Clinical–Pathological Conference
Diagnosis and Management of Resistant Hypertension
A Case Report
Zhen-Yu Zhang, Wen-Yi Yang, Anna F. Dominiczak, Ji-Guang Wang, Ying Wu,
Bader Almustafa, Siew Mooi Ching, Yan Li, Varahabhatla Vamsi, Michael Bursztyn,
Qiuyan Dai, Shaowen Liu, Jan A. Staessen
A 29-year-old man was admitted to our hospital after hav-
ing an upper respiratory tract infection and extremely
high blood pressure (230/105 mm Hg). He reported absence
of dyspnea or a history of hypertension. The patient was a
nonsmoker and did not consume alcohol or use recrea-
tional drugs. His father had hypertension. He was not on any
medication.
On admission, his heart rate was normal, at 100 bpm.
His body mass index was 33.7 kg/m2. There were no clinical
signs of congestion, that is, no jugular vein distension or ankle
edema was observed, the hepatojugular reflux was negative,
and the lung sounds were normal.
What would be your next step in the diagnostic workup?
Discussion
Dr Almustafa: I would expand the anamnesis, focusing on
familial diseases, and search for target organ damage, in-
cluding examination of the eyegrounds and refer the patient
for echocardiography.
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Dr Ching: I would consider the possibility of sleep apnea.
From the Studies Coordinating Centre, Research Unit Hypertension and
Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular
Sciences, University of Leuven, Belgium (Z.-Y.Z., J.A.S.); Department of
Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University
School of Medicine, China (W.-Y.Y., Y.W., Q.D., S.L.); Institute of
Cardiovascular and Medical Sciences, College of Medical, Veterinary and
Life Sciences, University of Glasgow, United Kingdom (A.F.D.); Center
for Epidemiological Studies and Clinical Trials and Center for Vascular
Evaluation, The Shanghai Institute of Hypertension, Ruijin Hospital,
Shanghai Jiao Tong University School of Medicine, China (J.-G.W., Y.L.);
Family Medicine & Chronic Care, Qatif Primary Health Care, Ministry
of Health, Riyadh, Saudi Arabia (B.A.); Department of Family Medicine,
Faculty of Medicine and Health Sciences, Universiti Putra Malaysia
(S.M.C.); Department of General Medicine, Zaporizhzhia State Medical
University, Ukraine (V.V.); Hadassah-Hebrew University Medical Center,
Jerusalem, Israel (M.B.); and Cardiovascular Research Institute (CARIM),
Maastricht University, Maastricht, the Netherlands (J.A.S.).
*Z.-Y. Zhang and W.-Y. Yang contributed equally to this work.
Presented in part at the Clinical–Pathological conference chaired by
Anna F. Dominiczak and Ji-Guang Wang at the 27th Scientific Meeting
of the International Society of Hypertension, September 26, 2018, in
Beijing, China. Zhen-Yu Zhang and Wen-Yi Yang presented the case and
led the discussion.
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
Correspondence to Zhen-Yu Zhang, Studies Coordinating Center,
Research Unit Hypertension and Cardiovascular Epidemiology, KU
Leuven Department of Cardiovascular Sciences, University of Leuven,
Leuven, Belgium. Email zhenyu.zhang@med.kuleuven.be
(Hypertension. 2019;74:1064-1067.
DOI: 10.1161/HYPERTENSIONAHA.119.13206.)
© 2019 American Heart Association, Inc.
Hypertension is available at https://www.ahajournals.org/journal/hyp
DOI: 10.1161/HYPERTENSIONAHA.119.13206
1064
Dr Ching: Even if the anamnesis was negative, I would
recommend conducting a urine drug screening.
Initial Diagnostic Workup
The fasting blood glucose level was 12.4 mmol/L, and the
glycated hemoglobin level was 8.7%. Plasma brain natriuretic
peptide (1390 pg/mL) and serum homocysteine (43.5 μmol/L)
levels were high. Serum electrolytes, uric acid, thyroid func-
tion, and hormone levels were all within the normal reference
ranges. The urinalysis demonstrated microalbuminuria (33.7
mg/L) and an albumin-to-creatinine ratio of 65.4 μg/mg, but
no other abnormalities. Electrocardiographically, the patient
had sinus tachycardia, a normal QRS complex, and nonspe-
cific ST-segment changes. Echocardiographically, mitral and
aortic regurgitation and left ventricular hypertrophy with an
ejection fraction of 33% were observed, without regional dys-
kinesia of the left ventricular wall. The chest x-ray confirmed
left ventricular enlargement without pulmonary or pleural
effusion. What would be your recommendations for further
workup of this patient with severe hypertension?
Discussion
Dr Ching: The main issue is to gradually reduce his blood
pressure, to protect the integrity of vital organs; for instance,
by intravenous administration of vasodilators.
Dr Vamsi: An ultrasound and a computed tomography
scan of the kidneys and adrenal glands are indicated.
Dr Mishchenko: Even in the presence of a normal en-
docrine screening result, I would recommend measuring the
aldosterone-renin ratio and monitoring cortisol and aldoste-
rone secretion.
Dr Almustafa: I agree with Dr Ching regarding the recom-
mendation of an abdominal ultrasound.
Initial Response to Medication
In combination with antidiabetic medication and appropriate
diet, antihypertensive medication was gradually up-titrated to
daily single doses of 5 mg of amlodipine and bisoprolol, and 20
mg of furosemide and spironolactone, along with perindopril
4 mg, twice, daily. During treatment, ambulatory blood pres-
sure monitoring revealed a nondipping pattern, with the day-
time and nighttime systolic/diastolic blood pressure averaging
154/102 and 161/105 mm Hg, respectively; the 24-hour blood
pressure was 156/103 mm Hg (Table). Echocardiographically,
the left atrial and left ventricular end-diastolic diameters meas-
ured 47 mm and 60 mm, respectively, and the intraventricular
septal and posterior wall thicknesses measured 11 mm. The
left ventricular ejection fraction was 53%.
 Zhang et al   Diagnosis and Management of Resistant Hypertension   1065

Table.  Ambulatory Blood Pressure on Antihypertensive Drug Treatment Dr Wang: This observation highlights the necessity to ask
Systolic Pressure, Diastolic Pressure, Heart Rate patients to keep a diary during their 24-hour blood pressure
Time, h:min mm Hg mm Hg Beats/min monitoring.
Dr Ching: This patient shows a high diurnal blood pres-
9:20 158 109 60
sure variation, which might predict risk over and beyond the
9:30 169 64 69 blood pressure level.
10:00 141 103 62
10:30 151 56 62
Differential Diagnosis
We would like to propose alternative explanations for the
11:00 150 102 56
reversed diurnal blood pressure profile (Table). The blood
11:30 133 87 56 pressure was recorded during hospitalization, wherein the
12:00 115 78 56 patient did not perform any physical activity during daytime
but was woken up at night by nurses to check his condition.
12:30 138 87 52
Notably, the blood pressure of this patient remained uncon-
13:00 133 73 47 trolled with intensive medication. The key question remains
13:30 137 95 58 whether we dealt with primary or secondary hypertension.
14:00 131 81 53
Discussion
14:30 154 104 61 Dr Bursztyn: I assume that the patient had secondary hyper-
15:00 166 116 60 tension. Findings favoring this diagnosis are his young age, the
15:30 168 118 68 presence of left ventricular hypertrophy and nephropathy, ex-
cluding an acute blood pressure elevation, and the presence of
16:00 163 118 68
uncontrolled diabetes. A pheochromocytoma, as well as car-
16:30 172 118 66 diomyopathy at young age, might also explain hypertension.
17:00 182 124 66 Dr Ching: I agree that the most likely diagnosis is sec-
ondary hypertension. What might also be causing hyper-
17:30 152 99 60
tension in this young patient is the use of pseudoephedrine
18:00 146 100 61 nose drops to alleviate the symptoms of a respiratory infec-
18:30 162 112 58 tion. However, on admission, the patient denied being on any
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20:00 162 122 68 medication.

Dr Almustafa: Was the endocrine screening test repeated?
21:00 176 125 66
Dr Yang: Yes.
21:30 185 120 75
22:00 140 93 50 Secondary Hypertension
The diagnostic workup until now indicated the diagnosis of
23:00 146 100 52
essential hypertension.
0:00 166 108 53
1:00 175 121 55 Discussion
2:00 185 124 57 Dr Almustafa: What might still be missing is a dexamethasone
suppression test.
3:00 155 111 60
Dr Zhang: We did not perform a dexamethasone suppres-
4:00 158 66 65 sion test because the endocrine screening test result was re-
5:00 166 117 60 peatedly negative.
Dr Varahabhatla Vamsi: I would like to emphasize that
6:00 161 108 53
upon admission, the serum homocysteine level was high.
6:30 161 114 62 This might cause arterial stiffness and systolic hypertension.
7:00 172 130 76 Therefore, I suspect hypertension secondary to cardiometa-
7:30 137 94 62
bolic dysregulation.
Dr Mishchenko: We need more information on possible
8:00 150 101 56 renal causes of hypertension.
Treatment consisted of amlodipine 5 mg, bisoprolol 5 mg, furosemide 20 mg, Dr Qi: Was any imaging study performed for the renal
and spironolactone 20 mg once daily combined with perindopril 4 mg twice daily. arteries?
Dr Yang: Plain computed tomography angiography and
Discussion 3-dimensional reconstruction of the renal arterial tree in the
Dr Bursztyn: I find it difficult to categorize this patient as a sagittal and axial planes did show a 30% ostial stenosis of the
nondipper. I noticed a low blood pressure in the early after- left renal artery, but no other abnormalities (Figure 1).
noon, probably shortly after lunch, and a high blood pressure Dr Bursztyn: The low plasma renin activity (3.25 ng/mL
that peaked at night, possibly because the patient had to stand per hour) on admission did not necessitate imaging of the ad-
to urinate (Table). renal glands or the renal arteries.
 1066  Hypertension  November 2019
Figure 1.  Computed tomography (CT) angiographic imaging of the
renal arteries. Three-dimensional reconstruction of the right and left renal
arterial tree in the sagittal (A) and axial (B) planes. Apart from a 30%
osteal stenosis of the left renal artery, there were no clinically significant
abnormalities.
Dr Zhang: Can we exclude myocardial infarction as a
cause of heart failure based on the electrocardiogram and the
absence of echocardiographic dyskinesia of the left ventric-
ular wall?
Dr Bursztyn: I think this patient is too young to consider
diabetic cardiomyopathy as a cause of heart failure, but pre-
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mature myocardial infarction might occur in patients with
diabetes. However, the absence of significant lesions on com-
puted tomography angiography imaging of the renal arteries
makes coronary heart disease less likely.
Dr Staessen: In this patient with severe hypertension, high
blood pressure is the most likely cause of heart failure.
Dr Zhang: We excluded viral myocarditis caused by
Coxsackievirus B by measuring acute and convalescent-phase
antibodies. Therefore, heart failure secondary to essential hy-
pertension remains the preferred differential diagnosis.
Dr Wang: Although heart failure caused by high blood
pressure is more likely to occur, an upper respiratory tract in-
fection might be a contributing factor.
Final Diagnosis and Long-Term Treatment
Our final diagnosis was primary hypertension complicated
by heart failure. Diabetes mellitus is a comorbidity, which
increases heart failure susceptibility.
Discussion
Dr Yeung: I would like to raise several caveats. First, this pa-
tient probably had chronic hypertension, which might be a
cause or consequence of chronic kidney disease, secondary to
diabetes. Was there examination of the eye fundi for hyperten-
sion, diabetes mellitus, or both? Was the 30% osteal stenosis
of the left renal artery a contributory cause of hypertension?
Have you excluded Takayasu’s arteritis?
Dr Yang: A unilateral renal artery stenosis of 30% cannot
cause hypertension. Takayasu’s arteritis is a rare, systemic, in-
flammatory large vessel vasculitis of unknown etiology that
Figure 2.  Recommendation for combining blood pressure-lowering drugs
according to the AB/CD rule. Adapted from Wei et al.2 Copyright © 2018,
Polish Cardiac Society. This is an Open Access article distributed under
the terms of the Creative Commons Attribution-Non Commercial-No
Derivatives 4.0 International License (CC BY-NC-ND 4.0).
most commonly affects women of childbearing age. In view
of the computed tomography angiography findings and the
clinical context, this diagnosis can be excluded.
Dr Wang: Were the eye fundi normal?
Dr Zhang: Retinoscopy is a routine eye examination in
patients with diabetes, hospitalized in the endocrine ward. As
this patient did not have symptoms of blurred vision, angina
and severe headache indicative of malignant hypertension,
retinoscopy was not checked during the short stay of hospital-
ization. However, it was recommended in out-patient clinics
after discharge.
Dr Cheng: Did you measure the dimensions of the kid-
neys? Was anemia present on admission, as is often detected
in chronic kidney disease?
Dr Zhang: The admission hemoglobin level was 15 g/dL.
The dimensions of the kidneys were normal.
Prof Dominiczak: Although a fundoscopy was not per-
formed, the admission blood pressure of 230/105 mm Hg
could still be indicative of malignant hypertension.
Dr Zhang: Does the audience have any suggestions for the
treatment of this patient’s hypertension?
Dr Ching: In the acute phase, I would administer a vasodi-
lator intravenously, such as nitrates.
Dr Zhang: As suggested, in the acute phase, we adminis-
tered nitrates intravenously. In the chronic phase, we applied
the ABCD rule (A, angiotensin-converting enzyme inhibitors
or angiotensin receptor blockers; B, β-blockers; C, calcium-
channel blockers; D, diuretics [thiazide/thiazide-like]), as
proposed in the NICE guidelines (Figure 2),1,2 and prioritized
antihypertensive drugs with a long elimination half-life, based
on their molecular structure. The blood pressure-lowering
treatment was combined with the antidiabetic treatment.
Resistant Hypertension Treatment
The patient was discharged with an office blood pressure
measurement of 168/112 mm Hg. On the long-term treat-
ment, the ambulatory blood pressure was also not controlled
(Table). We assessed the adherence using the 8-item Morisky
Medication Adherence Scale. His body mass index gradually
 Zhang et al   Diagnosis and Management of Resistant Hypertension   1067
decreased to <30 kg/m2. Because, 4 months after discharge,
this patient’s blood pressure remained uncontrolled while all
therapeutic options had been exhausted, and because we had
excluded pseudohypertension, we proposed renal denervation.
The patient gave his consent. We used the first-generation sin-
gle-tip SYMPLICITY catheter.
Renal denervation to lower blood pressure in patients with
hypertension and it is based on sound evidence of the role of
the sympathetic nervous system3,4 and kidneys5 in the patho-
genesis of the condition. A minimally invasive catheter-based
ablation of the renal sympathetic nerves represents a major
step forward, as compared with the unselective sympatholytic
surgery that was used as a therapy in primary hypertension
from the 1960s until the 1980s.6
An elevated ambulatory blood pressure is defined as resistant
hypertension, after the exclusion of secondary hypertension in
patients who are fully adherent to treatment with antihypertensive
drugs.7 Four trials assessed the efficacy and safety of renal dener-
vation in patients with resistant hypertension.8–11 SYMPATHY10
and INSPiRED11 were the two trials in which drug adherence
was assessed by measuring the urinary drug concentrations, both
at baseline and follow-up. As reviewed elsewhere,12 recent trials
assessed the efficacy and safety of renal denervation in un-
treated or minimally treated patients with hypertension, but this
indication falls beyond the scope of this case report.
Within 1 month of the procedure, the patient’s blood
pressure had lowered. One year later, the ambulatory blood
pressure was within the normal levels, on treatment with biso-
prolol (5 mg, once, daily), and perindopril (4 mg, twice, daily).
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Echocardiographically, the structure and function of the left
ventricle returned to normal. Six years later, the patient’s body
mass index decreased to 26 kg/m2, and antihypertensive med-
ication was further tapered to bisoprolol 5 mg and perindopril
4 mg, both taken once, daily.
Summary
We described the diagnostic workup and management of an
obese patient with resistant hypertension, who was hospital-
ized for heart failure. The case was complicated by comor-
bidities such as diabetes mellitus. After the exclusion of
pseudohypertension, renal denervation was the final treatment
option. Within 1 year, the procedure led to control of blood
pressure on just 2 antihypertensive agents and to normalization
of the structure and function of the left ventricle. Reduction of
the body mass index also contributed to maintaining a healthy
condition of up to 6 years after the surgical procedure.
Acknowledgments
We are grateful to the following session audience members for con-
tributing to the discussion: Yi-Bang Cheng, Larysa Mishchenko,
Li-Xing Qi, and Vincent Yeung.
Sources of Funding
None.
Disclosures
None.
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