Unexpected improvement of resistant hypertension in older adults: A red flag sign

Resistant hypertension is defined as failure to reach blood pressure (BP) targets despite the use of three classes of antihypertensive drugs, including a diuretic, at their maximal tolerated doses.1 A recent meta-analysis including 91 studies and >3 million patients with essential hypertension reported a prevalence of 10.3% for resistant hypertension, higher with advancing age or chronic kidney disease.2 The National Health and Nutrition Examination Surveys database also identified older age as a distinct risk factor for refractory hypertension.3 These patients pose a therapeutic challenge, because of their increased risk of major adverse cardiovascular events and end-organ damage.4 Thus, invasive treatments, such as renal denervation, had been tried, including among older adult patients, but remain under clinical trial.5, 6 In contrast, patients with longstanding resistant hypertension that suddenly spontaneously resolved are rarely encountered. Two such patients are briefly reported to suggest different mechanisms of this unusual, poorly-reported occurrence and its potentially urgent clinical significance in older adults. A 92-year-old community-dwelling woman had a long history of primary isolated systolic hypertension and chronic obstructive pulmonary disease on budesonide inhaler treatment. The chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease 3 when last tested a few months prior) did not cause dyspnea on effort, as she was bedridden for most of the day, helped by a caretaker. She had never been hospitalized, and adhered to a low-salt diet and medications administered by her live-in caregiver, including candesartan 16 mg/day, amlodipine 10 mg/day, bisoprolol 5 mg/day and clonidine 0.3 mg b.i.d. (thiazides could not be tolerated due to hyponatremia). Nevertheless, frequent episodic asymptomatic BP recordings of >200/83 mmHg continued, confirmed by 24-h Holter monitoring. I was consulted after her son became concerned that her BP readings suddenly were “too good”: 130/80 mmHg, without peaks. She was found apathetic, and was referred immediately to the hospital where respiratory acidosis and hypercapnic respiratory failure was detected (pH 7.269, PCO2 95). There were no other contributing associated conditions, such as chest infection. She was intubated, admitted to the intensive care unit and later discharged home on non-invasive ventilation, resuming her full anti-hypertensive treatment shortly after. A 76-year-old banker with a long history of primary hypertension and prediabetes (HbA1c 6.3%) was receiving valsartan 320 mg/day, disothiazide 25 mg/day, eplerenone 25 mg/day, bisoprolol 10 mg/day and metformin. Nevertheless, 24-h ambulatory blood pressure monitoring showed frequently abnormal BP (systolic 100%, diastolic 77% of the time). At home, values of 207/109 or 190/100 mmHg were not infrequently observed, despite adherence, low-salt diet and regular walking. He presented after his BP normalized, anxious to know why. The examination was unrewarding. Echocardiography, followed by thallium-201 myocardial perfusion scanning, showed that he had suffered a silent anteroseptal myocardial infarction, and ejection fraction (previously 60%) was down to 40%. As a banker, he practically moved from his car to the elevator to his office and reported no symptoms of heart failure. He subsequently had coronary angiography and stent placement, and was discharged on dual antiplatelets, high-dose statin, bisoprolol and sacubitril/valsartan. Two months later, hypertension again became a problem and full treatment resumed. Our two older adult patients had longstanding primary hypertension that was resistant and poorly controlled over long, well-documented periods, despite adherence to multidrug treatment and lifestyle recommendations. Their sudden BP normalization under the same treatment was unexpected and, rightfully, caused concern. In case 1, it was due to severe respiratory acidosis in a patient with chronic obstructive pulmonary disease, and in the second, to a silent anterior wall myocardial infarction. This presentation is rather unusual. As an ambulatory consultant in geriatric internal medicine and hypertension, I examine approximately 720 patients per year, and approximately 4:5 patients are hypertensive, with an estimated 15% of resistant primary hypertension. Over the past 5 years, I have encountered only these two cases of the “spontaneous” resolution of resistant hypertension, an estimated incidence of 0.11%/year of all resistant hypertension (0.56%/5 years). Two different mechanisms were involved. In case 1, spontaneous resolution of poorly-controlled hypertension was secondary to the development of respiratory acidosis. In fact, it was its initial and presenting manifestation. Isolated myocardial muscle and excised heart studies have long shown that respiratory acidosis depresses myocardial contractility. Whole animal studies later elucidated the underlying mechanisms,7, 8 suggesting that the patient's beta-blockade (bisoprolol) and alpha-2-adrenoreceptor-agonists (clonidine) might have deprived her of important compensatory responses and led to further deterioration in myocardial contractility. Silent myocardial infarction as reported in case 2 is not uncommon, identified in 153 of 925 (16.5%) of screened people in a recent magnetic resonance imaging-based series.9 Diabetes or prediabetes confer significantly increased risk (OR 3.99, 95% CI 1.48–12.85), and increased susceptibility to subsequent myocardial infarction, congestive heart failure, stroke and death.9, 10 An unexpected improvement of resistant hypertension is another notable outcome, likely related to the loss of functioning myocardium and diminished cardiac output. Thus, sudden BP normalization in older adult patients with longstanding, true resistant hypertension is a rare and potential red flag phenomenon that requires immediate attention, and may indicate diminished myocardial contractility and cardiac output. None. The authors declare no conflict of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.