REVIEW

Subclinical hyperthyroidism and cardiovascular manifestations:a reevaluation of the association

Angelo Carpi • Giuseppe Cini • Matteo Russo • Alessandro Antonelli •

Carlo Gaudio • Fabio Galetta • Ferdinando Franzoni • Giuseppe Rossi

Published online: 6 March 2013

� SIMI 2013

Abstract Subclinical hyperthyroidism (SH) has been

reported associated with atrial fibrillation (AF), heart fail-

ure (HF) and coronary heart disease events, including

mortality. An expert opinion indicates that AF is the pos-

sible link between SH and the other important cardiovas-

cular (CV) manifestations. We analyzed the data of three

recent studies including 60,883 subjects of whom 2,284 SH

patients. In these subjects, the ratio between the AF events

and each of the other above reported CV events varied

from 0.14 to 0.4 in SH and from 0.2 to 2.4 in euthyroidism

(ET). The general pattern of this ratio in 6 comparisons

performed was not significantly higher for SH than ET.

This data suggest that AF is not the major link between SH

and the related CV manifestations. We suggest that a fur-

ther link to be considered is the higher frequency of the

early atherosclerosis manifestations such as carotid intima

media thickness or carotid integrated back scatter, observed

in SH. This atherogenic effect of SH can affect the

occurrence of all the above clinical CV manifestations.

Keywords Subclinical hyperthyroidism �Atrial fibrillation � Cardiovascular disease

Introduction

Many studies analysed the relationship between subclinical

hyperthyroidism (SH) and the related cardiovascular

manifestations or diseases (CVD), including mortality

[1–3]. Conflicting results have been published [1, 3, 4].

However, a relatively strong association has been reported

in many studies between SH and AF [1, 2]. A recent article

collecting large preoperative cohorts reported that endog-

enous SH is associated with increased AF, total mortality,

coronary heart disease (CHD) mortality and CHD events

[1].

However, the pathogenetic relationship among these 3

events and the relationship between thyroid hormones and

these events is not quite clear as well as the clinical impact

of these events in the various population types of SH [4].

The aim of this article is to contribute to clarify some

controversial or pathogenetic aspects through a revised

analysis of recent clinical data.

Clinically relevant CV manifestations in subclinical

hyperthyroidism

A large study reported an increased risk of AF, heart failure

(HF), CHD mortality and CHD events in SH [1].

A. Carpi (&) � A. Antonelli � F. Galetta � F. Franzoni

Department of Clinical and Experimental Medicine,

University of Pisa, Via Savi, 6-7, 56126 Pisa, Italy

e-mail: angelo.carpi@med.unipi.it

G. Cini

Internal Medicine Department, University of Pisa, Pisa, Italy

M. Russo

Department of Cellular and Molecular Pathology,

IRCCS San Raffaele Pisana, Rome, Italy

M. Russo

Department of Experimental Medicine, ‘‘Sapienza’’ University

of Rome, Rome, Italy

C. Gaudio

Department ‘‘Attilio Reale’’, Sapienza University, Rome, Italy

G. Rossi

National Research Council (CNR), Unit of Epidemiology

and Biostatistics, Institute of Clinical Physiology

and G. Monasterio Foundation, Pisa, Italy

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Intern Emerg Med (2013) 8 (Suppl 1):S75–S77

DOI 10.1007/s11739-013-0913-2

The well known cardiovascular mechanisms reported in

SH are tachycardia and arrhythmia, left ventricular

hypertrophy and diastolic dysfunction with reduced exer-

cise tolerance [5]. Recently, a linear relationship between

thyroid function and intima media thickness (IMT) with

higher values in SH compared to ET has been reported [6].

Furthermore, more recently we confirmed in a small size

study that IMT is elevated in SH and added that carotid

integrated back scatter (C-IBS) mean value as well as the

number of regiones with higher C-IBS was significantly

higher in SH (unpublished). C-IBS is an ultrasonographic

index of atherosclerosis more precise than IMT because it

indicates artery wall degeneration and fibrosis being

strictly related to the collagen content of the artery wall.

Reports with dissociation of AF from clinically relevant

CV manifestations

AF is the most documented CV sign associated with SH.

Most studies report that AF occurs more frequently in SH

than in ET and that occurrence is higher with lower TSH

values [2]. An important opinion reports that ‘the mecha-

nism by which SH may be associated with an increased CV

risk may be linked to the risk of atrial arrhythmias, espe-

cially atrial fibrillation…’ [3]. Indeed AF might predispose

to cardiac failure, to coronary heart disease events and to

cerebral vascular stroke or mortality, with different path-

ogenetic mechanisms. However, the following reports

show data which cannot be interpreted by the hypothesis

that the elevated CV risk in SH is mediated by AF

(Table 1).

The PROSPER cohort study [7] in 5,316 older subjects

or patients included 71 participants with SH. Over 3.2-year

follow-up (ET), the incidence rate of HF events was higher

for SH (3.1 %) than for ET (1.2 %). However, the ratio AF/

HF events was 3/7 (0.43) in SH and 478/194 (2.46) in ET

(p = 0.005). This means that the occurrence of AF within

the HF events is much lower in SH than in ET and that HF

occurs independently on AF in almost all SH patients.

Collet et al. [1] pooled 52,674 young or old participants,

of whom 2,188 with endogenous SH, from 10 cohorts.

CHD events were analysed in 22,437 and AF in 8,711

subjects. SH was found associated with increased risk of

CHD mortality, CHD events and AF. However, the ratio

AF/CHD deaths was the same, 34/83 (0.41) in SH and

751/1,813 (0.41) in ET (p = 0.957); the ratio AF/CHD

events was 34/108 (0.31) in SH and 751/3,545 (0.21) in ET

(p = 0.047). This means that even if occurrence of AF

within the CHD events is slightly higher in SH, only 2 or 3

of 10 CHD events may be associated with AF. Indeed, the

study does not show the patients with AF who developed

CHD events.

Schultz et al. [8] performed a 5-year follow-up of 609

subjects of 50 years old or older, of whom 25 with SH, all

with normal left ventricular function. AF occurred in 16

(12.9 %) with ET and 1 (4 %) with SH. The ratio AF/CV

deaths was 1/7 (0.14) in SH and 16/79 (0.20) in ET; the

ratio AF/CV events was 1/7 (0.14) in SH and 16/71 (0.22)

in ET (p = 0.677); the ratio AF/number of strokes was 1/4

(0.25) in SH and 16/23 (0.69) in ET. However, no one of

the four SH patients who developed stroke had FA. This

study relatively limited in the size in cardiologically

defined subjects, shows no important link between AF and

relevant CV events, especially stroke, in subjects 50 years

old or older and with normal left ventricular function. This

result seems to contradict the general assertion that the risk

of stroke in SH patients with AF may be increased [5].

Discussion and conclusion

The clinical impact of the CV effects produced by mild

thyroid hormone excess as in SH is controversial [4].

It is difficult to compare or to interpret studies on the

association between CV events and SH principally because

they include different types of patients, different laboratory

and instrumental methods as well as different follow-up

[1, 3, 4]. Furthermore, the end points considered, FA, HF,

CHD events, mortality are all affected by multiple factors.

Table 1 Ratio AF/relevant cardiovascular manifestations in three recent selected studies

Study Participants (n) AF/HF events AF/CHD deaths AF/CHD events AF/CV deaths AF/CV events AF/strokes

Author (year) Total SH SH ET SH ET SH ET SH ET SH ET SH ET

Nanchen (2012) 5,316 71 0.4 2.4

p = 0.005

Collet (2012) 52,674 2,188 0.41 0.41 0.31 0.21

p = 0.095 p = 0.04

Schultz (2011) 609 25 0.14 0.20 0.14 0.22 0.25 0.69

p = 0.75 p = 0.67 p = 0.23

SH subclinical hyperthyroidism, ET euthyroidism, AF atrial fibrillation, HF heart failure, CHD coronary heart disease, CV cardiovascular

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AF can be triggered by thyroid hormone excess, CHD or

other factors. On the other hand, AF with different mech-

anisms can trigger or worsen HF, CHD events and cerebral

stroke. This can occur either in ET or in SH. The large and

recent studies here reported are not in line with the actual

opinion that AF is the principal link between SH and the

increased CV risk.

We suggest that a further link to be considered is the

higher frequency of the early atherosclerosis manifesta-

tions (IMT and C-IBS) in SH [6]. If we consider that these

effects are chronic, we can find further justification for FA

and the other CV manifestation in SH.

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