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Poor blood pressure control in adults with repaired coarctation of the aorta and hypertension: a register-based study of associated factors

Published online by Cambridge University Press:  13 July 2017

Daniel Rinnström ,
Mikael Dellborg ,
Ulf Thilén ,
Peder Sörensson ,
Niels-Erik Nielsen ,
Christina Christersson ,
Martin Ugander  and
Bengt Johansson
Daniel Rinnström*
Affiliation:
Department of Public Health and Clinical Medicine, Heart Centre, Umeå University, Sweden
Mikael Dellborg
Affiliation:
Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden
Ulf Thilén
Affiliation:
Department of Cardiology, Clinical Sciences, Lund University, Sweden
Peder Sörensson
Affiliation:
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Niels-Erik Nielsen
Affiliation:
Department of Medical and Health Sciences, Linköping University, Sweden
Christina Christersson
Affiliation:
Department of Clinical Sciences, Uppsala University, Sweden
Martin Ugander
Affiliation:
Department of Clinical Physiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Bengt Johansson
Affiliation:
Department of Public Health and Clinical Medicine, Heart Centre, Umeå University, Sweden
*
Correspondence to: D. Rinnström, MD, PhD, Department of Public Health and Clinical Medicine, Heart Centre, Umeå University, Moritzvågen 1B, Umeå, Våsterbotten 90342, Sweden. E-mail: dan_r_82@hotmail.com
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Abstract

Background

Arterial hypertension is common in adults with repaired coarctation of the aorta, and is associated with several severe complications.

Aims

This study aimed to investigate the prevalence of poorly controlled (⩾140/90 mmHg) blood pressure among patients with diagnosed hypertension and to identify associated factors.

Methods

In the national register for CHD, adults with repaired coarctation of the aorta and diagnosed hypertension – defined as a registry diagnosis and/or use of anti-hypertensive prescription medication – were identified. Logistic regression analysis was used to identify variables associated with poorly controlled blood pressure.

Results

Of the 243 included patients, 27.2% were female, the mean age was 45.4±15.3 years, and 52.3% had poorly controlled blood pressure at the last registration. In a multivariable model, age (years) (OR 1.03, CI 1.01–1.06, p=0.008) was independently associated with poorly controlled blood pressure and so was systolic arm–leg blood pressure gradient in the ranges [10, 20] mmHg (OR 4.92, CI 1.76–13.79, p=0.002) to >20 mmHg (OR 9.93, CI 2.99–33.02, p<0.001), in comparison with the reference interval [0, 10] mmHg. Patients with poorly controlled blood pressure had, on average, more types of anti-hypertensive medication classes prescribed (1.9 versus 1.5, p=0.003).

Conclusions

Poorly controlled blood pressure is common among patients with repaired coarctation of the aorta and diagnosed hypertension, despite what seems to be more intensive treatment. A systolic arm–leg blood pressure gradient is associated with poorly controlled blood pressure, even at low levels usually not considered for intervention, and may be an indicator of hypertension that is difficult to treat.

Keywords

Coarctation of the aortahypertensionadult CHDregister
Type
Original Articles
Information
Cardiology in the Young , Volume 27 , Issue 9 , November 2017 , pp. 1708 - 1715
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Copyright
© Cambridge University Press 2017 

Coarctation of the aorta is a relatively common condition that represents 5–10% of all structural congenital heart abnormalities.Reference Guntheroth 1 – Reference Canniffe, Ou and Walsh 6 Even after early repair of coarctation of the aorta, arterial hypertension is common, with prevalence between 25 and 68%, depending on the definition of hypertension and the population studied.Reference Canniffe, Ou and Walsh 6 Several factors are associated with the occurrence of hypertension in patients with coarctation of the aorta, including male sex, age at intervention, age at follow-up, type of intervention, residual arm–leg blood pressure gradient, preoperative blood pressure, and body mass index.Reference Cohen, Fuster and Steele 5 – Reference Smith-Parrish, Yu and Rocchini 12 In patients with repaired coarctation of the aorta, hypertension has been shown to be associated with the development of left ventricular hypertrophy, and is also an important risk factor for coronary events, stroke, and end-stage renal disease.Reference Cohen, Fuster and Steele 5 , Reference Koller, Rothlin and Senning 13 – Reference Sundstrom, Arima and Jackson 23

The underlying pathophysiology of hypertension after coarctation repair is likely multifactorial, but several studies have suggested that coarctation of the aorta is associated with vascular abnormalities not limited to the site of coarctation. Coarctation of the aorta has been shown to be associated with cystic medial necrosisReference Isner, Donaldson and Fulton 24 and decreased aortic distensibility,Reference Brili, Dernellis and Aggeli 25 – Reference Lam, Mullen and Kaya 27 as well as with a general vascular bed pathologyReference de Divitiis, Pilla and Kattenhorn 28 – Reference Meyer, Joharchi and Kundt 30 and decreased baroreceptor reflexReference Kenny, Polson and Martin 31 subsisting after the lesion itself has been repaired. Thus, there may be several factors that differ between hypertension in coarctation of the aorta and essential hypertension, but the current data are not conclusive, and a study from 2014 found no clinically significant difference in endothelial function between patients with repaired coarctation of the aorta and healthy controls.Reference Radke, Diller and Duck 32

At present, it is generally recommended that blood pressure should be lowered to <140/90 mmHg in patients with diagnosed hypertensionReference Mancia, De Backer and Dominiczak 33 regardless of age. In the present study, we sought to examine the prevalence of poorly controlled blood pressure (⩾140/90 mmHg) among patients with repaired coarctation of the aorta and diagnosed hypertension and to identify factors associated with poor blood pressure control among these patients.

Materials and methods

SWEDCON

This is a register study based on data acquired from the Swedish national register on CHD (SWEDCON, www.ucr.uu.se/swedcon/). Since 1998, the SWEDCON register has covered all seven healthcare regions in Sweden, but registration was initiated even earlier in some centres. Data collected by each centre contain information on diagnoses, interventions, demographics, functional class, symptoms, quality of life (EQ-5D), social variables, electrocardiographs, exercise tests, self-reported level of physical exercise, echocardiographies, medications, and pacemakers/ICDs. At the first entry in the register, information is usually retrospective, for example, regarding previous interventions, although usually based on access to relevant medical records such as surgical notes. After the first entry in the database, further data collection from clinic visits and investigations are prospective.

All data regarding patients with grown-up CHD, collected up to 17 February, 2013, were searched. For the present study, relevant data were then obtained from the last available clinic visit where systolic blood pressure had been registered.

Patients

SWEDCON was used to identify all registered patients with coarctation of the aorta (1026 out of 9864 patients). Of these, 916 were at least 18 years old at the time of their last clinic visit with recorded systolic blood pressure values. Patients with associated simple lesions, such as ventricular septal defect and aortic stenosis, were included, whereas those with major, complex pathologies or syndromes were excluded, leaving 810 patients. Of these, only patients who had undergone repair of coarctation of the aorta were included, thus excluding those with mild coarctation without previous intervention, leaving 677 patients. Only 11 patients whose interventions had taken place within 6 months before the clinic visit were excluded. Of the remaining 666 patients, 243 (36.5%) had been diagnosed with hypertension, 100 patients had hypertension as a diagnosis in the SWEDCON register, and 226 were prescribed anti-hypertensive medication, which also was considered proof that they had, at some point, been diagnosed with hypertension. These 243 patients made up the final study population (Fig. 1).

Figure 1 Flow chart of the inclusion and exclusion process generating the study population. GUCH=grown-up CHD; SWEDCON=Swedish national register of CHD; CoA=coarctation of the aorta; BP=blood pressure.

This study population is a subgroup of patients included in previously published studies,Reference Rinnstrom, Dellborg and Thilen 15 , Reference Rinnström, Dellborg and Thilén 34 as well as in ongoing studies.

This study was approved by the Regional Ethical Review Board in Umeå, Sweden (Dnr 08-218 M and 2012-445-32 M).

Definition of diagnosed hypertension and poorly controlled blood pressure

Cases with diagnosed hypertension were identified through the register and/or by the use of prescription medication such asβ-blockers, angiotensin converting enzyme inhibitors, calcium blockers, diuretics, angiotensin II antagonists, or other medications prescribed for systemic hypertension. Data regarding medication were acquired from the same visit as blood pressure.

It is generally recommended that blood pressure be measured in both arms in patients with coarctation of the aorta, registering the highest value. The last registered office blood pressures were compared with the recommended target values (i.e. <140/90 mmHg), and thus defined as within or above recommended limits.Reference Mancia, De Backer and Dominiczak 33 If either systolic or diastolic blood pressure was found to exceed the currently recommended limits (i.e. ⩾140/90 mmHg), the blood pressure was classified as poorly controlled. In cases where only one of the pressures – systolic or diastolic – was available, the blood pressure was classified as poorly controlled if the available pressure exceeded the recommended limits. The comparison was otherwise considered indeterminate, and thus classified as missing data.

The systolic arm–leg blood pressure gradient was calculated using the registered office blood pressures. Negative values – that is, higher blood pressure in the lower extremity – were assumed to signify pulse-wave reflections and were interpreted as no fall in pressure over the coarctation – that is, zero gradient. In the univariate and multivariable logistic regressions performed, the gradient was described by a scalar variable containing the ranges [0, 10], [10, 20], and >20 mmHg. The lowest range was used as reference in the analyses.

Anti-hypertensive medication

The data regarding medication among adult patients with repaired coarctation of the aorta in SWEDCON have been previously publishedReference Rinnstrom, Dellborg and Thilen 15 but were considered too relevant to exclude from the present study.

Statistics

All calculations were performed using SPSS 20–23 (IBM, Armonk, New York, United States of America).

Differences in means and ratios between groups were tested with Student’s t-test or the χ2-test as appropriate. Variables for multivariable analyses were selected from the candidate variables listed in Table 1, choosing only variables significant in univariate logistic regression. Multivariable logistic regressions were performed in a manual backward manner. The null hypothesis was rejected for p-values <0.05.

Table 1 Patient characteristics.

BP=blood pressure

* Time to follow-up denotes time from first intervention to last clinic visit

** In the study population, 56 patients had undergone at least one re-intervention for CoA, with a total of 68 re-interventions performed. Of these, 15 (22.1%) were end-to-end anastomoses, 5 (7.4%) were subclavian flap procedures, 19 (27.9%) were percutaneous interventions, and 29 (42.6%) were classified as other reconstructions

*** BP gradient denotes the systolic arm–leg blood pressure gradient as a continuous variable, with negative values defined as no gradient

p-values indicating significant outcomes are in bold

Results

Of the 243 patients included in the study, 27.2% were female. The mean age was 45.4±15.3 years, with an average of 31.1±16.3 years from first intervention to follow-up, and a total of 7557 patient years after intervention. At the last registration, 127 (52.3%) patients had poorly controlled blood pressure (Table 1).

Patients with poorly controlled blood pressure were prescribed, on average, more types of anti-hypertensive medication classes compared with those with blood pressure reaching the recommended treatment goals (1.7±1.1 versus 1.5±0.9, p=0.003). β-Blockers were the most common anti-hypertensive medication class, prescribed to 144/242 patients (59.5%), followed by angiotensin converting enzyme inhibitors that were prescribed to 92/242 patients (38.0%) (Table 2). In the present study population, 16/242 patients (6.6%) had no pharmacological treatment for hypertension, eight of whom had poorly controlled blood pressure. Patients prescribed only β-blockers did not differ from other patients, with regard to poorly controlled blood pressure (44.1 versus 55.2%, p=0.137).

Table 2 Anti-hypertensive medication use in the study population.

ACE=angiotensin converting enzyme; BP=blood pressure

To identify factors associated with poorly controlled blood pressure, variables that were significant in the univariate logistic regression were subsequently included in a multivariable logistic regression analysis. The initial multivariable regression included all univariatly significant variables – that is, age (years), weight (kg), body mass index (kg/m2), and systolic arm–leg blood pressure gradient (mmHg). To avoid interactions between weight and body mass index, the entire regression analysis was repeated twice with each of these two variables allowed to take precedence over the other. All analyses yielded the same final multivariable model, including age (years) (OR 1.03, CI 1.01–1.06, p=0.008) and systolic arm–leg blood pressure gradient in the ranges [10, 20] mmHg (OR 4.92, CI 1.76–13.79, p=0.002) to >20 mmHg (OR 9.93, CI 2.99–33.02, p<0.001), in comparison with the reference interval of [0, 10] mmHg (Table 3).

Table 3 Univariate logistic regressions and the final multivariable logistic regression model, with blood pressure ⩾140/90 mmHg as dependent variable.

The final model includes 156 patients, p<0.001

* Variables included in the first step of the multivariable logistic regression. The analysis yields the same final model regardless of whether weight and BMI are both included in the first step, or either variable is allowed to take precedence over the other

** Time to follow-up denotes time from first intervention to last clinic visit

*** End-to-end anastomosis is used as the reference category for type of first intervention

**** Arm–leg BP gradient denotes the systolic arm-leg blood pressure gradient as a categorical variable, with negative values defined as no gradient. BP gradient [0, 10]) mmHg is used as reference

p-values indicating significant outcomes are in bold

Patients with data on systolic arm–leg blood pressure gradient did not differ from those without with regard to poorly controlled blood pressure (53.8 versus 49.4%, p=0.508).

Discussion

We showed that more than half of the included adult patients with repaired coarctation of the aorta and diagnosed hypertension had poorly controlled blood pressure. Besides age, the systolic arm–leg blood pressure gradient was shown to be an important factor for explaining poorly controlled blood pressure in these patients, even in the range [10, 20] mmHg, which is usually considered tolerable.

Population

In this study, we chose to include only patients who had hypertension entered as a diagnosis in the register and/or patients using antihypertensive prescription medication. Thus, patients who were both undiagnosed and were not using medication were not considered “hypertensive” for the purposes of this study, even if they had poorly controlled blood pressure. This yielded a smaller study population than predicted; however, this was intentional as one can now reasonably assume that all patients in the study were known to have hypertension, and should therefore be undergoing treatment – pharmacological or otherwise. Poorly controlled blood pressure in this population thus suggests prevalence of hypertension that is, at least in part, resistant to treatment.

Although uncontrolled hypertension has been shown to be prevalent in other populations,Reference Torma, Carlberg and Eriksson 35 , Reference Sarganas and Neuhauser 36 this study showed an unsually high prevalence at 52.3%, and, importantly, hypertension tends to debut early in patients with repaired coarctation of the aorta, meaning that uncontrolled hypertension in these patients may affect the circulatory system over long periods of time.

Age

There was an association between age and poorly controlled blood pressure, and this association was not unexpected. The prevalence of essential hypertension tends to increase with age, and although it is worth noting that age was recently found to be unassociated with uncontrolled hypertension in another Swedish cohort,Reference Torma, Carlberg and Eriksson 35 several studies have previously shown an association between age and uncontrolled hypertension.Reference Wang and Vasan 37 – Reference Lloyd-Jones, Evans and Larson 39 The effect might partly be the result of increased arterial stiffness, but age, as a variable, might also to some degree signify the time it takes for other factors to work their influence on the development of uncontrolled hypertension.

Systolic arm–leg blood pressure gradient

The current guidelines recommend that all patients with a non-invasive systolic blood pressure gradient >20 mmHg between upper and lower limbs, regardless of symptoms, but with upper limb hypertension (>140/90 mmHg in adults), pathological blood pressure response during exercise, or significant left ventricular hypertrophy, should be considered for re-intervention.Reference Baumgartner, Bonhoeffer and De Groot 40 A lower threshold for re-intervention of aortic narrowing might be desirable,Reference Vriend, Zwinderman and de Groot 9 and it has also been previously shown that mild residual descending aortic narrowing in patients with repaired coarctation of the aorta is independently associated with mean daytime blood pressure,Reference Lee, Kowalski and Galati 41 with left ventricular hypertrophy,Reference Rinnstrom, Dellborg and Thilen 15 and with hypertension as a diagnosis regardless of treatment results.Reference Rinnström, Dellborg and Thilén 34 Our results add further to this, in that poorly controlled blood pressure in our population was associated with a systolic arm–leg blood pressure gradient even for gradients within the range [10, 20] mmHg.

It is worth noting that the current guidelines were originally established at a time when most re-interventions for coarctation of the aorta were surgical in nature, with all the risks thoracic surgery entails, as well as uncertain effects on small gradients and frequent need for prosthetic material. It is possible that a new risk–benefit analysis in light of the new findings and the current predominance of catheter-based techniques may yield a different conclusion. There may therefore be reasons to consider re-intervention at even smaller systolic arm–leg blood pressure gradients than that currently recommended, although further studies are necessary before any such conclusions can be reached.

Limitations

The present study is a register study, analysing data from the last clinic visit where systolic blood pressure measurements were available. The blood pressure measurements and medications prescribed are therefore those recorded at these visits, and we do not have access to data pertaining to further attempts at treatment. Although single office blood pressure measurements are less reliable than 24-hour registrations, it has been shown that elevated office blood pressure is associated with left ventricular hypertrophy in patients with repaired coarctation of the aorta.Reference Rinnström, Ugander and Johansson 14 , Reference Rinnstrom, Dellborg and Thilen 15 Although information is available regarding the number of anti-hypertensive medication classes, there are no data regarding dosage, or whether the treatment has recently been initiated or adjusted, and we have therefore chosen to mainly focus our analyses on other factors than pharmacological treatment. It is important, however, to note that lack of data does not mean that the pharmacological treatment is not an important factor.

β-Blockers were among the medication types considered anti-hypertensive in this study, but are also commonly used to treat arrhythmia. The register does not include data on why each medication type was prescribed, but it is worth noting that patients prescribed only β-blockers did not differ from the rest of the study population with regard to poorly controlled blood pressure.

The final multivariable model included only 156 patients because of missing data regarding systolic arm–leg blood pressure gradient, but poorly controlled blood pressure was more or less common in patients with registered gradient data.

This study did not include anatomical data regarding the aortic arch or the area of the repaired coarctation, but the systolic arm–leg blood pressure gradient can be considered to indirectly provide some information regarding the postinterventional aortic anatomy.

Conclusions

Among patients with repaired coarctation of the aorta and diagnosed hypertension, approximately half were found to have poorly controlled blood pressure, despite the majority receiving pharmacological treatment for hypertension at the time as well as on average being simultaneously treated with more types of anti-hypertensive medication classes compared with patients with blood pressure within the target range. We found an association between systolic arm–leg blood pressure gradient and poorly controlled blood pressure, even at gradients below the currently recommended limit for re-intervention. Thus, mild residual fall in pressure over the repaired coarctation may not be benign.

Acknowledgements

None.

Financial Support

The study was supported by the Swedish Heart and Lung Foundation, the Heart Foundation of Northern Sweden, Umeå University, and the County Council of Västerbotten.

Conflicts of Interest

None.

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Figure 0

Figure 1 Flow chart of the inclusion and exclusion process generating the study population. GUCH=grown-up CHD; SWEDCON=Swedish national register of CHD; CoA=coarctation of the aorta; BP=blood pressure.

Figure 1

Table 1 Patient characteristics.

Figure 2

Table 2 Anti-hypertensive medication use in the study population.

Figure 3

Table 3 Univariate logistic regressions and the final multivariable logistic regression model, with blood pressure ⩾140/90 mmHg as dependent variable.