-hospital complications were more frequent in patients with MVD (Table A.2). The in-hospital death rates were 2.0%, 3.5% and 4.5%, according to coronary status (1-VD, 2-VD and 3-VD, respectively; P < 0.001). Medications at discharge are listed in Table A.3. Overall, the use of recommended medications (beta-blockers, antiplatelet therapy, statins and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) was lower in patients with 3-VD.

At 1 year, only patients with 3-VD had significantly higher mortality compared with patients with 1-VD (for 2-VD: HR 1.22, 95% CI 0.87-1.72 [P = 0.25]; for 3-VD: HR 1.52, 95% CI 1.04-2.22 [P = 0.03]; for all MVD: HR 1.33, 95% CI 0.97-1.81 [P = 0.07]) (Table A.4). At 3 years, the mortality rate was higher in patients with MVD and in those with 3-VD only compared with patients with 1-VD (for 2-VD: HR 1.22, 95% CI 0.92-1.58 [P = 0.18]; for 3-VD: HR 1.52, 95% CI 1.68-2.26 [P < 0.001]; for all MVD: HR 1.34, 95% CI 1.05-1.71 [P = 0.02]) (Fig. 1, Table 3). Similar results were found after excluding patients who died during the index hospital stay (data not shown).

Finally, in patients with MVD, the prognosis at 3 years did not differ compared with patients with 1-VD in those with successful complete myocardial revascularization before discharge (HR 1.17, 95% CI 0.84- 2). Similar results were found after excluding patients who died during the index hospitalization (data not shown).

Discussion

Multivessel disease is currently found in approximately 50% of patients with STEMI undergoing primary PCI within the recommended delay. Patients with MVD have a more severe cardiovascular risk profile and, even in the current era, they receive fewer recommended secondary prevention medications compared with patients with 1-VD. The independent deleterious impact of CAD extent on mortality is mostly found in patients with 3-VD, but is no longer present in patients with MVD who get complete revascularization during the initial hospital stay.

Improvement in survival among patients with STEMI

Over the last 25 years, several registries specific to AMI and large administrative or billing databases have shown a decrease in mortality in patients with STEMI [START_REF] Fox | Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006[END_REF][START_REF] Kostis | Myocardial Infarction Data Acquisition System (MIDAS 14) Study Group. Trends in mortality of acute myocardial infarction after discharge from the hospital[END_REF][START_REF] Movahed | Trends in the age adjusted mortality from acute ST segment elevation myocardial infarction in the United States (1988-2004) based on race, gender, infarct location and comorbidities[END_REF][START_REF] Puymirat | Acute Myocardial Infarction: Changes in Patient Characteristics, Management, and 6-Month Outcomes Over a Period of 20 Years in the FAST-Infarction) 1995 to 2015[END_REF][START_REF] Puymirat | Association of changes in clinical characteristics and management with improvement in survival among patients with ST-elevation myocardial infarction[END_REF][START_REF] Rogers | Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006[END_REF][START_REF] Rosamond | Twenty-two-year trends in incidence of myocardial infarction, coronary heart disease mortality, and case fatality in 4 US communities, 1987-2008[END_REF][START_REF] Steiger | Significant decrease in in-hospital mortality and major adverse cardiac events in Swiss STEMI patients between 2000 and December 2007[END_REF][START_REF] Szummer | Improved outcomes in patients with ST-elevation myocardial infarction during the last 20 years are related to implementation of evidence-based treatments: experiences from the SWEDEHEART registry 1995-2014[END_REF][START_REF] Yeh | Population trends in the incidence and outcomes of acute myocardial infarction[END_REF]. Most benefits in short-and longterm outcomes in patients with STEMI were related to the uptake and increased use of new and, in time, established interventional and medical treatments [START_REF] Windecker | ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI)[END_REF]. Improvement in hospital survival was mainly related to the increased use of reperfusion treatment, including primary PCI, although the reduction in mortality was also associated with a substantial change in the patient risk profile [START_REF] Puymirat | Association of changes in clinical characteristics and management with improvement in survival among patients with ST-elevation myocardial infarction[END_REF].

Improved survival among patients with STEMI has been reported in all categories of patients over the last 25 years [START_REF] Fox | Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006[END_REF][START_REF] Kostis | Myocardial Infarction Data Acquisition System (MIDAS 14) Study Group. Trends in mortality of acute myocardial infarction after discharge from the hospital[END_REF][START_REF] Movahed | Trends in the age adjusted mortality from acute ST segment elevation myocardial infarction in the United States (1988-2004) based on race, gender, infarct location and comorbidities[END_REF][START_REF] Puymirat | Acute Myocardial Infarction: Changes in Patient Characteristics, Management, and 6-Month Outcomes Over a Period of 20 Years in the FAST-Infarction) 1995 to 2015[END_REF][START_REF] Puymirat | Association of changes in clinical characteristics and management with improvement in survival among patients with ST-elevation myocardial infarction[END_REF][START_REF] Rogers | Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006[END_REF][START_REF] Rosamond | Twenty-two-year trends in incidence of myocardial infarction, coronary heart disease mortality, and case fatality in 4 US communities, 1987-2008[END_REF][START_REF] Steiger | Significant decrease in in-hospital mortality and major adverse cardiac events in Swiss STEMI patients between 2000 and December 2007[END_REF][START_REF] Szummer | Improved outcomes in patients with ST-elevation myocardial infarction during the last 20 years are related to implementation of evidence-based treatments: experiences from the SWEDEHEART registry 1995-2014[END_REF][START_REF] Yeh | Population trends in the incidence and outcomes of acute myocardial infarction[END_REF]. To our knowledge, there is no recent comparison focused on patients with MVD compared with those with 1-VD. Using clinical trial data from patients with STEMI with myocardial revascularization and MVD from 2008, it is possible to estimate the trends in all-cause mortality over the last 10-year period [START_REF] Engstrom | Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial[END_REF][START_REF] Gershlick | Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial[END_REF][START_REF] Mehta | Complete Revascularization with Multivessel PCI for Myocardial Infarction[END_REF][START_REF] Smits | Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction[END_REF][START_REF] Wald | Randomized trial of preventive angioplasty in myocardial infarction[END_REF]. In the Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial, the rate of all-cause death (mean follow-up of 23 months) was 5.1% (12/234) in patients with preventive PCI and 6.9% (16/231) in those without preventive PCI [START_REF] Wald | Randomized trial of preventive angioplasty in myocardial infarction[END_REF]. In contrast, in the most recent study (Complete versus Culprit-Only Revascularization Strategies to Treat Multivessel Disease after Early PCI for STEMI [COMPLETE] trial), the rate of all-cause death (median follow-up of 3 years) was 2.6% in patients who had a complete revascularization strategy and 2.7% in those with culprit lesion-only PCI, which represents a decrease of 56% in terms of mortality over a 6-year period between the two trials [START_REF] Mehta | Complete Revascularization with Multivessel PCI for Myocardial Infarction[END_REF]. Similar trends have been reported for major cardiovascular events, although it is difficult to compare all these studies because primary outcomes and follow-up durations were not similar [START_REF] Engstrom | Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial[END_REF][START_REF] Gershlick | Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial[END_REF][START_REF] Mehta | Complete Revascularization with Multivessel PCI for Myocardial Infarction[END_REF][START_REF] Smits | Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction[END_REF][START_REF] Wald | Randomized trial of preventive angioplasty in myocardial infarction[END_REF]. These data suggest that the prognosis of patients with STEMI has changed, whatever the extent of CAD, and the difference in mortality according to coronary status has narrowed. In our analyses, the adjusted difference in mortality between 1-VD and MVD was observed only in patients with 3-VD.

Management of STEMI with MVD

Primary PCI is the preferred reperfusion strategy in patients with STEMI within 12 hours of symptom onset. MVD is commonly reported in this population (in approximately 50%), as observed in our study.

A series of clinical trials has proven the improved survival and lower morbidity with complete myocardial revascularization compared with culprit lesion-only PCI in patients with STEMI with MVD [START_REF] Engstrom | Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial[END_REF][START_REF] Gershlick | Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial[END_REF][START_REF] Mehta | Complete Revascularization with Multivessel PCI for Myocardial Infarction[END_REF][START_REF] Smits | Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction[END_REF][START_REF] Wald | Randomized trial of preventive angioplasty in myocardial infarction[END_REF]. This has led to very consistent global treatment recommendations. Therefore, the use of complete myocardial revascularization has increased over the last 10 years, even if the optimal timing of complete revascularization is a matter of debate [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[END_REF].

In the COMPLETE trial, the benefit of complete revascularization was consistently observed, regardless of whether non-culprit-lesion PCI was performed during the index hospitalization or several weeks after discharge from hospital [START_REF] Mehta | Complete Revascularization with Multivessel PCI for Myocardial Infarction[END_REF]. Our observational data suggest that complete revascularization performed before discharge is probably preferable to subsequent scheduled PCI of significantly narrowed non-culprit lesions.

On the other hand, the International Study of Comparative Health Effectiveness with Medical and

Invasive Approaches (ISCHEMIA) did not find evidence that the initial invasive strategy reduced the risk of ischaemic cardiovascular events or death from any cause [START_REF] Maron | Initial Invasive or Conservative Strategy for Stable Coronary Disease[END_REF]. These data were obtained in patients with coronary chronic syndrome and moderate or severe ischaemia (i.e. not in patients with recent myocardial infarction).

Study limitations

Our study suffers from the same limitations as all observational studies: namely, no causality can be asserted between variables that are correlated. Comparisons between patients with 1-VD and those with MVD with complete revascularization before discharge were not randomized and, despite careful adjustments on a large number of potentially confounding variables, the results can only be considered indicative. Only patients with STEMI of ≤ 24 hours' duration admitted to a cardiac catheterization laboratory were included, which represents a selection bias. Details of myocardial revascularization after discharge were not available, especially the rate of late complete revascularization. Patients with cardiogenic shock accounted for fewer than 5% of patients in the present study, and complete revascularization in this population needs to be confirmed. Finally, the fact that patients with complete revascularization had a long-term mortality rate similar to that of patients with 1-VD should not be viewed as an incentive to perform complete revascularization "at any cost". Indeed, it is expected that a substantial proportion of patients with incomplete revascularization had long-standing total coronary occlusions of arteries supplying a myocardial scar; in such patients, with permanently impaired left ventricular function, reopening the corresponding artery would be unlikely to improve long-term outcome.

Conclusions

Patients with STEMI with MVD still represent half of patients with STEMI, and maintain a more severe cardiovascular risk profile, with a higher rate of mortality at 3 years of follow-up. However, in the contemporary era, patients with MVD and complete revascularization before discharge have a longterm mortality that no longer differs substantially from that of patients with 1-VD. a Including patients with 2-VD and 3-VD.

b Comparison between patients with 1-VD versus 2-VD versus 3-VD.

  2005 registry was reviewed by the Committee for the Protection of Persons (CPP) in Biomedical Research of Saint Antoine University Hospital, Paris; the 2010 registry was reviewed and approved by the CPP of Saint Louis University Hospital, Paris; and the protocol of 2015 registry was reviewed and approved by the CPP of Saint Louis University Hospital, Paris, France. Data file collection and storage were approved by the Commission Nationale Informatique et Liberté. All patients were informed of the nature and aims of the surveys, and could request to be excluded; in addition, written consent was obtained for all three surveys.

  Fig. A.1).

Fig

  Fig. A.1 shows the patient recruitment flow chart. Briefly, out of 13,130 patients enrolled in the FAST-MI registries, 3907 patients with STEMI undergoing PCI within 24 hours of symptoms onset with available medical information were enrolled for the present analysis. The mean age of the population was 62.4 ±13.7 years (75.9% male). MVD was present in 47.9% of patients. Patient characteristics are presented in Table 1 according to coronary status (i.e. 1-VD, 2-VD, 3-VD and MVD). Overall, cardiovascular risk profile increased progressively from patients with 1-VD to patients with 3-VD.

Figure 1 .

 1 Figure 1. Three-year survival according to coronary status. 1-VD: single-vessel disease; 2-VD: twovessel disease; 3-VD: three-vessel disease; CI: confidence interval; HR: hazard ratio.

Figure 2 .

 2 Figure 2. Three-year survival according to coronary status and myocardial revascularization. MVD: multivessel disease; PCI: percutaneous coronary intervention; VD: vessel disease.

  1.64 [P = 0.35] in all patients with MVD; HR 1.19, 95% CI 0.83-1.73 [P = 0.35] in patients with 2-VD; HR 1.23, 95% CI 0.70-2.18 [P = 0.47] in patients with 3-VD). In contrast, patients with MVD without complete myocardial revascularization had higher mortality rates than patients with 1-VD (HR 1.54, 95% CI 1.16-2.04 [P = 0.003] in all patients with MVD; HR 1.34, 95% CI 0.96-1.86 [P = 0.09] in patients with 2-VD; HR 1.84, 95% CI 1.29-2.63 [P < 0.001] in patients with 3-VD), as did

	patients with failed PCI of the culprit lesion (HR 1.88, 95% CI 1.19-2.98 [P = 0.007] in all patients with
	MVD; HR 1.60, 95% CI 0.92-2.79 [P = 0.097] in patients with 2-VD; HR 2.46, 95% CI 1.47-4.11 [P <
	0.001] in patients with 3-VD) (Table A.5, Table A.6, Fig.

Table 1

 1 Baseline characteristics.

		All patients	1-VD	2-VD	3-VD	MVD a	P b
		(n = 3907)	(n = 2034)	(n = 1247)	(n = 626)	(n = 1873)
	Age (years)	62.4 ± 13.7	60.3 ± 13.7	64.2 ± 13.2	65.9 ± 13.4	64.8 ± 13.4	< 0.001
	Age ≥ 75 years	827 (21.2)	352 (17.3)	299 (24.0)	176 (28.1)	475 (25.4)	< 0.001
	Men	2964 (75.9)	1536 (75.5)	927 (74.3)	501 (80.0)	1428 (76.2)	0.002
	Risk factors
	Hypertension	1736 (44.4)	803 (39.5)	595 (47.7)	338 (54.0)	933 (49.8)	< 0.001
	Diabetes	655 (16.8)	253 (12.4)	263 (21.1)	139 (22.2)	402 (21.5)	< 0.001
	Hypercholesterolaemia	1530 (39.2)	713 (35.1)	557 (44.7)	260 (41.5)	817 (43.6)	< 0.001
	Current smoking	1695 (43.4)	985 (48.4)	482 (38.7)	228 (36.4)	710 (37.9)	< 0.001
	Family history	997 (25.5)	531 (26.1)	317 (25.4)	149 (23.8)	466 (24.9)	0.51
	BMI ≥ 30 kg/m²	764 (20.6)	399 (20.6)	233 (19.7)	132 (22.3)	365 (20.6)	0.45
	Medical history
	Previous MI	410 (10.5)	163 (8.0)	166 (13.3)	81 (12.9)	247 (13.2)	< 0.001
	Previous PCI	430 (11.0)	179 (8.8)	175 (14.0)	76 (12.1)	251 (13.4)	< 0.001
	History of stroke	159 (4.1)	69 (3.4)	51 (4.1)	39 (6.2)	90 (4.8)	< 0.001
	Peripheral artery disease	171 (4.4)	69 (3.4)	55 (4.4)	47 (7.5)	102 (5.4)	< 0.001

Table 2

 2 Clinical presentation and management.

	All patients	1-VD	2-VD	3-VD	MVD a	P b
	(n = 3907)	(n = 2034)	(n = 1247)	(n = 626)	(n = 2034)

Data are expressed as number (%), mean ± standard deviation or median (interquartile range). 1-VD: single-vessel disease; 2-VD: two-vessel disease; 3-VD: three-vessel disease; DBP: diastolic blood pressure; GRACE: Global Registry of Acute Coronary Events; IABP: intra-aortic balloon pump; LVEF: left ventricular ejection fraction; MI: myocardial infarction; MVD: multivessel disease; PCI: primary coronary intervention; SBP: systolic blood pressure; SRI: Simple Risk Index; TIMI: Thrombolysis In Myocardial Infarction.

myocardial infarction; MVD: multivessel disease; NOAC: non-vitamin K antagonist oral anticoagulant; PCI: percutaneous coronary intervention. a Including patients with 2-VD and 3-VD. b Comparison between patients with 1-VD versus 2-VD versus 3-VD.

Acknowledgements

The authors are deeply indebted to all patients who accepted to participate in the surveys, and to the physicians who took care of the patients at the participating institutions.

Boehringer Ingelheim, the Daiichi-Sankyo/Eli-Lilly alliance, GSK, MSD, Novartis, Pfizer, Sanofi and Servier, and by a grant from the French National Health Insurance body (CNAM-TS).

None of the companies had a role in the design and conduct of the study, or in the data collection and management.

Sources of funding

The FAST-MI 2005, 2010 and 2015 registries are the property of the French Society of Cardiology, and were funded by grants from the following companies: Amgen, AstraZeneca, Bayer, BMS,

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this manuscript.


Benoit Llopis

Pascal Robidou

Nadine Tissot

Bruno Pinna

Paul Gougis

Fleur Cohen Aubart

Luca Campedel

Baptiste Abbar

Damien Roos Weil

Madalina Uzunov

Rashmi Madhukar

Akshay T Jagadeesh

Melissa Y Y Moey

Martino Vaglio

Fabio Badilini

Monique Leban

Agnès Hartemann

Pauline Dureau

Christian Funck-Bretano

Olivier Bourron

Joe-Elie Salem
email: joe-elie.salem@aphp.fr

of thyroid-stimulating hormone with corrected QT interval variation: A prospective cohort study among patients with type 2 diabetes

Keywords: Thyroid-stimulating hormone, Electrocardiogram, QT prolongation, Arrhythmias

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Diabetes

Abbreviations: ANCOVA, analysis of covariance; CI, confidence interval; Cred-drugsTdP, drugs known to cause TdP according to the CredibleMeds website; DIACART, Diabète et Calcification Arterielle; HbA1c, haemoglobin A1c (glycated haemoglobin); IGF1, insulin-like growth factor 1; IQR, interquartile range; QTc, QT interval corrected for heart rate; QTcB, Bazett's corrected QT interval; QTcF, Fridericia's corrected QT interval; T2DM, type 2 diabetes mellitus; T3, triiodothyronine; T4, thyroxine; TdP, torsadesde-pointes; TSH, thyroid-stimulating hormone; VA, ventricular arrhythmia.

Background

Patients with type 2 diabetes mellitus (T2DM) have a predilection for prolonged QTc duration, ventricular arrhythmias (VAs) and sudden cardiac death [START_REF] Veglio | QT interval, cardiovascular risk factors and risk of death in diabetes[END_REF] compared with the general population. The QT interval corrected for heart rate (QTc) serves as an inexpensive and non-invasive modality by which clinicians can assess ventricular repolarization -heterogeneity of which may cause a particular form of VA, called torsades-de-pointes (TdP) [START_REF] Castro-Torres | Ventricular repolarization markers for predicting malignant arrhythmias in clinical practice[END_REF]. Apart from an increased risk of VAs, prolonged QTc has also been shown to be a predictor of mortality among patients with T2DM [START_REF] Veglio | QT interval, cardiovascular risk factors and risk of death in diabetes[END_REF].

The aetiologies for QTc prolongation and risk of VAs among patients with diabetes are complex, because of several concomitant conditions and hormonal fluctuations that can affect action potential duration. Conditions that are often prevalent in the diabetic population, such as systemic arterial hypertension, hypoglycaemia associated with autonomic dysfunction, left ventricular hypertrophy, conduction abnormalities and systolic dysfunction, have been previously shown to be associated with prolongation of QTc in T2DM [START_REF] Rana | Relation of QT interval dispersion to the number of different cardiac abnormalities in diabetes mellitus[END_REF]. Concomitant overt and subclinical thyroid disorders frequently observed among patients with diabetes may further increase the risk of QTc prolongation and VAs as a result of the effect of thyroid-stimulating hormone (TSH) on action potential duration [START_REF] Alonso | Thyroid stimulating hormone directly modulates cardiac electrical activity[END_REF]. In fact, changes observed in repolarization on electrocardiograms in patients with subclinical hypothyroidism (normal triiodothyronine

[T3] or thyroxine [T4] concentrations and elevated TSH) are similar to those in patients with overt hypothyroidism, which suggests a direct role for TSH in the regulation of the cardiac conduction system and risk of TdP [START_REF] Tayal | Thyroid dysfunction and electrocardiographic changes in subjects without arrhythmias: a cross-sectional study of primary healthcare subjects from Copenhagen[END_REF]. The temporal variations in these clinical and biochemical factors and in QTc duration, however, have not been fully elucidated.

We aimed to identify key clinical and biochemical covariates associated with Fridericia's corrected QT interval (QTcF) and their variation over time in a prospective cohort of patients with T2DM at high risk of cardiovascular disease.

Methods

Study design

Our work is ancillary to the Diabète et Calcification Arterielle (DIACART) study, a single-centre prospective observational cohort study among French patients with T2DM. The detailed protocol for our current study has been described elsewhere [START_REF] Bourron | Below-knee arterial calcification in type 2 diabetes: association with receptor activator of nuclear factor kappaB ligand, osteoprotegerin, and neuropathy[END_REF]. All patients provided written informed consent, and the study was approved by the institutional ethics committee. The DIACART study is registered at ClinicalTrials.gov (Identifier: NCT02431234).

Study population

Our study population consisted of a subset of patients who were recruited for the DIACART study; the selection of our study population from the DIACART study is outlined in Fig. 1. Over an 8-month period, 215 patients with T2DM aged ≥ 50 years (60 years for women), at high risk of cardiovascular disease (peripheral artery disease and heart failure), seen in the departments of cardiology and diabetology at the Pitié-Salpêtrière Hospital (Paris, France), were included in the DIACART study at times T1 (baseline) and T2 (follow-up). The main exclusion criteria were severe chronic kidney disease or end-stage renal failure (calculated as estimated glomerular filtration rate < 30 mL/min using the Modification of Diet in Renal Disease equation). As QTcF measurements are unreliable in patients with prolonged QRS (> 130 ms), multiple premature ventricular contractions, ventricular pacing and supraventricular tachycardia, patients with these conditions were excluded from this study (Fig. 1).

Clinical evaluation and laboratory tests

A detailed medical history was taken and a clinical examination was performed at the Centre d'Investigation Clinique-Paris Est (CIC-1901, Pitié-Salpêtrière Hospital, France). Medication history was obtained from the patients to identify those who were taking drugs known to increase the risk of TdP according to the CredibleMeds website (Cred-drugsTdP) [START_REF] Woosley | QT Drugs Lists[END_REF]. Urine and blood samples were collected after an overnight fast to perform routine biochemical tests, acquire lipid and thyroid profiles, measure blood glucose, haemoglobin A1c (HbA1c; glycated haemoglobin) and electrolytes and assess renal function.

Electrocardiography acquisition and QTc analysis

Electrocardiograms were recorded using a digital electrocardiograph (ELI 280, V1.02.01; Mortara Instrument, Inc., Milwaukee, WI, USA) by trained nurses, with a sampling rate of 1000 Hz and a filter of 150 Hz. The 12-lead 10-second resting triplicate electrocardiograms were analysed with the concatenation method: the three 10-second sequences of the triplicate electrocardiogram were used as a single 30-second electrocardiogram, followed by semiautomated QTc determination, using a unique superimposed median beat, by the overlap method (Fig. 2; CalECG® software; AMPS LLC, New York, NY, USA). In our centre, inter-and intraobserver variability assessment for QTc measurement using this method was performed, which has been detailed elsewhere [START_REF] Saque | Fast, accurate and easy-to-teach QT interval assessment: The triplicate concatenation method[END_REF]. The QT interval was corrected for heart rate by Fridericia's method. Although Bazett's method (QTcB) is most widely used, several studies have shown its inferiority compared with Fridericia's method, as QTcB tends to overcorrect the QT interval at low heart rate and undercorrect it at high heart rate in both sexes [START_REF] Vandenberk | Which QT Correction Formulae to Use for QT Monitoring?[END_REF]. In addition, in a hospitalized setting, QTcF was a better predictor of 30-day and 1-year all-cause mortality than QTcB [START_REF] Vandenberk | Which QT Correction Formulae to Use for QT Monitoring?[END_REF].

Statistical analyses

Data were analysed using the Statistical Package for Social Services, version 24 (IBM Corp. Armonk, NY, USA) and XLSTAT® (Addinsoft, Paris, France). Pearson's or Spearman's correlation coefficients and analysis of covariance (ANCOVA) were calculated to assess the associations between QTcF and patient characteristics, as appropriate. Studied variables were age, sex, homeostatic model assessment of insulin resistance, circulating concentrations of glucose, insulin, insulin-like growth factor1 (IGF1), albumin, creatinine, HbA1C, corrected calcium, potassium, TSH, T3, T4 and Cred-drugsTdP. A univariate correlation analysis between QTcF and patients' characteristics at both T1 and T2 was performed to select variables to be considered for the multivariable model. The multivariable models (ANCOVA at T1 and T2) were selected using a stringent criterion, i.e. the lowest Schwartz Bayesian criterion. Statistical analyses were two-tailed, with a P value < 0.05 deemed significant.

Results

Baseline demographics and clinical and biochemical characteristics in patients with T2DM

Out of the 215 cases enrolled in DIACART, 169 returned for follow-up measurements. Forty-five cases at T1 and 29 at T2 with conditions that rendered QTcF measurements unreliable (prolonged QRS, supraventricular tachycardia, ventricular pacing and multiple premature ventricular contractions) were excluded from the study (Fig. 1).

The demographic, clinical and biochemical profiles of the 170 and 140 patients with T2DM ultimately included at times T1 and T2, respectively, are shown in Table 1. T1 and T2 were separated by a median of 2.55 years (interquartile range [IQR] 2.34-2.81 years). Mean age was 63.9 ± 8.5 years at the beginning of the study, and 38/170 (22.35%) patients were female. Median HbA1c was 7.50% (IQR 7.00-8.33) at T1 and 7.65% (IQR 6.9-8.30) at T2. Normal, borderline and prolonged QTcF were defined as QTcF < 430 ms, 430-450 ms and > 450 ms, respectively, in men, and 20 ms above these thresholds in women. A total of 20/170 (11.8%) and 26/140 (18.6%) participants had prolonged QT (borderline or prolonged QT) at T1 and T2, respectively. A total of 8/170 (4.7%) patients at T1 and 8/140 (5.7%) at T2 were taking Cred-drugsTdP [START_REF] Woosley | QT Drugs Lists[END_REF]. A majority (88.8% at T1 and 91.4% at T2) of the study population were euthyroid, and only one patient had hypothyroidism at T1 (Table 1).

Clinical and hormonal correlations with QTcF in patients with T2DM

Results of the univariate association between QTcF and the tested clinical and hormono-metabolomic circulating concentrations in this T2DM cohort are shown in Table 2. The variables showing a significant univariate correlation with QTcF were then considered for multivariable analysis. Using multiple regression and analysis of covariance (Table 2), five covariates: sex (β = 0.24 ± 0.07 for females), Cred-drugsTdP (β = 0.19 ± 0.07), TSH concentration (β = 0.18 ± 0.07), triglyceride concentration (β = 0.16 ± 0.07) and potassium concentration (β = -0.19 ± 0.07) were associated with QTcF (r = 0.48, P < 0.0001) at T1. Similarly, at T2, four covariates: sex (β = 0.25 ± 0.08 for females), Cred-drugsTdP (β = 0.25 ± 0.08), TSH concentration (β = 0.19 ± 0.08) and hypertension (β = 0.2 ± 0.08), were associated with QTcF (r = 0.46, P < 0.0001). Compared with males, females had a 11.7 ms increase in QTcF at T1 (P = 0.001) and a 13.6 ms increase at T2 (P = 0.002). Patients taking Cred-drugsTdP had an 18.7 ms increase in QTcF at T1 (P = 0.007) and a 25.1 ms increase in QTcF duration at T2 (P = 0.01) versus those who were not taking Cred-drugsTdP. With every unit increase in normalized TSH concentration, there was a significant 3.2 ms increase in QTcF at T1 (P = 0.01) and a 3 ms increase in QTcF at T2 (P = 0.01). Of note, there was no significant correlation between QTcF and free T3 (T1: r = 0.04, P = 0.6; T2: r = -0.1, P = 0.3) or free T4 (T1: r = 0.01, P = 0.9; T2: r = 0.1, P = 0.3). IGF1 was associated with QTcF in univariate analysis at both T1 (r = -0.17, P = 0.03) and T2 (r = -0.25, P = 0.003), but was not retained in the stepwise variable selection model (Table 2).

Temporal variation in TSH and QTcF in patients with T2DM

There were 132 patients with paired values for T1 and T2, which were used to analyse the trends in QTcF over time and their relationship with variations in other covariates. There was a significant increase in mean QTcF from T1 to T2 (mean difference 3.60 ms, 95% confidence interval [CI] 0.42-6.77; P = 0.03) (Fig. 3). We studied the effects of variations in the covariates that were found to be significantly associated with QTcF at both T1 and T2 (use of Cred-drugsTdP and TSH) on the variation in QTcF (as given by values in T2 minus those in T1). Changes in TSH and in the patient's Cred-drugsTdP status were correlated with variation in QTcF (r = 0.24, P = 0.007, n = 123 and r = 0.2, P = 0.02, n = 132, respectively) (Fig. 4). Furthermore, as a sensitivity analysis, when excluding patients who were on a drug from the Cred-drugsTdP list either at T1 or T2, the significant association between change in TSH concentration and variation in QTcF persisted (r = 0.19, P = 0.04, n = 113).

Discussion

To the best of our knowledge, our study is the first to demonstrate an association between a change in QTcF over time and a change in TSH concentration in euthyroid patients with T2DM, even after correction for well-established associations of female sex and Cred-drugsTdP use [START_REF] Woosley | QT Drugs Lists[END_REF]. We also found a significant inverse correlation between prolonged QTcF and IGF1 at both T1 and T2 in univariate analysis.

TSH increase is associated with QTc prolongation

Temporal changes in TSH concentrations in the euthyroid patient with T2DM have been studied previously in large population groups. Among 17,061 patients without diabetes in South Korea undergoing routine yearly check-up visits and followed over a 4-year period, each 1 µIU/mL increase in TSH after multivariable adjustment was associated with a risk of developing diabetes. During the study follow-up period, among 956 patients with incident diabetes, TSH change rather than baseline TSH was found to be positively associated with a change in HbA1c and worsening metabolic risk factors, which included body mass index, body fat percentage and hyperlipidaemia. Compared with the remaining 16,105 patients who did not develop diabetes, TSH concentrations remained within normal limits [START_REF] Qin | Thyroid Hormone Changes in Euthyroid Patients with Diabetes[END_REF]. In another retrospective cross-sectional population study in China that examined patients with previously diagnosed T2DM versus newly diagnosed T2DM, the T4/T3 ratio was increased in patients with previously diagnosed T2DM, but TSH was chronically suppressed in both groups [START_REF] Jun | TSH increment and the risk of incident type 2 diabetes mellitus in euthyroid subjects[END_REF]. These results were interpreted as a lower rate of peripheral T4 turnover in patients with a longer duration of diabetes and increased risk of development of euthyroid sick syndrome. The authors further suggested that frequent screening of thyroid hormones in euthyroid patients with T2DM may not be necessary as the peripheral turnover of thyroid hormones is dynamic in euthyroid sick syndrome.

In our study, there was a significant association between TSH and QTcF, with an incremental increase of ≈3 ms in QTcF with every log-normalized unit increase in TSH. We observed a significant positive correlation with the temporal variation (either an increase or a decrease) in TSH, which persisted even after exclusion of patients with a change in QT-prolonging drug status. This finding highlights the possibility of an association between TSH concentrations and QTcF. As the log-normalized TSH value unit ranged within 4 units for normal euthyroid values and 12 units for dysthyroid patients, this could result in a potential increase of up to 12 ms to 36 ms in QTc duration within euthyroid and dysthyroid values, respectively, which may create significant variability in QTc prolongation from normal to borderline, or from borderline to prolonged QTc categories. Although TSH may be within the euthyroid range, a significant temporal change in TSH should draw attention to the potential of QTc prolongation and risk of TdP. Based on our findings and previous studies that demonstrated a positive association between an increase in TSH and fasting blood glucose, HbA1c and metabolic risk factors [START_REF] Jun | TSH increment and the risk of incident type 2 diabetes mellitus in euthyroid subjects[END_REF], we propose the consideration of more periodic TSH monitoring in those with T2DM and additional metabolic risk factors, as they may be at increased risk of significant QTc prolongation and TdP.

Previous studies have demonstrated the effects of thyroid activity on electrolyte homeostasis, such that serum magnesium and potassium concentrations are elevated and decreased, respectively, in patients with hypothyroidism/elevated TSH [START_REF] Schwarz | Thyroid function and serum electrolytes: does an association really exist?[END_REF]. Particularly among patients with T2DM, who may be at risk of diabetic ketoacidosis or hyperosmolar hyperglycaemia syndrome, hypokalaemia and hypomagnesaemia are typically prominent, and can further increase the risk of QTc prolongation and sudden cardiac death [START_REF] Xing | Impact of Diabetic Ketoacidosis on Thyroid Function in Patients with Diabetes Mellitus[END_REF]. Thus, in the previously euthyroid patient with T2DM who presents with TdP and QTc prolongation, in addition to ensuring normalization of potassium and magnesium concentrations, it would be prudent to evaluate thyroid activity using TSH concentration, and to correct with thyroid supplementation. The effects of levothyroxine treatment on electrocardiographic variables have not been studied on a large scale, but several case reports [START_REF] Lagan | Torsades de pointes cardiac arrest associated with severe hypothyroidism[END_REF][START_REF] Shojaie | Primary hypothyroidism presenting with Torsades de pointes type tachycardia: a case report[END_REF] have described the use of levothyroxine to correct QTc prolongation in rare presentations of TdP with severe hypothyroidism. A smaller patient population study by Unal et al. demonstrated that levothyroxine supplementation significantly decreased the QT interval (from 387.2 ± 10.8 ms to 345.6 ± 13 ms; P < 0.001) and QT dispersion (from 46.5 ± 5.3 ms to 30.7 ± 5.8 ms; P < 0.001) among 16 women with subclinical hypothyroidism, but had no effect on the R-R, PR or QRS intervals [START_REF] Unal | Effect of levothyroxine treatment on QT dispersion in patients with subclinical hypothyroidism[END_REF]. In addition, a correlation analysis showed that QT dispersion was positively related to logarithmic TSH concentrations. Similar findings were observed in another small study in 18 patients from South Korea with primary hypothyroidism who were treated with levothyroxine [START_REF] Kweon | The effects of L-thyroxine treatment on QT dispersion in primary hypothyroidism[END_REF] Although several studies have examined the relationship between hyperthyroid and hypothyroid states and QTc prolongation, only a few cross-sectional studies have looked at the relationship between thyroid hormones and QTc duration in the euthyroid population [START_REF] Tayal | Thyroid dysfunction and electrocardiographic changes in subjects without arrhythmias: a cross-sectional study of primary healthcare subjects from Copenhagen[END_REF][START_REF] Dorr | The relation of thyroid function and ventricular repolarization: decreased serum thyrotropin levels are associated with short rateadjusted QT intervals[END_REF][START_REF] Van Noord | High free thyroxine levels are associated with QTc prolongation in males[END_REF][START_REF] Zhang | Thyroid hormones and electrocardiographic parameters: findings from the third national health and nutrition examination survey[END_REF], with conflicting results. Among these reports, the association between TSH and QTc duration was based on static TSH quintiles rather than temporal changes in TSH, as in our study. In the US Third National Health and Nutrition Examination Survey and The Rotterdam Study, with 5990 (100%) and 880 (93.72%) euthyroid individuals, respectively, there was no significant association between TSH quintiles/concentrations and QTc (by residual method and Bazett's formula, respectively), in fully adjusted multivariable models [START_REF] Van Noord | High free thyroxine levels are associated with QTc prolongation in males[END_REF][START_REF] Zhang | Thyroid hormones and electrocardiographic parameters: findings from the third national health and nutrition examination survey[END_REF]. In contrast, the Study of Health in Pomerania, which included a representative sample of 3610 individuals, with 87.8% euthyroid patients, found a significant association between TSH (categorical concentrations) and Hodges linear function QTc, in a fully adjusted multivariable model, with depressed TSH concentrations associated with shorter QTc (odds ratio 0.73, 95% CI 0.55-0.97; P < 0.001) when compared with euthyroid controls [START_REF] Dorr | The relation of thyroid function and ventricular repolarization: decreased serum thyrotropin levels are associated with short rateadjusted QT intervals[END_REF]. Similarly, a large population registry-based study in Denmark, with 127,215 (95.86%) euthyroid patients, found a significant association between TSH (as a continuous covariate) and QTcB in an age-and sexstratified linear model, among young and middle-aged (16-60 years) groups of both sexes [START_REF] Tayal | Thyroid dysfunction and electrocardiographic changes in subjects without arrhythmias: a cross-sectional study of primary healthcare subjects from Copenhagen[END_REF].

In comparison with overt hypothyroid and hyperthyroid states, where T4 concentrations are correlated with QTc, there are limited studies on the correlations between T3 or T4 and QTc in the euthyroid individual. In our study, there was no association between free T3 or T4 and QTc, which contrasts with previous findings, and may result from the fact that hyperthyroid and euthyroid patients were grouped together in the correlation analyses [START_REF] Colzani | Hyperthyroidism is associated with lengthening of ventricular repolarization[END_REF]. Among the 880 (93.72%) euthyroid individuals in the Rotterdam Study, the highest quintile of free T4 in males was associated with a significant adjusted increase in QTc of 9.7 ms (95% CI 2.1-17.2), with a gradual increase (P = 0.008 for linear trend), as well as a significantly higher risk of a borderline QTc or QTc prolongation (adjusted odds ratio 2.12, 95% CI 1.02-4.40) compared with the first quintile (P = 0.009) [START_REF] Van Noord | High free thyroxine levels are associated with QTc prolongation in males[END_REF]. However, the US Third National Health and Nutrition Survey among 5990 euthyroid individuals did not find a significant association between T4 and QTc duration after fully adjusted models, although they did observe that men in the > 95th percentile of total T4 had longer residual adjusted QT intervals than those in the < 5th percentile [START_REF] Zhang | Thyroid hormones and electrocardiographic parameters: findings from the third national health and nutrition examination survey[END_REF]. Given that our study sample size was comparatively smaller, our analysis may have been insufficiently sensitive to detect this association.

The genomic and non-genomic actions of T4 and its largely peripherally deiodinated counterpart T3 on the cardiovascular system, through modulation of expression of multiple cardiac genes affecting ionchannel transport, sympathetic responses and myocardial contractility, are well established. Particularly within the conduction system, prolonged repolarization observed in hypothyroid patients is largely a result of a reduction in the transient outward potassium current (Ito) and an increase in the L-type calcium current channel (ICa-L) [START_REF] Alonso | Thyroid stimulating hormone directly modulates cardiac electrical activity[END_REF]. After detection of the functional expression of the TSH receptor in murine and human cardiomyocytes, recent studies have also demonstrated the direct action of TSH in the modulation of cardiac ion channels [START_REF] Alonso | Thyroid stimulating hormone directly modulates cardiac electrical activity[END_REF][START_REF] Fernandez-Ruocco | High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism[END_REF].

In human cardiomyocytes, TSH reduced expression of the potassium-voltage gated channel subfamily D member 3 and subfamily Q member 1 (KCND3 and KCNQ1, respectively), Ito and the delayed rectifier potassium current (IKs) encoding proteins [START_REF] Fernandez-Ruocco | High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism[END_REF]. Changes caused by TSH via protein kinase A signalling, consistent with that of primary hypothyroidism, resulted in characteristic early after depolarizations and subsequent arrythmias [START_REF] Fernandez-Ruocco | High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism[END_REF]. This was only seen during sympathetic/adrenergic stimulation suspected as a result of enhanced calcium accumulation within the sarcoplasmic reticulum and augmentation of the proarrhythmic sodium-calcium exchange (NCX) and ICa-L stimulation [START_REF] Fernandez-Ruocco | High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism[END_REF]. Furthermore, in a genome-wide association study among 37,154 North American individuals of European ancestry, a weighted polygenic predictor for TSH, and not T3 or T4, was significantly associated with arrhythmias, particularly atrial fibrillation or flutter [START_REF] Salem | Association of Thyroid Function Genetic Predictors With Atrial Fibrillation: A Phenome-Wide Association Study and Inverse-Variance Weighted Average Meta-analysis[END_REF].Taken together, this further highlights the important role of TSH in the homeostasis of electrical conductivity, and as a risk factor for arrhythmia vulnerability.

QTc duration and T2DM

Ventricular electrophysiological disturbances in patients with T2DM are thought to be caused by hyperglycaemia, autonomic neuropathy, ventricular inflammation and fibrotic changes [START_REF] Alonso | Thyroid stimulating hormone directly modulates cardiac electrical activity[END_REF]. Studies have shown that during episodes of severe hypoglycaemia, patients experience QTc prolongation and VAs suspected to be caused by autonomic dysfunction [START_REF] Sertbas | The Effect of Glucose Variability on QTc Duration and Dispersion in Patients with Type 2 Diabetes Mellitus[END_REF]. Increased variability in plasma fasting and postprandial glucose has also been associated with prolongation of QTc [START_REF] Sertbas | The Effect of Glucose Variability on QTc Duration and Dispersion in Patients with Type 2 Diabetes Mellitus[END_REF]. In our cohort, the included patients with T2DM were mostly well equilibrated, with HbA1c, glucose and insulin blood concentrations within normal or subnormal ranges; this may have blunted the association between the concentration of these hormones and QTc duration shown previously in patients with T2DM with more extreme values.

We observed a significant inverse correlation between prolonged QTcF and IGF1 at both T1 and T2 in univariate analysis, which is consistent with previous work in pooled subpopulations from the Study of Health in Pomerania and Rotterdam studies [START_REF] Ittermann | The association between insulin-like growth factor-I and cardiac repolarization[END_REF]. IGF1 concentrations demonstrate a U-shape association with insulin resistance, and both oversecretion, such as in acromegaly, and undersecretion of IGF1 are typically observed in patients with T2DM [START_REF] Friedrich | The association between IGF-I and insulin resistance: a general population study in Danish adults[END_REF]. Altered IGF1 concentrations have been associated with increased cardiovascular morbidity as a result of heart failure and cardiac arrhythmias [START_REF] Castellano | The GH/IGF-1 Axis and Heart Failure[END_REF]. These observed effects on QTc duration and risk of VAs, have been speculated to be related to growth hormone itself, which regulates several cellular mechanisms, including metabolic pathways, sympathetic signalling and ion-channel activities, affecting cardiac conduction [START_REF] Castellano | The GH/IGF-1 Axis and Heart Failure[END_REF]. Direct effects of IGF1 on cardiac electrophysiological activity might also exist, as shown in a recent in vitro study where VAs were reversed by increasing connexin-43 expression in rat cardiomyocytes with IGF1 treatment and hepatocyte growth factor [START_REF] Yao | Combination of HGF and IGF-1 promotes connexin 43 expression and improves ventricular arrhythmia after myocardial infarction through activating the MAPK/ERK and MAPK/p38 signaling pathways in a rat model[END_REF]. Given that low IGF1 concentrations are associated with T2DM [START_REF] Friedrich | The association between IGF-I and insulin resistance: a general population study in Danish adults[END_REF], it may be of interest to explore IGF1 concentrations as a biomarker of VAs, especially in individuals with diabetes.

Study limitations

There are several limitations to our study. First, it was a single-centre institutional study, and extrinsic validation of our findings is required. Second, our regression analysis did not include the effects of various sex hormones on QTc. Our study was observational and cannot conclude for the causality of association between TSH concentrations and QTc variations. Interventional or preclinical mechanistic studies are required to further assess this point.

Conclusions

Serum TSH concentration and its variation was associated with QTcF and its variation, even after correcting for QTc prolonging drugs. Optimization of TSH concentration in T2DM deserves further investigation to establish its impact on risk of TdP and sudden cardiac death. a Coronary artery disease defined as history of myocardial infarction, coronary angioplasty or bypass grafting.

b Patients taking a drug at known risk of torsades-de-pointes (www.crediblemeds.org [START_REF] Woosley | QT Drugs Lists[END_REF]): at T1, these drugs included amiodarone (n = 3), domperidone (n = 1), escitalopram (n = 1) and sotalol (n = 3); at T2, all eight patients were taking amiodarone.

c Corrected for albumin concentrations. b Patients taking a drug at known risk of TdP (www.crediblemeds.org [START_REF] Woosley | QT Drugs Lists[END_REF]): at T1, these drugs included amiodarone (n = 3), domperidone (n = 1), escitalopram (n = 1) and sotalol (n = 3); at T2, all eight patients were taking amiodarone.

c Normalized before entering into multiple linear model.

d Corrected for albumin concentrations.

Figure 1 .

 1 Figure 1. Flow chart of patient selection from the Diabète et Calcification Arterielle (DIACART) study. ANCOVA: analysis of covariance; AV: atrioventricular; ECG: electrocardiogram; T1: baseline; T2: followup; y: year. a Median follow-up period with interquartile range. [Publishers: * to be changed to a in figure.]

Figure 2 .Figure 3 .

 23 Figure 2. Example of QT measurement by the overlap method. QTcB: Bazett's corrected QT interval; QTcF: Fridericia's corrected QT interval;

Figure 4 .

 4 Figure 4. A. Correlation (Spearman's) between thyroid-stimulating hormone (TSH) (mUI/L) and Fridericia's corrected QT interval (QTcF) (ms) at T1 (baseline). B. Correlation (Spearman's) between TSH (mUI/L) and QTcF (ms) at T2 (follow-up). C. Correlation (Spearman's) between the variation in QTcF and the variation in TSH. Variations in QTcF over time between T1 and T2 by quartile of TSH concentration at T1.

d

  Normal values for thyroid function: TSH, 0.45-4.49 mIU/L; free T4, 11-25 pmol/L [19].e Normal values for QTcF were taken as: normal < 430 ms, borderline 430-450 ms, abnormal > 450 ms in males; and normal < 450 ms, borderline 450-470 ms, abnormal > 470 ms in females[START_REF] Van Noord | High free thyroxine levels are associated with QTc prolongation in males[END_REF].

Figure 1 .

 1 Figure 1.

Figure 2 . 24 Figure 3 .

 2243 Figure 2.

Table 1

 1 Demographic, clinical, biochemical and electrocardiographic measurements at baseline and follow-up.

	Measurement at T1	Measurement at T2
	(n = 170)	(n = 140)

Table 2

 2 Correlation and regression analyses with Fridericia's corrected QT interval as outcome variable at T1 and T2. Univariate analysis with Pearson's coefficient for normally distributed variables, and Spearman's coefficient for nonnormally distributed variables. Only variables with correlations with P < 0.05 with Fridericia's corrected QT interval are shown. Other tested variables include weight, height, body mass index, history of coronary artery disease, haemoglobin A1C (glycated haemoglobin), blood glucose, insulin, homeostatic model assessment of insulin resistance, total cholesterol, high density lipoprotein, low density lipoprotein, creatinine, creatinine clearance, free T3 and free T4.

	T1

ANCOVA: analysis of covariance; IGF1: insulin-like growth factor 1; TdP: torsades-de-pointes; TSH: thyroid stimulating hormone.

a

Sources of funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-forprofit sectors.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.