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Lankenau Medical Center, Lancaster Avenue, Suite 130, Wynnewood, PA USA, 19096
Abstract
Conservatively, ten million people in the USA alone may suffer from RH and may be similarly prevalent elsewhere. Given the strong linear correlation between hypertension and cardiovascular outcomes, better control is paramount. We favor a multi-pronged approach. It may not suffice to address this by pharmacologic means only. Careful attention to modifiable risk factors, particularly sodium intake, adhering to a proper diet (i.e. DASH), and avoiding agents, i.e. non-steroidals, that can elevate the blood pressure, is key. Frequent follow up to establish the right treatment regimen and home blood pressuring monitoring can have a strong impact on control. Finally, consideration of device therapy may be a more viable option in the future.
Keywords
Resistant hypertensionHyperaldosteronismRenovascular hypertensionObstructive sleep apneaCushing syndromeChronic kidney diseaseLiddle syndromeCoarctation of aortaPheochromocytomaSympathectomyCarotid sinus baroreceptor electrical stimulation1 Introduction
Hypertension is the most common chronic disease in the developed world. Between 2005 and 2008, the National Health and Nutrition Examination Survey (NHANES) estimated that nearly one quarter of U.S. adults were hypertensive, and of those only one half were considered controlled. Therefore, adequate control is of utmost public health importance given the linear relationship between blood pressure and cardiovascular risk.
While essential hypertension (EH) usually results from a complex interaction between genetic traits and lifestyle factors such as weight, stress, and sodium intake, several other defined forms of hypertension exist. Among these are white coat hypertension, masked hypertension, resistant hypertension (RH), refractory hypertension and pseudohypertension. This chapter will focus on RH which is defined as a blood pressure of >140/90 despite appropriate adherence to a regimen of three antihypertensive agents including a diuretic. Its actual prevalence unknown, estimates in several recent studies show it to be an increasingly common finding.
Therapy in RH, as in EH, requires not only pharmacologic intervention, but also lifestyle modification, careful scrutiny of pharmacologic and herbal remedies, supplements, and over the counter agents. Device therapy may offer promise in the future. Certain epidemiologic factors appear more prevalent in the RH population than in other hypertensive cohorts. Recognition of these patients is a challenge to clinicians but several clues may identify patients for targeted therapies.
In this chapter, we will describe the epidemiology, prognosis, disease states, diagnostic evaluation, non-pharmacologic and pharmacologic treatment of RH.
2 Establishing the Diagnosis
Distinguishing RH from other forms of hypertension is critical. The sine qua non of RH is a blood pressure > 140/90 on three maximally dosed/tolerated drugs including a well-dosed diuretic, preferably a thiazide or mineralocorticoid antagonist rather than a loop diuretic which tends to be less effective in blood pressure control (Sarafidis 2011). Correct blood pressure measuring is also critical and is described elsewhere (Kaplan and et al. 2010). Table 1 lists the forms of hypertension and associated diagnostic criteria.
Table 1
Lists the forms of hypertension and associated diagnostic criteria
Cause | Criteria |
|---|---|
Essential hypertension | Lacks specific known/causative condition; genetics, diet, environmental factors play role |
White coat hypertension | Office BP > 140/90 with reliable out of office readings < 140/90; Can confirm with ABPMa |
Masked hypertension | Office BP < 140/90; home readings > 140/90 |
Pseudohypertension | Radial pulse remains palpable despite occlusion of brachial artery, the Osler Maneuver |
Resistant hypertension | BP > 140/90 on 3 antihypertensives including a diuretic |
Refractory hypertension | Like resistant hypertension but on 4 antihypertensives and less likely to respond to MRAb (Kaplan et al. 2010) |
3 Epidemiology
The actual prevalence of RH is unknown but estimates range from 8 to 15 % of all hypertensive subjects. An ethnically diverse cross-sectional study done in the Kaiser-Permanente system in Southern California between 2006 and 2007 revealed 12.8 % of all hypertensive individuals met criteria for RH. This was particularly common among males, those of black race, obese, and older subjects. Diabetes mellitus, ischemic heart disease, congestive heart failure, and chronic kidney disease (CKD) also associated with RH (Pimenta et al. 2012).
In the most recent National Health and Nutrition Examination Survey (NHANES) between 2005 and 2008, among 6000 adults with hypertension, 11.8 % had RH. Between 1988–1994 and 1999–2004 the prevalence was estimated to 5.5 and 8.5 % respectively. In today’s terms, based on the latest NHANES data some 76 million Americans are hypertensive, of which 12 % or nine million individuals may be resistant (Pimenta et al. 2012; Persell 2011).
In the Antihypertensive and Lipid-Lowering Treatment To Prevent Heart Attack trial (ALLHAT), International Verapamil-Trandolapril Study (INVEST), and Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trials RH was estimated at 8–15 % of these hypertensive cohorts (The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group 2002; Pepine et al. 1998; Jamerson et al. 2008).
4 Prognosis
Patients with RH are at greater risk for end organ damage such as left ventricular hypertrophy (LVH), CKD, and albuminuria than those patients who have controlled blood pressure (Sarafidis 2011).
Retrospectively, Daugherty et al. found that RH was significantly associated with a 47 % increased risk of adverse cardiovascular outcomes (Daugherty 2012). Armario studied 513 patients in a Spanish cohort with RH finding LVH by echocardiography in 57 %; 46 % had albuminuria (Armario 2011).
Successfully lowering blood pressure in RH may reduce cardiovascular events. Pisoni et al showed a 96 % reduction in cardiovascular events over 18 months with the use of 3 antihypertensive agents versus placebo in patients with severe diastolic hypertension (Pisoni 2009).
Sales et al demonstrated the additional clinical benefits of ambulatory blood pressure monitoring (ABPM) in RH and found that elevated systolic and diastolic blood pressures predicted cardiovascular and overall mortality (Salles et al. 2008).
5 RH: Associated Medical Conditions: Secondary Causes of Hypertension and Workup
Table 2 lists the most common causes of RH.
Table 2
Lists the most common causes of RH
Diagnosis | Etiology | Clues to its diagnosis |
|---|---|---|
Primary aldosteronism | Bilateral hyperplasia, solitary adrenal adenoma | Hypokalemia, metabolic alkalosis, mild hypernatremia (Acelajado 2011). |
Renovascular hypertension | Renal artery stenosis, fibromuscular dysplasia | Flash pulmonary edema with preserved systolic function, atherosclerotic disease, abdominal or femoral bruit, absent pedal pulses, assymetric kidneys on imaging (Cooper et al. 2014). |
OSA | Partial or complete collapse of the airway during sleep | Fatigue, day time somnolence, poor sleep (Drager 2010) |
CKD | Acute glomerulonephritis, APCKD, renal cell carcinoma, renin-producing tumors, vasculitis and chronic pyelonephritis | Elevated creatinine, abnormal urine studies (Thomas 2015) |
Cushing syndrome | Excess endogenous or exogenous glucocorticoids | Moon facies, abdominal striae, truncal obesity, hirsuitism and kyphoscoliosis (Moneva 2002) |
Coarctation of the aorta | Discrete narrowing in the region of the ligamentum arteriosum | Hypertension in the upper extremities with hypotension in the lower extremities, a systolic-diastolic murmur audible on the chest or back and a time delay between brachial and femoral pulses or pulse diminishment (Prisant 2004) |
Liddle syndrome | Causal mutation of the beta subunit of the amiloride sensitive sodium channel | Hypokalemia, mild hypernatremia and metabolic alkalosis (Rose 2001) |
Pheochromocytoma | Catecholamine-secreting tumors of the adrenal medulla and the sympathetic ganglia | Episodic headache, sweating, and tachycardia (Stein 1981) |
5.1 Primary Hyperaldosteronism
Among patients with RH, primary hyperaldosteronism (PHA) is likely the most common identifiable cause. In an analysis of 88 patients with RH, 20 % had PHA (Calhoun et al. 2002). Acelajado et al. found a 17 % prevalence of RH due to PHA (Acelajado 2011).
Screening should occur in hypertensive subjects with unexplained or unprovoked hypokalemia, or if induced by diuretics, resisting correction. Those with a strong family history of hypertension, especially early-onset (<40 years), drug resistant hypertension, hypertensive with an adrenal “incidentaloma,” should also be screened. Morning samples for plasma aldosterone concentration (PAC), plasma renin activity (PRA) and an aldosterone to renin ratio (ARR) are obtained. We suggest holding MRAs and continuing all other drugs to avoid accelerating hypertension.
An ARR above 20 is consistent with PHA. Additionally, a PAC of greater than 15 ng/dl yields a positive screening result. Twenty-four urinary aldosterone measurements confirm the diagnosis. Salt sensitivity is diagnosed when the Aldosterone levels are relatively high but fail to reach threshold values for PHA. These patients are highly responsive to MRAs but also to simple sodium restriction.
Computed tomography (CT) represents the best test for this for confirming an adrenal tumor. Incidental adrenal adenomas are found in 4 % of the general population on CT, and are particularly common after the age of 40. Proceeding to adrenal vein sampling is reasonable in the hypertensive patient over 40 with an adenoma. This can help lateralize the hormonal excess and direct surgical excision. In bilateral adrenal hyperplasia medical therapy with MRAs is best. (Mantero 2000).
5.2 Renovascular Hypertension
Renovascular hypertension is common among hypertensive patients with multiple risk factors for atherosclerotic disease, particularly those with RH.
An abdominal bruit and known history of athereosclerosis and tobacco use are commonly seen. Patients challenged with ACE inhibitors (ACE I) or Angiotensin Receptor Blockers (ARB may get ischemic nephropathy due to the effects on Angiotensin II and the efferent renal arteriole. Bloodwork usually shows an elevated PRA and PAC. Once suspected, imaging modalities, particularly duplex ultrasonography, magnetic resonance angiography (MRA) and computed tomography angiography (CTA) are performed.
In duplex ultrasonography, reliable detection of RAS is operator dependent and sensitivity and specificity do not compare favorably with MRA or CTA. MRA confers the risk of gadolinium induced nephrogenic systemic fibrosis, a syndrome linked to individuals with a GFR <30 ml/min. CTA requires a significant volume of contrast and may be contraindicated in those with advancing CKD. Conventional intraarterial angiography can confirm diagnosis. Unfortunately, three separate trials have shown no benefit to interventional approaches relative to medical management and this often leads to a diagnostic quandary as to whether to pursue this diagnosis at all (Cooper et al. 2014; The Astral Trial Investigators 2009; Bax et al. 2009).
Therapy usually includes dual anti-platelet therapy, antihyperlipidemic drugs, and blood pressure control. Use of ACE I or ARB is generally discouraged due to the risk of ischemic nephropathy (Cooper et al. 2014).
5.3 Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) occurs when there is a partial or complete collapse of the airway during sleep. Affecting nearly 2.4 % of adults, it is associated with mortality and cardiovascular risks (Drager 2010). The Ohasama study showed each 5 % deficiency in the normal decline in nocturnal blood pressure was associated with an approximate 20 % increase in risk of cardiovascular mortality (Ohkubo et al. 2000). The prevalence of OSA in hypertensive patients may be as high as 56 % and in resistant hypertensive patients, nearly 80 %.
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