Hypertension targets: a focus on the artery, the kidney and the heart

Abstract

2012 Annual Scientific Meeting and Exposition of the American Society of Hypertension

New York, NY, USA, 19–22 May 2012

For the last several years, the annual American Society of Hypertension meeting has held a segment called ‘Hypertension Highlights’ featuring state-of-the art talks by leaders in the field who share current research, and clinical management, organized around themes in hypertension. This year there were nine lectures grouped into three domains: the artery, the kidney and the heart.

The artery

The artery segment initiated the 27th annual American Society of Hypertension meeting. Paul Sanders from The University of Alabama in Birmingham (AL, USA) discussed the role of salt intake in mortality and used an old paper dealing with mortality in rodents whose life span was progressively shortened as dietary sodium chloride increased. The mortality rate was lower when potassium supplementation was used. He noted that sodium intake affects conduit artery function (by increasing large artery stiffness) and reviewed the from his laboratory showing the involvement of TGF-β in this process. He also briefed the complex mechanisms that reveal how this fibrosing cytokine is influenced by the Pyk2 (proline-enriched tyrosine kinase-2) pathway. Salt stimulates the TGF-β pathways, through shearing stress at the endothelial level, creating a picture of accelerated aging in the vessel wall.

Gary Mitchell from Boston, MA, USA spoke on the role of central blood pressures and reflected pulse-wave physiology from his experience in Framingham and his collaboration with investigators in Iceland in the Reykjavik longitudinal study [1]. He divided the target organ effects of blood pressures into load factors (left ventricular hypertrophy, heart failure [HF] and atrial fibrillation [AF]), atherosclerosis-based (heart attack and stroke) and microvascular disease (white matter hyperintensities seen on MRI, cognitive function impairment, retinopathy and renal disease progression). He showed striking associations between arterial stiffness and cardiovascular (CV) outcomes where the stiffest quartile of pulse-wave velocity (>11.8 m/s) had more than a threefold increase in CV events. Controversially, he presented an argument that reflected pulse-wave energy, when distributed into the terminal portions of the circulation with lower reflection back to the heart, could be a severe situation as it transfers the energy into target organs, challenging the view that reflected waves generate damage by being reflected back to the heart, increasing the systolic load and reducing the efficiency of coronary perfusion.

Sandra Taler from the Mayo Clinic, Rochester, MN, USA reviewed her experience using bioimpedance technology to hemodynamically profile blood pressure in uncontrolled hypertension. This technology estimates cardiac output, and, coupled with knowledge of the arterial pressure, calculates systemic vascular resistance based on measuring changes in central blood volume with each heart beat (stroke volume). She focused on comparing this technology with a hypertension specialist to achieve blood pressure control. All patients had a drop in blood pressure, but the magnitude was greater in those who had the added hemodynamic measurement, and also in those for whom the likelihood of achieving controlled blood pressure was higher.

The kidney

Out-of-office blood pressure measurements in patients with chronic kidney disease (CKD) were covered by Aldo Peixoto from Yale University in New Haven, CN, USA. He reviewed out-of-office blood pressure measurement techniques (home monitors and ambulatory blood pressure monitoring [ABPM]) and their prognostic role in patients with CKD who are not on dialysis or are transplanted. He emphasized that although the actual technique of blood pressure measurement is the same whether or not CKD is present, there are circumstances, such as the presence of an arterio–venous fistula, in which blood pressure readings (e.g., diastolic blood pressure) are altered by the arterio–venous anastomosis, noting that patients with CKD have substantial visit-to-visit variability in blood pressure measurements.

ABPM in CKD shows a failure to suppress blood pressure at night (‘non-dipping’) in 40%, and also ‘reverse dipping’ or ‘rising’ in approximately 40%, leaving only 20% of patients with a decline in nocturnal blood pressures. Reasons include autonomic nervous system activity, activation of the renin–angiotensin system, sleep disordered breathing and reduced daytime physical activity. Proteinuria markedly suppresses the normal circadian pattern of blood pressure. He concluded with a study of ABPM in patients with CKD from Naples, Italy, in which ABPM was better than office values for predicting CV or kidney-related end points [2]. Out-of-office values for blood pressure are feasible, useful in assessing both safety and efficacy (of treatment) and prognosis, and ABPM seems better than home, which in turn seem better than the clinic setting, in patients with CKD.

Next, Titte Srinivas from the Cleveland Clinic in Cleveland, OH, USA reviewed hypertension in the transplant patient. Although many factors complicate managing a person with an organ transplant, blood pressure is the single most important modifiable predictor of bad events in a transplant recipient’s future. Although calcineurin inhibitors frequently have high blood pressure associated with their use, poorer allograft survival occurs in regimens lacking these agents. Calcineurin inhibitor nephrotoxicity is worsened by salt depletion making it challenging to use diuretics in these patients. He reviewed the effects of glucocorticoids on blood pressure by enhancing the effect of vasoconstrictors, weight gain and glucose intolerance and their disturbance of sleep cycles, with the observation that despite these effects, the benefit on blood pressure after withdrawal of steroids is quite variable and not dependably favorable, advising listeners not “to monkey with the rejection regimen” in the interest of improving blood pressure control.

He then reviewed transplant kidney artery stenosis and the role of native nephrectomy in patients with difficulty to control hypertension, closing with an emphasis on the need to individualize the therapy and using treatment goals from the general population.

The final lecture in this segment featured the effect of erythropoiesis-stimulating agents (ESAs) on blood pressure in CKD by Jeffrey Berns from the University of Pennsylvania (PA, USA). He reviewed an experiment on rodents making two points: ESAs raise resting blood pressure in rodents, and raise it further when it naturally increases during physical activity. This was followed by a human study in athletes who used ESAs for ‘doping’ showing essentially the same thing.

The mechanisms by which ESAs increase blood pressure are speculative, involving increases in blood viscosity, reduced nitric oxide availability, increases in blood volume and amelioration of anemia-induced vasodilation when ESAs are used.

To address how much of an ESA can be safely given to achieve desired hemoglobin levels, he reviewed studies in which patients on dialysis, or those with CKD who are not on dialysis, were enrolled and randomly assigned a lower hemoglobin target of about 11 g/dl compared with a closer-to-normal value of 13 g/dl. Uniformly, these studies failed to show benefit of the higher hemoglobin target, and in some cases (e.g., stroke occurrence) suggested harm. He also pointed out that the blood pressure increases with ESAs occur less commonly now, and mentioned the diastolic pressure increases more than the systolic pressure from ESA exposure, that severe blood pressure increases including the occurrence of seizures are rare occurrences now, that an increase in hemoglobin was not required to see an increase in blood pressure, that there is no clear relationship between baseline blood pressure and the pressure response to ESA, there is a suggestion that the pressure increase is ESA-dose dependent.

He the reviewed the newest ESA, peginesatide, stating that the registration data showed that major CV events and death were higher in the nondialyzed CKD group, but that signal was not evident in dialysis patients, and that the current indications for this agent limit its usage to the dialysis population.

The heart

The final segment covered atrial arrhythmias and left ventricular hypertrophy. The first lecture was given by Patrick Ellinor from the Massachusetts General Hospital in Boston (MA, USA) focusing on genetic approaches to nonvalvular AF, which affects about 3 million US adults and one in ten people over the age of 80 years. It is a risk for stroke, and for death and is often associated with high blood pressure. He pointed out that if you have a young person with AF, the chances of AF being present in a first- or second-degree relative are one in three. He also pointed out that AF fibrillation is a heritable trait, and using genome-wide association studies they are attempting to understand what it is that predisposes a person.

The second lecture in this segment was delivered by James Reiffel from Columbia University Medical Center in New York (NY, USA) and covered the issue of the pathogenesis of AF. He noted that AF is more common in hypertension, that all atrial arrhythmias increased in incidence with increasing left ventricular dysfunction, and that left atrial size is a marker of chronicity. He reiterated the role of comorbidities in AF prevalence such as obstructive sleep apnea and pointed out that the signals that initiate AF arise in the pulmonary veins.

He discussed several clinical aspects of AF, noting that hypertensives with left ventricular hypertrophy or coronary ischemia had worse symptomatology and worse prognosis with AF. He reviewed the CHADS₂ scoring system for AF, which is used to assess the risk/benefit of anticoagulation in AF [3]. The C is for congestive HF, the H is for hypertension, the A for age more than 75 years, the D for diabetes and the S for stroke. A point scoring system (allotting points for the presence of each of the five factors) helps to support the decision to anticoagulate in AF. From trials of antithrombotic therapies he made the point, with respect to warfarin, that half the people who are candidates for warfarin actually received it, and that half of those who receive it have International Normalized Ratios that are in the guideline range for AF; sobering statistics. He closed by reinforcing the connection between hypertension and AF, noting that anticoagulant therapy does improve outcomes, and that the prognosis when hypertension and AF occur together is worse than the outlook of either occurring alone.

The last of the nine lectures was given by Prakash Deedwania from The University of California San Francisco in Fresno (CA, USA) covering HF with preserved ejection fraction (HFPEF). He initiated the discussion noting that HFPEF is more common in the older people, diabetics, those with left ventricular hypertrophy and those with CKD.

He discussed the approach to HF evaluation, beginning with determining the ejection fraction, typically by echocardiography. Next steps are excluding noncardiac causes (such as pulmonary embolism), and then looking closely to see if valvular disease or cardiomyopathy are present. A stress test and even angiography (based on clinical judgment) are appropriate steps in some patients, however, measurement of ventricular diastolic function (by evaluating the A and E wave relationships on echocardiography) is not recommended because these measurements can be misleading and look ‘normal’ (‘pseudonormalization’) as ventricular function declines. He reviewed the treatment options in HFPEF, which are symptoms based, rather than evidence based and contrasted systolic HF with HFPEF noting that:

• • Systolic HF has an evidence base for management;

• • Treatment is based on outcomes in randomized trials;

• • Systolic HF has a reasonable consensus agreement on its pathophysiology.

By contrast, HFPEF is lacking in most of the above. He reviewed why people with HFPEF decompensate, including salt and water intake excess, diuretic under usage, use of NSAIDs, intercurrent or worsened comorbidities like anemia and CKD, worsened coronary ischemia, AF and iatrogenic volume overload.

In reviewing trial evidence for HFPEF therapy, he noted that renin–angiotensin system blockade did not improve outcomes, stressing prevention (e.g., through guideline management of hypertension).

The highlights were a great start to 3.5 days of outstanding science in the field of hypertension. The American Society of Hypertension website [101] can be consulted for details on the rest of the program.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.