Clive Rosendorff

Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention

Epidemiological studies have established a strong association between hypertension and coronary artery disease (CAD). Hypertension is a major independent risk factor for the development of CAD, stroke, and renal failure. The optimal choice of antihypertensive agents remains controversial, and there are only partial answers to important questions in the treatment of hypertension in the prevention and management of ischemic heart disease (IHD), such as: ● What are the appropriate systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets in patients at high risk of developing CAD or in those with established CAD? ● Are the beneficial effects of treatment simply a function of blood pressure (BP) lowering, or do particular classes of drugs have uniquely protective actions in addition to lowering BP? ● Are there antihypertensive drugs that have shown particular efficacy in the primary and secondary prevention of IHD? ● Which antihypertensive drugs should be used in patients who have established CAD with stable or unstable angina pectoris, in those with non–ST-elevation myocardial infarction (NSTEMI), and in those with ST-elevation myocardial infarction (STEMI)?

Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease

Recent epidemiological evidence suggests that some antihypertensive medications may reduce the risk for Alzheimer disease (AD). We screened 55 clinically prescribed antihypertensive medications for AD-modifying activity using primary cortico-hippocampal neuron cultures generated from the Tg2576 AD mouse model. These agents represent all drug classes used for hypertension pharmacotherapy. We identified 7 candidate antihypertensive agents that significantly reduced AD-type beta-amyloid protein (Abeta) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Abeta peptides into high-molecular-weight (HMW) oligomeric peptides, known to be involved in cognitive deterioration. We found that preventive treatment of Tg2576 mice with valsartan significantly reduced AD-type neuropathology and the content of soluble HMW extracellular oligomeric Abeta peptides in the brain. Most importantly, valsartan administration also attenuated the development of Abeta-mediated cognitive deterioration, even when delivered at a dose about 2-fold lower than that used for hypertension treatment in humans. These preclinical studies suggest that certain antihypertensive drugs may have AD-modifying activity and may protect against progressive Abeta-related memory deficits in subjects with AD or in those at high risk of developing AD.

The renin-angiotensin system and vascular hypertrophy.

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.

Creatine kinase release not associated with myocardial necrosis after short periods of coronary artery occlusion in conscious baboons

The effects of 15 minute periods of coronary artery occlusion on plasma creatine kinase (CK) and CK-MB isoenzyme activity, regional myocardial function and subsequent myocardial necrosis were studied in six conscious baboons 2 to 3 weeks after recovery from instrumentation. Mid left anterior descending coronary artery occlusion induced complete loss of systolic wall thickening (ultrasound transit time technique) and decreases in epicardial (-93%) and endocardial (-96%) blood flows (microsphere technique). Reperfusion after 15 minutes resulted in complete recovery of regional function 24 hours later. Serial plasma enzyme activity revealed a significant increase in total CK from 71 +/- 11 to 976 +/- 158 U/liter and in CK-MB from levels that were too low to measure to 21.4 +/- 2.9 U/liter. At autopsy, neither gross pathologic evidence (triphenyltetrazolium chloride staining technique) nor histologic evidence of myocardial necrosis was observed. Thus, in the conscious baboon short episodes of myocardial ischemia are associated with a significant appearance of CK and CK-MB in the blood in the absence of cellular necrosis.

Progression of Kidney Disease in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin Versus Usual Care: A Report From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

BACKGROUND Dyslipidemia is common in patients with chronic kidney disease. The role of statin therapy in the progression of kidney disease is unclear. STUDY DESIGN Prospective randomized clinical trial, post hoc analyses. SETTING & PARTICIPANTS 10,060 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (lipid-lowering component) stratified by baseline estimated glomerular filtration rate (eGFR): less than 60, 60 to 89, and 90 or greater mL/min/1.73 m(2). Mean follow-up was 4.8 years. INTERVENTION Randomized; pravastatin, 40 mg/d, or usual care. OUTCOMES & MEASUREMENTS Total, high-density lipoprotein, and low-density lipoprotein cholesterol; end-stage renal disease (ESRD), eGFR. RESULTS Through year 6, total cholesterol levels decreased in the pravastatin (-20.7%) and usual-care groups (-11.2%). No significant differences were seen between groups for rates of ESRD (1.36 v 1.45/100 patient-years; P = 0.9), composite end points of ESRD and 50% or 25% decrease in eGFR, or rate of change in eGFR. Findings were consistent across eGFR strata. In patients with eGFR of 90 mL/min/1.73 m(2) or greater, the pravastatin arm tended to have a higher eGFR. LIMITATIONS Proteinuria data unavailable, post hoc analyses, unconfirmed validity of the Modification of Diet in Renal Disease Study equation in normal eGFR range, statin drop-in rate in usual-care group with small cholesterol differential between groups. CONCLUSIONS In hypertensive patients with moderate dyslipidemia and decreased eGFR, pravastatin was not superior to usual care in preventing clinical renal outcomes. This was consistent across the strata of baseline eGFR. However, benefit from statin therapy may depend on the degree of the cholesterol level decrease achieved.

Effects of coronary artery reperfusion on regional myocardial blood flow and function in conscious baboons.

The effects of coronary artery reperfusion initiated 1 hr and 3 hr after coronary artery occlusion were evaluated on measurements of overall and regional left ventricular function and on regional myocardial blood flow. These experiments were conducted in conscious baboons 2 to 3 weeks after recovery from instrumentation with a solid state left ventricular pressure gauge, aortic and left atrial catheters, a hydraulic occluder around the mid left anterior descending coronary artery, and pairs of ultrasonic transducers implanted in the endocardium of the left ventricular free wall or across the free wall to measure endocardial segment shortening and wall thickening, respectively. Coronary artery occlusion induced similar effects in both groups. At 1 hr after occlusion, the ischemic zone was characterized by severe and equal reductions in both endocardial (-97 +/- 1%) and epicardial (-95 +/- 4%) blood flows and complete loss of regional systolic function, which was replaced by paradoxical wall motion. Reperfusion initiated after 1 hr of ischemia was associated with a marked transient increase in endocardial (+386 +/- 51%) and epicardial (+544 +/- 79%) blood flows. During the subsequent 4 weeks, segment shortening and wall thickening tended to improve. However, at 4 weeks after reperfusion, segment shortening was still depressed by 45 +/- 12% and wall thickening by 58 +/- 14%. In contrast, reperfusion initiated after 3 hr of ischemia was not associated with a significant hyperemic response, and systolic segment shortening and wall thickening did not recover during the subsequent 4 week period.(ABSTRACT TRUNCATED AT 250 WORDS)

Better memory functioning associated with higher total and low-density lipoprotein cholesterol levels in very elderly subjects without the apolipoprotein e4 allele.

OBJECTIVE To examine the association of cholesterol with cognitive functioning in oldest old community dwelling individuals with and without the apolipoprotein e4 (APOE4) allele. METHOD One hundred eighty-five nondemented, community dwelling individuals (>or=85) were assessed with a broad neuropsychological battery. Bloods were drawn to assess total, low-density lipoprotein (LDL), and high-density lipoprotein cholesterol, as well as for APOE genotyping. RESULTS In contrast to our expectations, high total cholesterol and high LDL cholesterol were associated with higher memory scores for noncarriers of the APOE4 allele. No significant associations between cognitive performance and lipid profile were found for carriers of the APOE4 allele. CONCLUSIONS In oldest old nondemented noncarriers of the APOE4 allele, high cholesterol is associated with better memory function. Further examination of the role of APOE genotype on the association between cholesterol and cognitive performance, especially in the oldest old is warranted.

Treatment of Hypertension in Patients With Coronary Artery Disease

1. Relationship Between Hypertension and CAD e437 2. Prevention of Cardiovascular Events in Patients With Hypertension and CAD e443 3. BP Goals e445 4. Management of Hypertension in Patients With CAD and Stable Angina e449 5. Management of Hypertension in Patients With ACS e451

Hypertension and Coronary Artery Disease: A Summary of the American Heart Association Scientific Statement

The American Heart Association scientific statement on the treatment of hypertension in the prevention and management of ischemic heart disease was published recently. The main recommendations were as follows: (1) For most adults with hypertension, the blood pressure (BP) goal is <140/90 mm Hg but should be <130/90 mm Hg in patients with diabetes mellitus, chronic kidney disease, known coronary artery disease (CAD), CAD equivalents (carotid artery disease, abdominal aortic aneurism, and peripheral vascular disease), or 10‐year Framingham risk score of ≥10%. For those with left ventricular dysfunction, the recommended BP target is <120/80 mm Hg. (2) For primary CAD prevention, any effective antihypertensive drug or combination is indicated, but preference is given to angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide diuretics. (3) For the management of hypertension in patients with established CAD (stable or unstable angina, non–ST‐segment elevation myocardial infarction, ST‐segment elevation myocardial infarction), β‐blockers and ACE inhibitors (or ARBs) are the basis of treatment. If further BP lowering is needed, a thiazide diuretic and/or a dihydropyridine CCB (not verapamil or diltiazem) can be added. If a β‐blocker is contraindicated or not tolerated, diltiazem or verapamil can be substituted. (4) If there is left ventricular dysfunction, recommended therapy consists of an ACE inhibitor or ARB, a β‐blocker, and either a thiazide or loop diuretic. In patients with more severe heart failure, an aldosterone antagonist and hydralazine/isosorbide dinitrate (in black patients) should be considered.

Treatment of hypertension in patients with coronary artery disease: A scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension

Note: Authors from the National Institutes of Health/National Heart, Lung, and Blood Institute represent themselves and not the opinions of the National Institutes of Health/National Heart, Lung, and Blood Institute. The American Heart Association, the American College of Cardiology, and American Society of Hypertension make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This document was approved by the American Heart Association Science Advisory and Coordinating Committee on September 22, 2014, by the American College of Cardiology on October 10, 2014, and by the American Society of Hypertension on September 30, 2014. The American Heart Association requests that this document be cited as follows: Rosendorff C, Lackland DT, Allison M, Aronow WS, Black HR, Blumenthal RS, Cannon CP, de Lemos JA, Elliott WJ, Findeiss L, Gersh BJ, Gore JM, Levy D, Long JB, O’Connor CM, O’Gara PT, Ogedegbe G, Oparil S, White WB; on behalf of the American Heart Association, American College of Cardiology, and American Society of Hypertension. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. Hypertension. 2015;65:1372–1407. This article has been copublished in Circulation, the Journal of the American College of Cardiology, and the Journal of the American Society of Hypertension. Copies: This document is available on the World Wide Web sites of the American Heart Association (my.americanheart.org), the American College of Cardiology (www.cardiosource.org), and the American Society of Hypertension (http://www.ash-us.org/). A copy of the document is available at http:// my.americanheart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-2162533 or e-mail kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the “Policies and Development” link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/CopyrightPermission-Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page. (Hypertension. 2015;65:1372-1407. DOI: 10.1161/HYP.0000000000000018.)