Chapter 26 Systemic Hypertension: Mechanisms, Diagnosis and Treatment PDF

**CHAPTER 26 SYSTEMIC HYPERTENSION: MECHANISMS, DIAGNOSIS AND TREATMENT** \*\* After tobacco use and diabetes, **uncontrolled primary hypertension is the most important risk factor for peripheral vascular disease** (the second leading cause of loss of limbs in the United States). \*\* **Uncontroll...

**CHAPTER 26 SYSTEMIC HYPERTENSION: MECHANISMS, DIAGNOSIS AND TREATMENT** \*\* After tobacco use and diabetes, **uncontrolled primary hypertension is the most important risk factor for peripheral vascular disease** (the second leading cause of loss of limbs in the United States). \*\* **Uncontrolled primary hypertension is the most important modifiable risk factor for stroke**, the leading contributor to all common forms of heart failure, the **second most common cause of end-stage kidney disease** and also contributes to memory loss. **DEFINITIONS OF HYPERTENSION:** \- The *traditional "threshold BP value"* to secure a diagnosis of hypertension comes from large epidemiologic studies demonstrating a higher mortality at levels **above 140/90 mm Hg** \* **US guidelines** define Hypertension as **\>/= 130/80 mmHg.** **\* European guidelines** define hypertension as **\>/= 140/90 mmHg.** **EPIDEMIOLOGY:** \*\*A natural history study of over a million people demonstrates that CV risk becomes most pronounced above levels of 140/90 mmHg. \*\* Increasing age is a major risk factor for developing hypertension, as well as a very strong confounder of its independent influence on CV and renal events. \*\* In the Framingham study, lifetime risk of 55 to 65 year old men or women for developing hypertension was above 90%... Overall, *each 20 mmHg increase in SBP doubled the risk for CV death*. \*\* Currently there are more than 125 different medications, almost all of which are generically available. **PATHOPHYSIOLOGY:** The factors that generate BP comprise the integration of cardiac output (CO) and systemic vascular resistance (SVR):\ \ **BP** = CO × SVR.\ Note that **CO** = heart rate × stroke volume; **SVR** = 80 × (mean arterial pressure − central venous pressure)/CO.\ \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **Pressure natriuresis and Salt sensitivity:** **Pressure natriuresis:** defined as the increase in renal sodium excretion due to mild increases in BP, typically because of extracellular fluid volume expansion, allowing BP to remain in the normal range **Set-point BP**: BP at the point when extracellular volume and pressure natriuresis are in equilibrium. Presure Natriuresis occurs over hours to days and is modulated by both biophysical and humoral factors.\ Expansion of extracellular fluid volume and increased Bp result in a rise in blood flow through the vasa recta, which stimulates the production of paracrine factors such as NO and ATP, which can inhibit tubular sodium reabsorption at multiple sites of the nephron. **Renin-Angiotensin-Aldosterone System:** The enzyme renin and prorenin are synthesized and stored in the juxtaglomerular cell apparatus located in the kidney adjacent to the afferent arteriole and distal tubule. Renin is released in response to decreased renal afferent perfusion pressure, decreased sodium delivery to the macula densa, and activation of renal nerves (via β1- adrenergic receptor stimulation) and by a variety of metabolic prod- ucts,including prostaglandin E2 and several others.The main function of renin is to cleave angiotensinogen into angiotensin I. Angiotensin II, formed by the cleavage of angiotensin I by ACE, is at the center of the pathogenetic role of the RAAS in hypertension. Primarily through its actions mediated by the angiotensin II type 1 receptor (AT1R), angiotensin II is a potent vasoconstrictor of vascular smooth muscle, causing systemic vasoconstriction Angiotensin II produces increased sodium reabsorption in the prox- imal tubule by increasing the activity of the sodium:hydrogen exchanger (NHE3), the sodium-bicarbonate exchanger, and Na+-K+- ATPase and by inducing aldosterone syn- thesis and release from the adrenal zona glomerulosa **Angiotensin II** is associated with endothelial cell dysfunction and produces extensive fibrotic and inflammatory changes, largely mediated by increased oxidative stress,resulting in renal,cardiac,and vascular injury,thus giving angiotensin II a tight link to target-organ injury in hypertension. In contrast, stimulation of the angiotensin II type 2 receptor (AT2R) is associated with opposite effects, resulting in vasodilation, natriuresis, and antiproliferative effects. Aldosterone, the adrenocortical hormone synthesized in the zona glomerulosa, plays a critical role in hypertension through its effects on sodium reabsorption largely mediated by transcriptional effects, via activation of the mineralocorticoid receptor, leading to increased expression of the epithelial sodium channel (ENaC). **ACE2** is expressed largely in the heart, kidney, and endothelium; it has partial homology to ACE and is unaffected directly by ACE inhibitors (ACEIs).52 It has a variety of substrates, but its most important action is the conversion of angiotensin II to angiotensin (1 to 7). Angiotensin (1 to 7) is formed primarily though the hydrolysis of angiotensin II by ACE2, and its actions are opposite to those of angiotensin II,including vasodilatory and antiproliferative properties that are mediated by the Mas receptor,a G protein--coupled receptor that, upon activation, forms complexes with the AT1R, thus antagonizing the effects of angiotensin II \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **SYMPATHETIC NERVOUS SYSTEM:\ **Many patients with hypertension are in a state of autonomic imbalance that encompasses increased sympathetic and decreased parasympathetic activity. In human hypertension, plasma catecholamine levels, microneurographic recordings, and systemic catecholamine spillover studies have consistently found elevation of these markers in obesity, the metabolic syndrome, and hypertension complicated by heart failure or kidney disease. The key factor in the maintenance of sustained hypertension is increased renal sympathetic nerve activity and its attendant sodium avidity. **NATRIURETIC PEPTIDES:** **Atrial (ANP), brain (BNP) and Urodilantin** play important role in salt sensitivity, heart failure and hypertension. *All natriuretic peptides directly increase GFR*, which in volume-expanded states is mediated by an increase in efferent arteriolar tone and increased filtration coefficient (Kf). Natriuretic peptides also inhibit renal sodium reabsorption through both direct and indirect effects. Direct effects include decreased activity of Na+-ATPase and the sodium-glucose cotransporter in the proximal tubule and inhibition of the ENaC in the distal nephron. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **ENDOTHELIUM** Endothelial cells produce a host of vasoactive substances, of which **Nitric Oxide is the most important to BP regulation**. Interruption of NO production via inhibition of the constitutively expressed nitric oxide synthase 3 (eNOS) causes BP elevation and development of hypertension in both animals and humans. **ET-1** is the endothelial cell product that counteracts NO to maintain balance between vasodilation and vasoconstriction. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **ARTERIAL STIFFNESS IN HYPERTENSION** Important factor in the pathogenesis of hypertension, particularly the syndrome of Isolated systolic hypertension with aging. *High sodium/ Lower potassium* diets over time predispose to increased arterial stiffness. **Cullin-3 mutations** in vascular smooth muscle appear to be responsible for arterial aging. **Factors strongly associated with arterial stiffening** include aging, hypertension, diabetes mellitus, chronic kidney disease (CKD) smoking and high sodium intake. A commonly used measure to assess arterial stiffness in humans is **carotid-femoral pulse wave velocity (cf-PWV).** Increased PWV is associated with increased mortality and CV events as well as with a variety of subclinical CV injury markers, such as coronary calcification, cerebral white matter lesions, abnormal ankle-brachial index and albuminuria. **What is the clinical importance of arterial stiffness?\ **1. Increased arterial stiffness predicts the onset of ESRD in adults with polycystic kidney disease.\ 2. Poorer and reduced response of NO to any vasoconstriction stimuli.\ 3. Results in more labile hypertension and increased BP variability.\ \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **IMMUNE SYSTEM IN HYPERTENSION** Innate responses, especially those mediated by macrophages, have been linked to hypertension induced by angiotensin II, aldo- sterone, and NO antagonism. Reductions in macrophages have been linked to hypertension induced by angiotensin II, aldosterone, and NO antagonism. Abnormalities in both proinflammatory T cells and regulatory T cells alike are implicated in complications of hypertension, because they appear to regulate vascular and renal inflammation that underlies target-organ injury. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **FACTORS INVOLVED IN PREDISPOSITION TO HYPERTENSION** **GENETICS:** Hypertension clusters in families; an individual with a family history of hypertension has a fourfold greater chance of developing hypertension. Among these genes, FOS (for protooncogene) and PTGS2 (COX-2) have been replicated in a number of studies. Monogenic causes of hypertension, although quite rare, have pro- vided substantial insight into the pathogenesis of hypertension. Of the monogenic forms of hypertension with well-described molecular mechanisms, all have one thing in common: **a defect in renal sodium handling**. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **OBESITY:** Obesity related hypertension is characterized primarily by impaired sodium excretion and endothelial dysfunction dependent on SNS overactivity, activation of the RAAS and increased oxidative stress. Fat tissue in obesity is hypertrophied, meaning *larger cells* versus more cells and marked by increased macrophage infiltration in the adipose tissue. Impaired NO synthesis (eNOS inhibition) and enhances ET-1 production, shifts the vasodilation/vasoconstriction balance toward vasoconstriction. Visceral adipocyte mass is directly correlated with aldosterone secretion by the zona glomerulosa, a process mediated by angio- tensinogen production by adipocytes as well as increased secretion of Wnt signaling molecules that modulate steroidogenesis. There is consistent evidence that obese individuals tend to have lower natriuretic peptides than lean individuals, and this relative deficiency is amplified in obese hypertensives. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **DIAGNOSTIC APPROACH TO PRIMARY HYPERTENSION** The evaluation of patients with hypertension focuses on six key components: The confirmation that the patient is indeed hypertensive through careful measurements of BP. Assessment of clinical features that might suggest specific remediable causes of hypertension. Identification of comorbid conditions that confer additional CV risk, or that may impact treatment decisions. The discussion of patient-related lifestyle factors and preferences that will affect management The systematic evaluation of hypertensive target-organ damage Shared decision making about the treatment plan. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **HISTORY AND PHYSICAL EXAMINATION:** The medical history and physical examination are essential to uncovering possible secondary causes of hypertension, identifying symptoms suggestive of hypertensive target-organ damage, and diagnosing comorbid conditions that may affect treatment decisions High BP is typically asymptomatic, but some symptoms are common among patients with very high BP levels, such as headaches, epistaxis, dyspnea, chest pain, and faintness, all of which were present in more than 10% of patients presenting with DBP levels above 120 mm Hg. Obtaining a detailed family history as it pertains to hypertension is essential. Focus should be on the development of hypertension at a young age or clustering of endocrine (pheochromocytoma, multiple endocrine neoplasia \[MEN\], primary aldosteronism) or renal problems (polycystic kidney disease or any inherited form of kidney disease). When obtaining the history, the clinician should explore issues related to lifestyle, cultural beliefs, and patient preferences that will be essential in designing an effective treatment plan. The physical examination is designed to complement the items discussed in the history. One should pay attention to **syndromic features** of **cortisol excess** (moon face, central obesity, frontal balding, cervical and supraclavicular fat deposits, skin thinning, abdominal striae), **hyperthyroidism** (tachycardia, anxiety, lid lag/proptosis, hypertelorism, pretibial myxedema), **hypothyroidism** (bradycardia, coarse facial features, macroglossia, myxedema, hyporeflexia), **acromegaly** (frontal bossing, widened nose, enlarged jaw, dental separation, acral enlargement, carpal tunnel syndrome), **neurofibromatosis** (neurofibromas, café au lait spots,as neurofibromatosis is associated with pheochromocytoma and renal artery stenosis), or **tuberous sclerosis** (hypopigmented ash leaf patches, facial angiofibromas, as tuberous sclerosis is associated with renal hypertension, usually related to angiomyolipomas). A **coarctation of the aorta** should be considered in younger patients with unexplained, difficult-to-treat hypertension and is evaluated by measurement of BP in both arms and in one thigh. If present, there will be a significantly lower BP in the thigh (typically by more than 30 mm Hg). Sometimes, in case of a lesion proximal to the left subclavian, there may be a significant interarm BP difference, lower on the left. **Fundoscopic examination** is recommended to evaluate for vascular changes associated with hypertension.\ **Acute changes in fundoscopy (hours to days)** and range from arteriolar spasm in most patients with uncontrolled Bp to retinal infarcts (exudates) and microvascular rupture (flame hemorrhages), to papilledema.\ **Chronic changes** include vascular tortuosity (arteriovenous nicking) due to perivascular fibrosis, followed by progressive arteriolar wall thickening that prevents visualization of the blood column thus leading to the appearance of copper wiring, then silver wiring. Subclinical atherosclerosis can be identified by the presence of bruits over the carotid arteries, as the prevalence of carotid atherosclerosis is increased in patients with hypertension, as well in the abdomen, primarily looking for renal arterial bruits heard over the epigastrium and/or flanks.These bruits are of greater significance if occurring on both systole and diastole. To wrap up the examination, a focused neurlogic examination looks for obvious cranial nerve abnormalities, motor deficits or speech or gait abnormalities. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **BLOOD PRESSURE MEASUREMENT** Cuff-based brachial BP is the most used method to measure BP, typically in the office setting. **OFFICE BP MEASUREMENT:** \*Office BP is the time-honored method for the diagnosis and management of hypertension.\ \* BP should be measured in the arm while in the seated position, once an arm is selected it should always be used for subsequent BP readings.\ \*In situations when thigh measurements are used, an appropriately sized thigh cough should be used, obtained in the prone position to allow the cuff to be at the level of the heart.\ \* Aneroid and electronic oscillometric manometers are accurate but should have periodic maintenance (**every 12 months**), to ensure that they are properly calibrated, as well as any time poor function is suspected. **MASKED HYPERTENSION\ **- Condition in which a patient's office BP level is normal but ambulatory or home BP readings are in the hypertensive range.\ - *Opposite of white coat hypertension* When assessing BP on the initial visit, **orthostatic BP** should be obtained, especially among older patients, in whom it occurs in 8% to 34%.\ \* Orthostatic vital signs (heart rate and BP) are best obtained after at least 5 minutes in the supine position followed by immediate assumption of the standing position, when sequential measurements are taken for up to 3 minutes.\ \* If orthostatic hypotension is checked **from a seated position to standing** a *fall of **15/7** mm Hg may be used for the definition of orthostatic hypotension* when the test is performed using the seated BP as baseline as compared with the **generally accepted definition of orthostatic hypotension as a drop in BP of more than 20/10 mm Hg that occurs after 3 minutes of standing**. **OFFICE VERSUS HOME BP**\ \***ABPM** has stronger associations with LVH, albuminuria, kidney dysfunction, retinal damage, carotid atherosclerosis, and aortic stiffness than office BP, although this is not consistent among studies.\ \* Likewise, **home BP** is a better marker than office BP for LVH and proteinuria, though it is not consistently superior for other measures of target-organ damage.\ \* In the assessment of hard CV endpoints, out-of-office BP has consistently outperformed office BP in studies that account for the values observed in the office; in other words, no matter what the office BP, it is the out-of-office BP that decisively drives outcomes.\ \* In a meta-analyses of studies that evaluated both office and ABPM on outcomes, only ABPM values retained significance and was useful in masked hypertension.\ \* The normal circadian BP pattern includes a fall in BP of approximately 15% to 20% during sleep.Patients who lack this normal BP dip during sleep are called **"nondippers"** (arbitrarily defined as a sleep BP that falls by less than 10% compared with awake levels) and have increased target-organ damage and overall CV risk.\ \* In a large observational studies, patients whose SBP falls by 20% or more during the night have lower fatal and nonfatal CV event rates than those whose BP decreases by less than 20%.\ \* ABPM also provides information on BP variability throughout the day. Increased BP variability (measured as the standard deviation of BP) has been associated with increased event rates.\ \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **CLINICAL USE OF AMBULATORY AND HOME BP MONITORING\ \ **\* Although not feasible, 24-hour ABPM is recommended for all newly diagnosed individuals with hypertension to eliminate the diagnosis of WCH or masked hypertension and to evaluate dipping status while sleeping.\ \* A **typical measurement interval** is *every 20 minutes during the daytime (7 am to 11 pm)* and *every 30 minutes at night (11 pm to 7 am)*. Although the frequency and time windows can be adjusted based on clinical needs.\ \* The preferred devices use arm cuffs. **Finger cuffs are inaccurate and should not be used**.Wrist cuffs often provide incorrect readings because of inappropriate technique but, if used correctly, can be convenient and accurate, and particularly useful in obese patients.\ \* To allow management decisions, home BP monitoring is best performed using specific periods of monitoring.For most patients, a **BP log obtained over 7 days before each office visit** suffices because it retains excellent reproducibility.\ \* We recommend that the patient obtain readings in **duplicate (approximately 1 minute apart), twice daily (in the morning before taking medications and in the evening before dinner)**. \*\*\* The ACC/AHA guidelines recommend the use of out-of-office BP to evaluate patients who are receiving treatment for hypertension but remain above goal in the office.\ \*\*\* The high prevalence (approximately **40% to 51%**) of a white coat effect in patients with resistant hypertension supports this recommendation. Patients with **office BP above 160/100 mm Hg** do not need further confirmation of hypertension and should be treated.\ \ \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **LABORATORY AND OTHER COMPLEMENTARY TESTS:** In the absence of worrisome signs or symptoms during initial evaluation, a **basic set of tests** include: *Renal function, Electrolytes, Calcium, Glucose and Hemoglobin; a lipid profile, urinalysis and electrocardiogram.* **ECHOCARDIOGRAPHY\ **\* **LVH is the most common target-organ damage in hypertension** and is independently associated with worse prognosis, marked by increased risk for CV events (coronary, cerebrovascular), heart failure, and death.\ \* The Electrocardiogram is very specific but insensitive for the detection of LVH. Incidence of LVH among patients is approximately 18% based on electrocardiographic criteria. This number increases unto 40% when more sensitive echocardiographic criteria are used.\ \* LV systolic dysfunction is uncommonly seen in hypertension (approximately 4%) but is associated with worse prognosis. **EVALUATION OF SODUM AND POTASSIUM INTAKE\ **\*A 24 hour urine collection for electrolytes can be performed on a patient with stable dose of diuretic.\ \* *Do not allow Hypokalemia*, because it will increase BP. **RENIN PROFILING\ **\* The premise for this approach is mechanistic: patients with high plasma renin activity levels (\>0.65 ng/mL/hr, and particularly \>6.5 ng/mL/hr) have vasoconstriction mediated by the RAAS as the primary operative mechanism of hypertension, whereas those with suppressed plasma renin activity levels (\65 YEARS)** \*The primary agents used in the treatment of hypertension in older people with the greatest efficacy are thiazide-type diuretics and CCBs. \*ACEI and ARBs are effective adjuncts but because of the lower renin status in older people they are not as successful in lowering BP. \*Thiazide diuretics such as hydrochlorothiazide, chlorthalidone, indapamide, and bendrofluazide, as well as calcium antagonists, are recommended for initiating therapy in the older patient. **Systolic Blood Pressure Intervention Trial (SPRINT)\ **- Older group of patients randomized to a lower level of **BP less than 120 mmHg** *did well* and in many cases better than those at BPs targeted to less than 140 mm Hg, leading to the **assertion that older patients should be treated to lower levels of BP**. **Calcium antagonists\ **- well suited for older patients whose hyper- tensive profile is based on increasing arterial dysfunction secondary to decreased atrial and ventricular compliance.\ - Most adverse effects relate to vasodilation, causing ankle edema, headache, or postural hypotension. Ankle edema is not secondary to sodium retention, because calcium antagonists are natriuretic when given initially, but the profound vasodilation with poor venous return in older people is the major contributor. \*RAAS blockers, such as ACEIs, ARBs, and direct renin inhibitors, may be used in older adults. **ACCOMPLISH TRIAL:\ **- ACCOMPLISH suggested that a CCB-ACEI combination led to fewer people going on dialysis than a diuretic-ACEI combination; an outcome not explained by the BP difference of 1.2 mm Hg systolic between the two arms. \*Nebivolol, a selective beta1 blocker with NO properties, does not show associated symptoms of depression, sexual dysfunction, dyslipidemia, and hyperglycemia in older adults, unlike earlier generations of beta blockers. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **MANAGEMENT OF HYPERTENSION IN CHRONIC KIDNEY DISEASE** \*The strongest level of evidence to support slowing of CKD progression argues for BP levels below 140/90 mm Hg and the use of RAAS-blocking agents in people with stage 3 or higher CKD who have very high albuminuria. \*There is weaker evidence to support RAAS-blocker use in people with CKD without proteinuria, and very weak evidence supporting a BP of less than 130/80 mm Hg even for those who have a urine albumin level of 1 g or more and an eGFR of less than 60 mL/min/1.73 m2. \*A review of clinical trials where hyperkalemia developed when managing hypertension in CKD found three risk predictors: (1) eGFR of less than 45 mL/min/1.73 m2, (2) serum potassium level above 4.5 mEq/L, and (3) body mass index of less than 25. \*Further, critically important nuances in BP management in CKD patients are sodium restriction to less than 2400 mg/day, reduced alcohol consumption, and aerobic but not isometric exercise. \*Studies evaluating the effect of sodium intake on BP control in people with stage 4 CKD show that approximately every 400 mg above a sodium intake base of 3000 mg/day requires an additional BP medi- cation to maintain BP control. **ACCORD Trial**\ - Action to Control Cardiovascular Risk in Diabetes\ \*The results of the BP arm of the ACCORD trial failed to show a reduction in major CV events from more aggressive BP control. **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_** **BLOOD PRESSURE MANAGEMENT IN PATIENTS UNDERGOING DIALYSIS** \- Elevations in BP in dialysis patients are almost exclusively due to excessive volume. Hypertension control related directly to volume management is a more common problem in hemodialysis than in peritoneal dialysis. \*Elevated BP by home or ABPM is clearly associated with shorter survival. Sodium and volume excess is the prominent mechanism of hypertension in dialysis patients, but other pathways, such as arterial stiffness, activation of the RAAS and SNSs, endothelial dysfunction, sleep apnea, and the use of erythropoietin-stimulating agents may also be involved. \*If BP remains elevated after appropriate treatment of sodium- volume excess, the use of antihypertensive agents is necessary. Drug treatment in the dialysis population should take into consideration the patient's comorbidities and specific characteristics of each agent, such as dialyzability (i.e., metoprolol and atenolol are both 50% dialyzable, so effect dose is reduced). \*The following points are vital to have an accurate assessment of BP:\ (1) the most representative BP is the one taken the morning after dialysis,\ and (2) there should be a minimum of two and ideally three readings obtained 1 to 2 minutes apart during those morning readings and then averaged. \*Given that heart failure and sudden death are the most common causes of death in dialysis patients, beta blockers have an important role in the BP-lowering armamentarium, unlike the general population. **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_** **HEART FAILURE** \- It is important to recognize the unique contribution of hypertension to HFpEF, a phenotype of heart failure which is now the predominant clinical syndrome recognized in hospital settings and responsible for more than 50% of all acute heart failure admissions. \- Of all potential strategies that might reduce the incidence of heart failure, none appears to have higher yield than the treatment of hypertension. **Systolic Hypertension in Elderly Program (SHEP)\ -** One of the first hypertension trials to include a prespecified endpoint examining the efficacy of antihypertensive therapy (chlorthalidone 12.5 to 25 mg plus atenolol 25 to 50 mg, if needed) in the prevention of heart failure.\ - Participants randomized to diuretic- based stepped care had a 49% reduction in fatal and nonfatal heart failure events during an average follow-up of 4.5 years. **Hypertension in the Very Elderly Trial (HYVET)\ -** Patients randomized to the indapamide plus perindopril (as needed to achieve a target BP of 150/80 mm Hg) group achieved a 64% reduction in heart failure events compared with placebo at 2 years **Heart Outcomes Prevention Evaluation (HOPE)\ -** Demonstrated that ACEIs could also reduce heart failure events in high-risk participants.\ - Among participants with diabetes mellitus or established vascular disease, ramipril treatment was associated with a 23% reduction in heart failure events after a mean of 4.5 years of follow-up. **Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)\ -** Tested the efficacy of chlorthalidone compared with lisinopril, amlodipine, and doxazosin in 42,418 participants with hypertension and at least one other CV risk factor.\ - In direct and indirect comparisons, thiazide diuretics were marginally superior to ACEIs and ARBs; CCBs, beta blockers, and alpha blockers were the least effective agents for heart failure prevention. **Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved** and **Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE).\ -** Both trials failed to meet their primary outcome that included composite endpoints consisting of all-cause mortality, CV death, heart failure hospitalization, and/or hospitalization for a CV cause. **Treatment of Preserved Cardiac Function Heart Failure with an Aldo- sterone Antagonist (TOPCAT)\ **- Largest trial to test the effects of mineralocorticoid receptor antagonists in patients with HFpEF.\ - After a mean follow-up of 3.3 years, spironolactone did not reduce the primary outcome of composite CV events,but it did reduce heart failure hospitalizations by 17%. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **RESISTANT HYPERTENSION\ **- Defined as the **failure to achieve a goal BP of less than 140/90 mm Hg in patients who are adherent with maximal tolerated doses of three antihypertensive drugs, one of which must be a diuretic appropriate for kidney function**.\ - Prevalence of resistant hypertension is approximately 8% to 12% of adult patients with hypertension (6 to 9 million people)\ - Common causes of resistant hypertension include nonadherence with medication and volume overload secondary to poor kidney function and nonadherence with a low-sodium diet.\ - Once a diagnosis of resistant hypertension is made, a fourth drug is needed after use of a calcium antagonist, diuretic, and RAAS blocker.\ - A mineralocorticoid inhibitor inhibitor such as spironolactone has demonstrated significant benefit in controlling BP in these patients. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **RENAL DENERVATION** \- The renal nerves enter the kidney at the hilum and branch out into segmental arteries throughout the kidney.They contain sympathetic efferent and sensory afferent fibers and are recognized as important controllers of kidney function and BP. The first definitive randomized, sham- controlled trial, **SYMPLICITY HTN-3.\ **- RDN and sham groups, had **no significant differences in 24-hour ambulatory SBP**. After 12 months, the reductions in office BP were similar in the RDN and sham groups.\ - The main reasons for the poor outcome revolved around procedural adequacy of denervation and location of denervation. **SPYRAL HTN-OFF MED trial\ **- demonstrated a clear 6.6/4.4--mm Hg reduction in office systolic pressure. **SPYRAL HTN-ON MED trial\ **- Office and 24-hour ambulatory BP decreased significantly from baseline to 6 months in the RDN group but not in controls, and baseline-adjusted treatment differences in 24-hour SBP/DBP averaged −7.0/−4.2 mm Hg.\ - The BP reductions with RDN increased during 6 months of follow-up, and there were no procedural or intermediate-term adverse safety events reported. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **BARORECEPTOR ACTIVATION** **DEBuT-HT\ **The DEBuT-HT European trial (Device Based Therapy in Hypertension Trial)\ - Evaluated 45 patients with resistant hypertension, SBP ≥160/ DBP ≥90 mm Hg.\ - Confirmed the sustained antihypertensive effects of baroreceptor-activation (BA) therapy **Rheos Pivotal Trial\ **- subjects were implanted with the Rheos system, and 265 patients were randomized 2:1 1 month after surgery to receive BA the first 6 months (immediate BA) or to delay BA for the first 6 months of the trial (delayed BA).\ - The trial was successful in meeting the prespecified sustained 12-month efficacy endpoint; however, the acute 6-month primary efficacy endpoint was missed. **Barostim Neo Trial\ **The Barostim Neo trial was a single-arm, open-label study that eval- uated efficacy and safety of the second-generation system for BA in 30 patients with resistant hypertension.\ - The primary efficacy objective of this trial was to describe reductions in office BP through 6 months of BA.287 Compared with the Rheos-HT trial, the num- ber of patients who suffered from procedural complications decreased from 25% to 3%. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **HYPERTENSIVE URGENCY AND EMERGENCY** A hypertensive emergency is the combination of elevated BP levels (with no specific diagnostic BP level) and signs or symptoms of acute, ongoing target-organ damage. \- The initial evaluation of a severely hypertensive patient includes a thorough inspection of the optic fundi (looking for acute hemorrhages, exudates, or papilledema); a mental status assessment; a careful cardiac, pulmonary, and neurologic examination; a quick search for clues that might indicate secondary hypertension (e.g., abdominal bruit, striae, radial-femoral delay); and laboratory studies to assess renal function (dipstick and microscopic urinalysis, determination of serum creatinine level). Several options for intravenous drug treatment exist, but **nitroprusside** is the least expensive and most widely available.\ \ - **Nitroprusside** - must be kept in the dark and is metabolized to cyanide and/or thiocyanate, particularly during long-term infusions.\ - **Fenoldopam mesylate,** a dopamine-1 agonist, is very effective and acutely improves several parameters of renal function.\ - **Clevidipine** is a DHP calcium antagonist that is hydrolyzed within minutes by ubiquitous serum esterases; it is administered in an emulsion containing soy and egg proteins (either of which can cause immunologic reactions in allergic patients).\ - **Nimodipine** is typically used only for subarachnoid hemorrhage.\ - **Labetalol** can be given as an intravenous infusion and easily converted to an ongoing oral dose. \*\*\*The quickest therapeutic response to a hypertensive emergency is recommended for an **acute aortic dissection**. In this condition the BP should be l**owered *within 20 minutes* to an SBP below 120 mm Hg** (neither of which is supported by a strong evidence base), typically with a beta blocker (to reduce shear stress on the dissection) and a vasodilator. In **acute ischemic stroke** if the patient is a candidate *for acute thrombolytic therapy and the BP is higher than 180/110 mm Hg,acute BP lowering is recommended*. \*\*\*All other types of hypertensive emergencies can be handled with a **gradual lowering of BP (typically 10% to 15% during the first hour** and a further **10% to 20% during the next hour**, for a **total of approximately 25%**). Hypertensive encephalopathy is a diagnosis of exclusion, it is often very rewarding to monitor these patients closely because their mental status improves markedly (and usually rather quickly) as the BP is carefully lowered. Patients who present with hypertensive crises involving cardiac ischemia/infarction or pulmonary edema can be managed with nitro- glycerin, clevidipine, nicardipine, or nitroprusside, although typically a combination of drugs (including an ACEI for heart failure or left ventricular dysfunction) is used in these settings. **Hypertensive emergency involving the kidney** commonly is followed by a further deterioration in renal function even when BP is lowered properly.\ - The most important predictor of the need for acute dialysis is not the BP level but instead the **degree of renal dysfunction** ([both eGFR and degree of albuminuria]).\ - Some physicians prefer fenoldopam to nicardipine or nitroprusside in this setting because of its lack of toxic metabolites and specific renal vasodilating effects. Hypertensive emergency resulting from catecholamine excess states (e.g., pheochromocytoma, monoamine oxidase inhibitor crisis, cocaine intoxication) are most appropriately managed with an intra- venous alpha blocker (e.g., phentolamine), with a beta blocker added later,if needed. Many patients with severe hypertension caused by sudden withdrawal of antihypertensive agents (e.g., clonidine) are easily managed by giving one acute dose of the missed drug. **Hypertensive emergency during pregnancy** must be managed in a more careful and conservative manner because of the presence of the fetus.\ - Magnesium sulfate, methyldopa, and hydralazine are the drugs of choice, with oral labetalol and nifedipine being drugs of second choice in the United States; nitroprusside, ACEIs, and ARBs are contraindicated.\ - Delivery of the infant is often hastened by the obstetrician to assist in management of hypertension in pregnancy. \* Whether hypertensive urgencies (elevated BP, but without acute ongoing target organ damage) ought to be treated acutely is controversial because there is no evidence that such treatment improves prognosis. \* The BP in many such patients spontaneously falls during a 30-minute period of quiet rest. Conversely, immediate-release nifedipine capsules can cause precipitous hypotension, stroke, myocardial infarction, and death.According to the FDA, they "should be used with great caution, if at all." \*\*\*The most important aspect of managing a hypertensive urgency is to refer the patient to a good source of ongoing care for hypertension, where adherence to antihypertensive therapy during long-term follow-up will be more likely. **As a summary:**\ - Patients presenting with a hypertensive emergency should be diagnosed quickly and started promptly on effective parenteral therapy (often nitroprusside 0.5 μg/kg/min) in an intensive care unit.\ - BP should be reduced by approximately 25%, gradually over 2 to 3 hours.\ - Oral antihypertensive therapy should be instituted, usually after approximately 8 to 24 hours of parenteral therapy; evaluation for sec- ondary causes of hypertension may be considered after transfer from the intensive care unit Because of advances in antihypertensive therapy and management, **"malignant hypertension" is a term that should be eliminated** because the prognosis of patients with this condition has improved greatly since the term was introduced in 1927. **\ **