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There is a need for a brief, open access, self-report medication adherence scale that overcomes challenges of existing adherence tools, is associated with incident cardiovascular disease (CVD), and identifies low 'implementation' adherers to antihypertensive medications to facilitate blood pressure management.Antihypertensive medication adherence was assessed in a cohort of 1532 older hypertensive adults without prior CVD using the self-report 4-item Krousel-Wood Medication Adherence Scale (K-Wood-MAS-4), a hybrid tool developed to predict pharmacy refill and which captures four domains of adherence behavior: self-efficacy, physical function, intentional medication-taking, and forgetfulness. The 4-item scale categorized participants as low and high adherers using scores at least 1 and less than 1, respectively. Participants were followed after K-Wood-MAS-4 assessment to identify incident CVD events (stroke, myocardial infarction, congestive heart failure, or CVD death). The prevalence of low adherence was 38.7%. During a median follow-up of 2.8 years (maximum 3.8 years), 136 (8.9%) participants had an incident CVD event; 12.8 and 6.4% in low and high adherers, respectively. The adjusted hazard ratio (aHR) for incident CVD associated with low versus high adherence was 2.29 [95% confidence interval (CI): 1.61, 3.26]. Results were similar when stratified by age [75 years - aHR 3.53 (95% CI: 1.65, 7.56); ≥75 years - aHR 1.98 (95% CI: 1.32, 2.97)], sex [women - aHR 1.90 (95% CI: 1.16, 3.12); men - aHR 2.80 (95% CI: 1.68, 4.65)], and race [black - aHR 2.22 (95% CI: 0.93, 5.31); white - aHR 2.26 (95% CI: 1.54, 3.34)].Low medication adherence using the 'hybrid' K-Wood-MAS-4 predicts incident CVD in a cohort of older adults with established hypertension.

BACKGROUND: Sex-race stratification may lead to identification of risk factors for low antihypertensive medication adherence that are not apparent when assessing risk factors in women and men without race stratification. We examined risk factors associated with low pharmacy refill adherence across sex-race subgroups (white women, black women, white men, black men) within the Cohort Study of Medication Adherence among Older Adults (n=2,122). METHODS: Pharmacy refill adherence was calculated as proportion of days covered (PDC) using all antihypertensive prescriptions filled in the year prior to a baseline risk factor survey. Sex- and sex-race-stratified multivariable Poisson regression models with robust standard errors were used to estimate adjusted prevalence ratios and 95% confidence intervals for associations between participant characteristics and low adherence. RESULTS: Prevalence of low adherence was 22.9% versus 40.7% in white versus black women (p

The changes in American academic medicine in the last 6 decades has been a success. During these years, I participated in this development through patients care, research, editorship of major Journals and as a member of governing boards of several professional organizations. This discussion will describe some of the developments of medicine and will recount my own professional career and my mentors who help me to achieve my goals.

This article provides a preview to the forthcoming articles in this issue, which are written by well-known and authoritative authors for the readers' pleasure and reference. This article hopes to provide a general overview that stimulates interest, better understanding, and continued joint commitment to the important subject of hypertension.

Objective To determine the association of post-traumatic stress disorder (PTSD) symptoms following Hurricane Katrina with incident cardiovascular disease (CVD) events in older, hypertensive, community-dwelling adults both overall and stratified by age, sex, and race. Methods This was a prospective cohort study performed in Southeastern Louisiana 12–24 months following Hurricane Katrina through February 2011. Participants were community-dwelling older adults (n = 2,073) enrolled in the Cohort Study of Medication Adherence Among Older Adults with no known history of CVD events. PTSD symptoms were assessed via telephone interview 12–24 months following Hurricane Katrina using the PTSD CheckList-Specific Version. The presence of PTSD symptoms was defined by scores greater than or equal to 37. Incident CVD events (stroke, myocardial infarction, hospitalization for congestive heart failure, or CVD death) were identified and adjudicated over a median 3.8-year follow-up period. Results Overall, 8.6% of participants screened positive for PTSD symptoms, and 11.6% had an incident CVD event during follow-up. PTSD symptoms were associated with an adjusted hazard ratio (aHR) for CVD events of 1.7 (95% confidence interval [CI], 1.1, 2.6). The association was present among blacks (aHR, 3.3, 95% CI, 1.7, 6.3) but not whites (aHR, 0.9, 95% CI, 0.4, 1.9); the interaction of PTSD symptoms and race on CVD events was statistically significant. Conclusion PTSD symptoms following Hurricane Katrina were associated with a higher risk of incident CVD in older adults with hypertension, with a stronger association in blacks compared with whites.

Excessive dietary salt intake induces extensive cardiovascular and renal damage in spontaneously hypertensive rats (SHR) that may be prevented by antihypertensive agents. This study examines whether salt-induced cardiac damage may be reversed by angiotensin II (type 1) receptor blockade (telmisartan). Eight-week-old male SHRs were divided into four groups; Group 1 (NS) was fed regular rat chow, and Group 2 (HS) received high-salt diet (HS; 8% NaCl). After 8 weeks on their respective diets, systemic hemodynamics and indices of left ventricular (LV) function were determined. Group 3 (HSnoT) was given HS for 8 weeks and then switched to a regular chow (0.6% NaCl) diet with no other treatment, and Group 4 (HSArb) received HS for 8 weeks and was then given regular diet plus telmisartan. Rats from these latter two groups were monitored for the ensuing 30 days. Compared with the NS group, rats in the HS group exhibited increased mean arterial pressure (161 ± 7 vs. 184 ± 8 mm Hg) and LV diastolic dysfunction, as evidenced by a decreased rate of LV pressure decline (-8754 ± 747 vs. -4234 ± 754 mmHg/sec) at the end of the 8 weeks of their respective treatment. After switching to regular chow, only one of 11 rats in the HSnoT group survived for the 30 days, whereas 10 died within 18 days; in the HSArb group only one of nine rats died; eight survived 30 days (P.01). Telmisartan significantly improved LV function and survival in those SHR rats having extensive cardiovascular damage induced by dietary salt excess.

This review provides an overview of our current understanding of the relation of salt consumption to hypertension and cardiovascular disease.

It is with a great deal of sadness that we notify the readers of Hypertension and the members of the American Heart Association Council on Hypertension of the death of Walmor C. De Mello, MD, PhD, on January 20, 2017, in San Juan, Puerto Rico. At the time of his death, Doctor De Mello was still a highly productive and respected investigator and teacher. Aside from his leadership in medical research and education, our colleague had a major impact in educating an almost entire generation of physicians and scientist since his original appointment in 1972 as Professor and Chair of the Department of …

Few data are available on the predictors of decline in antihypertensive medication adherence and the association of decline in adherence with subsequent blood pressure (BP) control. The current analysis included 1965 adults from the Cohort Study of Medication Adherence Among Older Adults recruited between August 2006 and September 2007. Decline in antihypertensive medication adherence was defined as a ≥2-point decrease on the 8-item Morisky Medication Adherence Scale assessed during telephone surveys 1 and 2 years after baseline. Risk factors for decline in adherence were collected using telephone surveys and administrative databases. BP was abstracted from outpatient records. The annual rate for a decline in adherence was 4.3% (159 participants experienced a decline). After multivariable adjustment, a decline in adherence was associated with an odds ratio (OR) for uncontrolled BP (≥140/90 mm Hg) at follow-up of 1.68 (95% CI: 1.01–2.80). Depressive symptoms (OR: 1.84 [95% CI: 1.20–2.82]) and a high stressful life events score (OR: 1.68 [95% CI: 1.19–2.38]) were associated with higher ORs for a decline in adherence. Female sex (OR: 0.61 [95% CI: 0.42–0.88]), being married (OR: 0.68 [95% CI: 0.47–0.98]), and calcium channel blocker use (OR: 0.68 [95% CI: 0.48–0.97]) were associated with lower ORs for decline. In summary, a decline in antihypertensive medication adherence was associated with uncontrolled BP. Modifiable factors associated with decline were identified. Further research is warranted to determine whether interventions can prevent the decline in antihypertensive medication adherence and improve BP control.

In the present review we reevaluated the experimental and clinical evidence that there is a local renin angiotensin system in the heart as well as the presence of a functional intracrine component which is activated during pathological conditions like heart failure and hypertension. The implications of these findings for cardiology were discussed. The novel finding that cell swelling impairs cell coupling and impulse propagation through activation of ionic channels with consequent generation of cardiac arrhythmias and the evidence that AT1 receptors are mechanosensors able to alter the heart function independently of Ang II were discussed. Particular attention was given to the role of salt loading on the activation of a local cardiac renin angiotensin and its consequences.

OBJECTIVE This study aimed to examine the effects of salt loading, with or without simultaneous angiotensin receptor blocker (ARB) treatment, on the systemic and tissue renin-angiotensin system (RAS) in spontaneously hypertensive rats (SHRs). METHOD Evaluation was performed early (4 weeks) in the course of salt loading in order to examine initial mediating events of cardiovascular and renal damage produced by salt excess. Four groups of rats were studied. Group 1 received regular rat chow (normal-salt diet); group 2 received normal-salt diet and an ARB (losartan, 30 mg/kg per day); group 3 received high-salt (8%) chow; and group 4 received high-salt diet and losartan. RESULTS High-salt diet increased systolic pressure to 193±1 mmHg compared to 180±2 in normal-salt diet group. Losartan reduced SBP in SHRs fed normal-salt diet but did not reduce SBP in the SHRs fed high-salt diet (192±2 mmHg). High-salt diet markedly increased urinary protein excretion from 27±4 to 64±13 mg/day and this increase was ameliorated by losartan (40±9 mg/day). In SHRs on high-salt diet, plasma angiotensin II concentration increased three to four-fold, whereas urinary angiotensinogen excretion increased 10-fold; and these changes were significantly reduced by losartan. High-salt diet accelerated glomerular injury and interstitial fibrosis in SHRs which were reduced by losartan. CONCLUSION These results demonstrate that the activity of RAS was either not suppressed or, even augmented, after 4 weeks of salt loading despite high salt intake and increased SBP. The data suggest that an augmented intrarenal RAS during high-salt diet may contribute to the development of renal injury in this experimental model.

The heart is a remarkably adaptive organ, capable of increasing its minute output and overcoming short-term or prolonged pressure overload. The structural response, in addition to the foregoing functional demands, is that of myocardial hypertrophy. Then, why should an adaptive response increase cardiovascular risk in hypertensive patients with left ventricular hypertrophy (LVH)? Evidence shows that the functional performance of hypertrophied cardiomyocytes is impaired, and that additional alterations develop in cardiomyocytes themselves, the extracellular matrix and the intramyocardial vasculature, leading to myocardial remodelling and providing the basis for the adverse prognosis associated with pathological LVH in hypertensive patients (i.e., hypertensive heart disease, HHD). As molecular information accumulates, the pathophysiological understanding and the clinical approach to HHD are changing. The time has come to develop novel diagnostic and therapeutic strategies aimed at improving the prognosis of HHD on the basis of reversing or even preventing the aforementioned changes in the ventricular myocardium.

Little is known about the associations between depressive symptoms, social support and antihypertensive medication adherence in older adults.We evaluated the cross-sectional and longitudinal associations between depressive symptoms, social support and antihypertensive medication adherence in a large cohort of older adults.A cohort of 2,180 older adults with hypertension was administered questionnaires, which included the Center for Epidemiologic Studies-Depression Scale, the Medical Outcomes Study Social Support Index, and the hypertension-specific Morisky Medication Adherence Scale at baseline and 1 year later.Overall, 14.1% of participants had low medication adherence, 13.0% had depressive symptoms, and 33.9% had low social support. After multivariable adjustment, the odds ratios that participants with depressive symptoms and low social support would have low medication adherence were 1.96 (95% confidence interval (CI) 1.43, 2.70) and 1.27 (95% CI 0.98, 1.65), respectively, at baseline and 1.87 (95% CI 1.32, 2.66) and 1.30 (95% CI 0.98, 1.72), respectively, at 1 year follow-up.Depressive symptoms may be an important modifiable barrier to antihypertensive medication adherence in older adults.

This study examined the role of the renin-angiotensin-aldosterone system (RAAS) in mediating cardiovascular and renal damage in spontaneously hypertensive rats (SHR) given salt excess. Since the circulating RAAS is inhibited in this model, it permits examination of the role of local tissue RAASs in mediating this injury. To this end, male 8-wk SHR were divided into 7 groups. The control group (C) received normal NaCl (0.6%) diet. All other groups were given 8% NaCl chow. In addition, group 2 was given placebo, group 3 the mineralocorticoid receptor blocker eplerenone (100 mg·kg−1·day−1), group 4 the angiotensin converting enzyme inhibitor quinapril (3 mg·kg−1·day−1), group 5 the angiotensin II type 1 receptor blocker candesartan (10 mg·kg−1·day−1), and groups 6 and 7 eplerenone and either quinapril or candesartan. The treatments lasted 8 wk. Compared with controls, mean arterial pressure (MAP), renal blood flow, coronary flow reserve, minimal coronary vascular resistance, diastolic time constant, and maximal rate of ventricular pressure fall were all adversely affected by salt loading. Left ventricular mass and fibrosis as well as proteinuria were also markedly increased by salt overload. Eplerenone induced only slight changes, whereas quinapril and candesartan normalized all indexes except MAP. Combination therapy also normalized all indexes, including MAP. These data suggest that 1) cardiovascular and renal damage induced by salt excess in the SHR were not pressure dependent; 2) mineralocorticoids were only marginally involved in this model; and 3) local tissue generation of angiotensin II may be, at least in part, responsible for the other adverse effects.

The spectrum of the cardiac complications of arterial hypertension includes heart failure (HF), sudden death, and cardiac dysrhythmias, as well as the exacerbation of coincidental diseases (ie, atherosclerosis and chronic renal disease).1 However, knowledge of the cardiac impact of chronic elevation of arterial pressure has so evolved that hypertensive heart disease (HHD) may be thought as those consequences derived from left ventricular (LV) responses to fundamental disease mechanisms triggered by mechanical overload and neurohumoral stimuli.2 For instance, the long-held views are that LV hypertrophy (LVH), as the result of cardiomyocyte growth in response to pressure overload, serves to restore heart muscle economy back to normal and to preserve LV function.3 However, a number of alterations of the cardiomyocyte and the noncardiomyocyte components of the myocardium (including apoptosis, fibrosis, and changes in the microcirculation) also develop in HHD that lead to pathological myocardial remodeling not only in the left ventricle but also the left atrium and right ventricle.2 These alterations may explain the overall risk of LVH and its associated cardiac and noncardiac complications in hypertensive patients.4 Although LVH may be detected early and accurately in hypertensive patients by electrocardiography and echocardiography, newer cardiac imaging methods and the monitoring of several circulating biomarkers hold promise as noninvasive tools for the diagnosis of myocardial remodeling. Numerous clinical studies have shown that effective long-term antihypertensive treatment may be associated with a decreased LV mass (LVM), which has been attributed to diminished risk. However, no large study (or meta-analysis) has demonstrated that diminished risk from the contemporary reduction of arterial pressure by virtue of its a priori design. Therefore, because overall risk remains unacceptably high, especially from HF, new therapeutic strategies aimed not only to decrease arterial pressure and LVM but also to repair and even prevent myocardial remodeling …

The aortic blood pressure curve involves two components: a steady component, the mean arterial pressure (MAP), which is dependent on cardiac output and vascular resistance, and a pulsatile component pulse pressure (PP), which is dependent on arterial stiffness and pulse wave reflections. The transduction mechanisms of MAP and PP differ markedly, involving focal adhesion kinase for MAP and oxygen free radicals for PP. Angiotensin II (ANG II) and its blockade are associated with changed vascular resistance and MAP; however, their effects on PP (peripheral and mostly central PP) have been inadequately investigated. In hypertensive rats, when compared with their normotensive controls, ANG II blockade normalizes central PP (5-integrin to its ligand fibronectin, and decreased circulating C-reactive protein. When given a normal salt diet, each of these factors contributes separately in reducing arterial stiffness and wave reflections. These responses disappear with a high-salt diet, a condition that usually involves the activation of the local vascular renin-angiotensin-aldosterone system and can be prevented by its selective blockade. Thus ANG II inhibition seems to contribute independently in reducing central PP and aortic stiffness.

Over the past four or five decades, hypertension and cardiovascular medicine has experienced dramatic and innovative changes that have significantly reduced morbidity and mortality. A vast array of new antihypertensive compounds have been developed, which are able to inhibit many pathophysiologic mechanisms of the disease and prevent many of the outcomes in patients with hypertension. Much of this series of therapeutic breakthroughs have been the result of active participation of clinical scientists with tremendous and remarkable knowledge of and experience with the fundamental mechanisms of disease. In more recent years, much new information has appeared concerning the basis genetic and biologic mechanisms involved in cardiovascular and renal diseases. What remains of utmost importance is for members of the academic community with a wide spectrum of experience and points of view to continue to work with the fundamental problems and mechanisms of the diseases.

It was unclear whether increased heart rate (HR) increased long-term mortality after heart transplantation (HT). The aim of this study was to evaluate whether HR predicted survival after HT. A retrospective analysis of patients who underwent HT at our institution was performed. Ethnicity, gender, date of birth, age at transplantation, length of follow-up after transplantation, cardiac rhythm within 3 months after transplantation, age at death, reason for transplantation, cause of death, and baseline medications after transplantation were recorded. Continuous variables, such as HR, blood pressure, cardiac ejection fraction, presence of allograft vasculopathy, and serum creatinine, were recorded at3 months, 6 months, and 1 year after HT, then annually to 10 years after HT. Seventy-eight patients with a mean age of 50 +/- 13 years were identified. Mean survival was 8.5 +/- 6.5 years. Of 78 patients, 32 patients had an HRor=90 beats/min, and 46 patients had an HR90 beats/min within 3 months after HT. There was a mean decrease in HR of 6 beats/min during 10 years (p0.03). Multivariate survival analysis showed that HR90 beats/min was a significant predictor of early mortality (hazard ratio 2.8, 95% confidence interval 1.5 to 5.1, p0.0013). Patients with a net increase in HR during 10 years had an increased risk of death compared with patients with no change or a net decrease in HR (hazard ratio 4.7, 95% confidence interval 1.9 to 12.0, p0.002). No significant differences in cause of death between patients with an HRor=90 or90 beats/min existed. In conclusion, HT patients with an HR90 beats/min within the first 3 months after HT were 2.8 times more likely to die than patients with an HRor=90 beats/min. Patients with a net increase in HR were 4.7 times more likely to die than those whose HR did not change or decreased over time.

Background Partial adherence to antihypertensive therapy remains a public health challenge and may be associated with increased cardiovascular risk. We quantitatively evaluated cardiovascular risk inherent in partial therapy adherence in spontaneously hypertensive rats with accelerated hypertension. Methods Adult spontaneously hypertensive rats were divided into 5 groups; Group 1 (controls) did not receive any treatment, whereas all other rats (Groups 2–5) were given nitric oxide synthase inhibitor N ω -nitro-l-arginine methyl ester (L-NAME) to exacerbate hypertension. Group 2 (untreated/nonadherers) was given L-NAME but not antihypertensive medication; Group 3 (Perfect Adherers) was treated daily with candesartan (10 mg/kg); Group 4 was given candesartan 3 times a week, whereas Group 5 received candesartan only during the last 6 days of the 3-week experiment (Partial Adherers). At the end, indices of systemic and regional (kidneys, brain, and heart) hemodynamics, and indices of left ventricular function were determined. Results Treatment with L-NAME aggravated hypertension, adversely affected target organ blood flows and resistances, and grossly impaired ventricular function. Perfect adherence with candesartan completely reversed the adverse cardiovascular effects of L-NAME intervention. In partial adherers (Groups 4 and 5), arterial pressure decreased and reached control values. However, target organ hemodynamics and heart function showed only slight improvements, if any. Conclusions The results demonstrate that partial adherence to therapy reduces arterial pressure, but may not prevent target organ damage. If replicated in humans, these results may have important clinical implications in hypertensive patients.

Our recent studies have demonstrated that salt excess in the spontaneously hypertensive rat (SHR) produces a modestly increased arterial pressure while promoting marked myocardial fibrosis and structural damage associated with altered coronary hemodynamics and ventricular function. The present study was designed to determine the efficacy of an angiotensin II type 1 (AT1) receptor blocker (ARB) in the prevention of pressure increase and development of target organ damage from high dietary salt intake. Eight-week-old SHRs were given an 8% salt diet for 8 wk; their age- and gender-matched controls received standard chow. Some of the salt-loaded rats were treated concomitantly with ARB (candesartan; 10 mg·kg−1·day−1). The ARB failed to reduce the salt-induced rise in pressure, whereas it significantly attenuated left ventricular (LV) remodeling (mass and wall thicknesses), myocardial fibrosis (hydroxyproline concentration and collagen volume fraction), and the development of LV diastolic dysfunction, as shown by longer isovolumic relaxation time, decreased ratio of peak velocity of early to late diastolic waves, and slower LV relaxation (minimum first derivative of pressure over time/maximal LV pressure). Without affecting the increased pulse pressure by high salt intake, the ARB prevented the salt-induced deterioration of coronary and renal hemodynamics but not the arterial stiffening or hypertrophy (pulse wave velocity and aortic mass index). Additionally, candesartan prevented the salt-induced increase in kidney mass index and proteinuria. In conclusion, the ARB given concomitantly with dietary salt excess ameliorated salt-related structural and functional cardiac and renal abnormalities in SHRs without reducing arterial pressure. These data clearly demonstrated that angiotensin II (via AT1receptors), at least in part, participated importantly in the pressure-independent effects of salt excess on target organ damage of hypertension.

We have previously shown that salt excess has adverse cardiac effects in spontaneously hypertensive rats (SHR), independent of its increased arterial pressure; however, the renal effects have not been reported. In the present study we evaluated the role of three levels of salt loading in SHR on renal function, systemic and renal hemodynamics, and glomerular dynamics. At 8 wk of age, rats were given a 4% ( n = 11), 6% ( n = 9), or 8% ( n = 11) salt-load diet for the ensuing 8 wk; control rats ( n = 11) received standard chow (0.6% NaCl). Rats had weekly 24-h proteinuria and albuminuria quantified. At the end of salt loading, all rats had systemic and renal hemodynamics measured; glomerular dynamics were specially studied by renal micropuncture in the control, 4% and 6% salt-loaded rats. Proteinuria and albuminuria progressively increased by the second week of salt loading in the 6% and 8% salt-loaded rats. Mean arterial pressure increased minimally, and glomerular filtration rate decreased in all salt-loaded rats. The 6% and 8% salt-loaded rats demonstrated decreased renal plasma flow and increased renal vascular resistance and serum creatinine concentration. Furthermore, 4% and 6% salt-loaded rats had diminished single-nephron plasma flow and increased afferent and efferent arteriolar resistances; glomerular hydrostatic pressure also increased in the 6% salt-loaded rats. In conclusion, dietary salt loading as low as 4% dramatically deteriorated renal function, renal hemodynamics, and glomerular dynamics in SHR independent of a minimal further increase in arterial pressure. These findings support the concept of a strong independent causal relationship between salt excess and cardiovascular and renal injury.

Hypertension plays major causative roles in development of cardiac failure and end-stage renal disease (ESRD). Cardiac and renal involvements in hypertension and relevant pharmacological interventions have been extensively studied in our laboratories. Our findings demonstrated that aged spontaneous hypertensive rats (SHR) developed reduced coronary flow reserve, increased coronary vascular resistance and cardiac fibrosis, and impaired cardiac function. Moreover, aged SHR naturally developed glomerular hypertension and ischemia, proteinuria, and glomerular sclerosis and interstitial fibrosis. These naturally-occurring cardiac and renal involvements in aged SHR are very similar to these target organ changes in essential hypertension. Furthermore, we have been able to reproduce similar derangements in younger adult SHR by nitric oxide synthesis inhibition. These changes are identical to the pathophysiological alterations in heart and kidney found in old SHR as well as clinically. Antihypertensive therapeutic interventions provided cardiac and renal protection and, perhaps even prevention in the aged SHR and younger adult SHR with suppressed nitric oxide synthesis. Recent clinical trails have translated these pathophysiological observations demonstrating that angiotensin II inhibition affords remarkable cardiac and renal benefits to patients with essential hypertension. Thus, both the aged SHR as well as younger adult SHR with suppressed nitric oxide synthesis very closely mimic the cardiac and renal outcomes seen in patients with essential hypertension. They accordingly have become extremely useful experimental models of hypertensive heart disease and ESRD seen with severe nephrosclerosis. The latter hypertensive rat model with induced endothelial dysfunction is recommended enthusiastically for its foregoing as well as time-saving and economic values.

Background: Many epidemiological, clinical, and experimental reports have demonstrated an association between serum uric acid concentration and a variety of cardiovascular and renal diseases, particularly in hypertension. At present, there seems to be no resolution to the question whether this relationship is causal or coincidental. Summary: This discussion examines a number of biological, pathophysiological, fundamental, and clinical relationships between serum uric acid concentration and several of these disorders. To this end, discussion and review provide some specific insight conclusions and recommendations related to their clinical relevance. Key Messages: We suggest that, in most instances (especially in patients with essential hypertension), the increase in serum uric acid concentration is coincidental, serving as a useful biomarker that relates the magnitude of circulating plasma uric acid concentration with the extent of impaired cardiovascular and renal function. Moreover, the value of certain pharmaceutical agents affecting the serum uric acid level should be considered carefully by taking into consideration the associated pathophysiological derangements.

Reports relating hyperuricemia and hypertension have been filed for many decades. Nevertheless, controversy remains concerning serum uric acid concentration as an independent risk factor underlying coronary heart disease (CHD) and essential hypertension or as an indirect marker of renovascular involvement. Earlier studies in normotensive subjects and hypertensive patients demonstrated that serum uric acid concentration was closely related to intrarenal hemodynamic alterations, suggesting that it is an excellent marker of vascular involvement. Our data from clinical studies and in an animal model of severe hypertensive nephrosclerosis have strengthened this concept. Conversely, other reports have suggested that uric acid may be a pathogenetic factor. Supporting arguments for this theory maintain that experimental hyperuricemia induces hypertension and renal damage. Epidemiologically, hyperuricemia is associated with hypertension, CHD, renal disease, toxemia of pregnancy, and other outcomes, although mechanisms remain unclear. Additionally, there are no available data on the effects of lowering uric acid on pressure control and organ protection.

The renal and glomerular dynamic effects of combining thiazide and angiotensin antagonists have not been reported. The present study was designed to examine the effects of hydrochlorothiazide (HCTZ) alone or in combination with an angiotensin-converting enzyme inhibitor or ANG II type 1-receptor blocker on renal hemodynamics, glomerular dynamics, renal function, and renal histopathology in the Nω-nitro-l-arginine methyl ester-treated spontaneously hypertensive rat (l-NAME/SHR) model. HCTZ (80 mg·kg−1·day−1) alone or in combination with enalapril (30 mg·kg−1·day−1) or losartan (30 mg·kg−1·day−1) or enalapril (15 mg·kg−1·day−1) plus losartan (15 mg·kg−1·day−1) was administered to l-NAME/SHR (5.0 ± 0.10 mg·kg−1·day−1) for 3 wk. Mean arterial pressure, total peripheral resistance, renal plasma flow, glomerular filtration rate, glomerular hydrostatic pressure, afferent and efferent glomerular arteriolar resistances, single nephron plasma flow, single nephron glomerular filtration rate, serum creatinine concentration, 24-h urinary protein excretion, and glomerular and arteriolar injury scores were determined. HCTZ reduced mean arterial pressure, total peripheral resistance, glomerular hydrostatic pressure, and afferent and efferent glomerular arteriolar resistances ( P < 0.05, at least) but slightly increased renal plasma flow and single nephron plasma flow associated with reduced serum creatinine concentration, urinary protein excretion, and arteriolar injury score compared with l-NAME/SHR control. However, the combination of enalapril and/or losartan with HCTZ markedly improved each of these functions. These results demonstrated minor benefits of HCTZ monotherapy and a marked superiority of its combination with enalapril and/or losartan over HCTZ monotherapy on renoprotection in l-NAME/SHR, thereby providing strong evidence of their clinical benefits for hypertensive patients with renal functional impairment.

This study was performed to validate echocardiographic and Doppler techniques for the assessment of left ventricular (LV) diastolic function in spontaneously hypertensive rats (SHR) and normotensive Wistar rats. In 11 Wistar rats and 20 SHR, we compared 51 sets of invasive and Doppler LV diastolic indexes. Noninvasive indexes of LV relaxation were related to the minimal rate of pressure decline (−dP/d tmin), particularly isovolumic relaxation time (IVRT), the Tei index, the early velocity of the mitral annulus ( Em) using Doppler tissue imaging, and early mitral flow propagation velocity using M-mode color ( r = 0.28–0.56 and P < 0.05–0.0001). When the role of systolic load was considered, the correlation between Doppler indexes of LV diastolic function and relaxation rate [(−dP/d tmin)/LV systolic pressure] improved ( r = 0.48–0.86 and P = 0.004–0.0001, respectively). Similarly, Doppler indexes of LV diastolic function and the time constant of isovolumic LV relaxation (τ) correlated well ( r = 0.50–0.84 and P = 0.0002–0.0001, respectively). In addition, eight SHR and eight Wistar rats were compared; their LV end-diastolic diameters were similar, whereas the SHR LV mass was greater. Furthermore, IVRT and Tei index were significantly higher and Em was lower in SHR. Moreover, τ was higher in SHR, demonstrating impaired LV relaxation. In conclusion, LV relaxation can be assessed reliably using echocardiographic and Doppler techniques, and, using these indexes, impaired relaxation was demonstrated in SHR.

Background: Aldosterone has been implicated as a potential mediator of cardiac and vascular damage in a variety of disorders. This study examined the role of aldosterone and its interplay with the renin-angiotensin system in the pathogenesis of hypertension. To this end, the effects of the aldosterone antagonist eplerenone and the angiotensin converting enzyme inhibitor lisinopril on cardiovascular mass, myocardial collagen, and coronary circulation were examined in spontaneously hypertensive rats. Methods: Male, 22-week-old rats were randomly divided into 4 groups (12 in each). The control group received no treatment, the second group was given eplerenone (100 mg/kg/day), the third received lisinopril (3 mg/kg/day), and the fourth was given eplerenone and lisinopril. After 12 weeks of respective treatments, systemic and regional hemodynamics and cardiovascular mass indexes were measured in conscious instrumented rats. Results: Eplerenone decreased arterial pressure but did not affect left ventricular mass or hydroxyproline concentration (an estimate of collagen). It did, however, reduce minimal coronary vascular resistance and increased coronary flow reserve. Lisinopril decreased arterial pressure and ventricular mass but did not affect regional hemodynamics. The combination therapy produced synergistic effects. Conclusion: Aldosterone antagonism improved coronary and systemic hemodynamics in adult spontaneously hypertensive rats but did not affect cardiovascular mass indexes. The finding that lisinopril and eplerenone decreased arterial pressure to the same extent but had different cardiovascular effects suggested that these effects might be pressure independent.

Background/Aims: Prolonged nitric oxide synthase (NOS) inhibition with Nω-nitro-L-arginine methylester in normotensive and hypertensive rats has been demonstrated to produce severe systemic and glomerular hypertension with glomerular sclerosis, and these changes have become a useful experimental model of hypertensive nephrosclerosis. This review summarizes data from our serial studies as well as work of others who are also investigating the effects of the commonly used antihypertensive drugs (including calcium antagonist, angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blocker, aldosterone antagonist and thiazide diuretic) on renal and glomerular hemodynamics, renal function and glomerular histopathology using this model. Methods: A Medline search was performed to identify the relevant literature describing renal effects of antihypertensive drugs in models of hypertension and nephrosclerosis produced or exacerbated by NOS inhibition. Results: Existing data have indicated that most of these drug classes have produced dramatic renoprotective effects, structurally or functionally, on nephrosclerosis induced by prolonged NOS inhibition. Conclusion: This review of experimental studies has provided strong evidence supporting the clinical benefits of antihypertensive drugs for hypertensive patients with renal impairment particularly those with endothelial dysfunction associated with NOS deficiency.

Increased dietary salt intake induces cardiac fibrosis in the spontaneously hypertensive rat (SHR), yet little information details its effects on left ventricular (LV) function. Additionally, young normotensive rats are more sensitive to the trophic effect of dietary sodium than older rats. Thus cardiac responses to salt loading were evaluated at two ages in the SHR; LV collagen content was also examined. SHR (8 or 20 wk of age) were given an 8% salt diet; their age-matched controls received standard chow. Echocardiographic indexes, arterial pressure, and LV hydroxyproline concentration were measured at 16 and 52 wk in the younger and older SHR groups, respectively. In most SHR, salt excess increased arterial pressure, LV mass, and hydroxyproline concentration and impaired LV relaxation manifested by prolonged isovolumic relaxation time, decreased early and atrial filling velocity ratio (V(E)/V(A)), and slower propagation velocity of E wave (V(P)). LV systolic function remained normal. However, one-quarter of the young salt-loaded SHR developed cardiac failure with systolic and diastolic dysfunction associated with greater LV mass and ventricular fibrosis. They also had lower arterial pressure, decreased fractional shortening, and a restrictive pattern of mitral flow. Moreover, the shorter deceleration time of the E wave and increased V(E)/V(P), an index of LV filling pressure, indicated increased LV stiffness in these rats. These findings demonstrated that sodium sensitivity in SHR is manifested not only by further pressure elevation but also by significant LV functional impairment that most likely is related to enhanced ventricular fibrosis. Moreover, the SHR are more susceptible to cardiac damage when high dietary salt is introduced earlier in life.

Objectives This investigation evaluated the relationship between obesity and B-type natriuretic peptide (BNP) in heart failure. Background Obesity is a major risk factor for the development of heart failure, but the precise mechanisms remain uncertain. Physiologically, natriuretic peptides and lipolysis are closely linked. Methods A total of 318 patients with heart failure were evaluated between June 2001 and June 2002. Levels of BNP were compared in obese (body mass index [BMI] ≥30 kg/m 2 ) and nonobese (BMI 2 ) patients with respect to New York Heart Association functional class and lean body weight–adjusted peak aerobic oxygen consumption. In a subset of 36 patients, plasma levels of tumor necrosis factor-alpha, interleukin-6, and soluble intercellular adhesion molecule-1 were measured. Results The population's BMI was 29.4 ± 6.6 kg/m 2 ; 24% were lean (BMI 2 ), 31% overweight (BMI ≥25 to 29.9 kg/m 2 ), and 45% obese (BMI ≥30 kg/m 2 ). Obese patients were younger, more often African American, and more likely to have a history of antecedent hypertension, but less likely to have coronary artery disease and with only a trend toward diabetes mellitus. Levels of BNP were significantly lower in obese than in nonobese subjects (205 ± 22 and 335 ± 39 pg/ml, respectively; p = 0.0007), despite a similar severity of heart failure and cytokine levels. Multivariate regression analysis identified BMI as an independent negative correlate of BNP level. There were no differences in emergency department visits, heart failure hospitalization, or death between the obese and nonobese patients at 12-month follow-up. Conclusions Our investigation indicates that a state of reduced natriuretic peptide level exists in the obese individual with heart failure.

Increased formation of advanced glycosylation end-products on body proteins is a consequence of aging and leads to exaggerated collagen cross-linking eventually increasing cardiovascular stiffness. This study reports our initial inquires into the cardiovascular and renal effects of a cross-link breaker (ALT-711) in aged spontaneously hypertensive rats (SHR).The first experiment, in 45-week-old SHR, showed that (among four doses) the dose of 1 mg/kg/d of ALT-711 given for 4 months was most effective in reducing left ventricular and aortic mass indexes. ALT-711 also reduced left ventricular hydroxyproline concentration (5.8 +/- 0.2 v 5.1 +/- 0.3 mg/g in controls, P.05); however, it did not affect systemic or regional hemodynamics. In older SHR, ALT-711 (1 mg/kg/d) reduced (P.05) systolic pressure (tail-cuff) (from 203 +/- 3 mm Hg at outset to 187 +/- 3 mm Hg at 8 weeks). Systolic pressure remained unchanged in placebo-treated rats. In addition, left ventricular index (3.09 +/- 0.10 v 3.44 +/- 0.05 mg/g) and aortic mass index (1.54 +/- 0.04 v 1.74 +/- 0.05 mg/mm) were reduced by ALT-711. In the third experiment, 1-year-old SHR were given vehicle or ALT-711 (1 mg/kg/d) or placebo until natural death. After 3 months, ALT-711 markedly reduced urinary protein excretion (74.5 +/- 8.6 v 135.4 +/- 11.8 mg/24 h). Echocardiographic studies, performed at the outset and after 3 and 6 months, revealed two changed indexes. Left ventricular end-diastolic diameter increased more in control than in ALT rats, whereas E-wave deceleration time decreased more in control than in ALT rats.Therapy with ALT-711 exerted beneficial cardiovascular and renal effects in aged SHR, improving systolic pressure, left ventricular mass, geometry, and hydroxyproline content while reducing urinary protein excretion.

Aging, diabetes, and hypertension are conditions in which arterial and myocardial stiffness is increased. Increased arterial stiffness is manifested by an increased systolic arterial pressure, pulse pressure and pulse wave velocity, whereas increased myocardial stiffness is manifested by impaired left ventricular diastolic filling. Moreover, increased arterial stiffness increases cardiac workload, further aggravating already existing adverse changes in left ventricular structure and function. Indeed, studies in human beings have clearly shown that increased cardiovascular stiffness is a reliable predictor of cardiovascular morbidity and mortality. Increased cardiovascular stiffness is usually attributed to the development of fibrosis (i.e., accumulation of collagen). It has also been recognized that the increased cardiac and vascular stiffness may be due to increased collagen cross-linking due to the formation of advanced glycosylation end-products (AGEs). In agreement with this notion is the finding that an inhibitor of AGEs formation improves vascular stiffness in diabetic rats. More recently, cross-link breakers have been developed, and the beneficial effects of one such agent (ALT-711) have been shown in experimental and clinical settings. This report briefly summarizes age related changes in cardiovascular structure and function and describes results of experimental and clinical studies involving collagen cross-link breakers.

The major message from this discussion is that the end points from hypertensive disease (stroke, CHD, and hypertensive emergencies) are now preventable. Cardiac failure and ESRD, however, two exceedingly common end points from long-standing hypertension, remain as major disabilities and causes of death. The former is the most common cause of hospitalization in industrialized societies; hypertension and diabetes mellitus are the most common causes of the latter. The mechanisms of risk of these target organ diseases is not LVH per se, or the elevated arterial pressure alone in the kidney, but the coronary and renal ischemia, organ fibrosis, and, perhaps, apoptosis. Present day therapy now can effectively reverse these costly (economically and by human suffering) complications. Recent experimental studies suggest that, when used early enough, these newer pharmacologic agents may even prevent their occurrences and consequences. The very practical lesson from these experiences is that early detection and treatment of hypertension, effective control of arterial pressure, and the suppression of the underlying disease mechanisms markedly reduce the now increasing prevalence of both cardiac and renal failure.

Cardiovascular disease is a major cause of mortality in individuals with diabetes. Many factors, including hypertension, contribute to the high prevalence of CVD in this population. Hypertension occurs approximately twice as frequently in patients with diabetes compared with patients without diabetes. Conversely, recent data suggest that hypertensive persons are more likely to develop diabetes than normotensive persons. In addition, up to 75% of CVD in patients with diabetes may be attributed to hypertension, leading to recommendations for more aggressive blood pressure control (ie, < 130/85 mm Hg) in persons with coexistent diabetes and hypertension. Increasing obesity further contributes to both diabetes and hypertension and significantly increases CVD morbidity and mortality. Other important risk factors for CVD in these patients include atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and diabetic cardiomyopathy. The current knowledge regarding these risk factors has been reviewed, placing special emphasis on the metabolic syndrome, hypertension, microalbuminuria, and the role of obesity in these disorders. Although not discussed in detail, it is acknowledged that both hygienic measures (weight loss and aerobic exercise) and treatment strategies that include aspirin, statins, INS sensitizers, and antihypertensive agents that reduce renin-angiotensin-aldosterone system activity have been shown to reduce inflammation, coagulation abnormalities, endothelial function, proteinuria, and in some cases reduce CVD and renal disease progression. Additional therapeutic agents are currently being developed specifically to improve INS sensitivity and other CVD risk factors that are components of the cardiometabolic syndrome.

Background: The renin-angiotensin-aldosterone system participates importantly in the progression of hypertensive renal disease. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists have been demonstrated to afford renoprotection in L-NAME-exacerbated nephrosclerosis in SHR rats. This study was designed to examine the effects of the aldosterone antagonist eplerenone on systemic and renal hemodynamics, glomerular dynamics, renal function and histopathology in L-NAME/SHR, and determine whether aldosterone antagonism would enhance the effectiveness of ACE inhibition. Methods: Six groups of 20-week-old SHR were studied using renal micropuncture and histopathological techniques after 3 weeks of treatment: SHR control (tapwater, n = 10); SHR + eplerenone (101 ± 8.3 mg/kg/day, n = 10); SHR + L-NAME (5.0 ± 0.12 mg/kg/day, n = 9); SHR + L-NAME + eplerenone (n = 8); SHR + L-NAME + lisinopril (3 mg/kg/day, n = 9), and SHR + L-NAME + eplerenone + lisinopril (n = 9). Results:L-NAME-treated SHR developed massive proteinuria, severe hypertensive nephrosclerosis, and tubulointerstitial damage. Eplerenone significantly reduced proteinuria (127.4 ± 26.5 vs. 51.9 ± 16.7 mg/24 h, p < 0.01), improved glomerular and arteriolar injuries (65 ± 9 vs. 29 ± 9 score/100 glomeruli, p < 0.01; 116 ± 18 vs. 41 ± 13 score/100 arterioles, p < 0.01, respectively), and decreased tubulointerstitial damage index (1.43 ± 0.07 vs. 0.39 ± 0.07, p < 0.01) without altering mean arterial pressure or glomerular dynamics. Combined therapy of eplerenone with lisinopril produced no further benefits than lisinopril alone. Conclusion: The aldosterone antagonist eplerenone significantly ameliorated proteinuria and nephrosclerosis in the L-NAME/SHR model, independent of hemodynamic effects.

Long-term follow-up of left ventricular (LV) function using echocardiography has not been reported and, in this study, was carried out in normotensive (WKY) rats and spontaneously hypertensive rats (SHR). In 10 WKY rats and SHR, LV diastolic and systolic diameter (LVEDD and LVSD), shortening fraction (SF), and weight (LVW) were determined at 8, 15, 20, 35, and 80 wk of age. The ratio of early to late mitral flow and mitral annulus velocity ( VE/ VA and Em/ Am), isovolumic relaxation time (IVRT), deceleration time of the E wave (DTE), Tei index, and mitral flow propagation velocity ( Vp) were measured. No difference in LVEDD was found between SHR and WKY rats; however, LVEDD was increased at 80 wk in both strains. SF decreased slightly in old WKY rats. LVW progressively increased from 20 to 80 wk in both strains and was greater in SHR. VE/ VA and Em/ Am decreased at 80 wk in WKY rats. LV relaxation (IVRT, Tei index, and Vp) was progressively impaired in SHR compared with WKY rats. LV compliance (DTE) was altered in old SHR. Echocardiography permitted a long follow-up of LV function in SHR and WKY rats. Ventricular relaxation was impaired early in the life of SHR and progressed with aging. Furthermore, LV compliance was altered, but systolic function remained unchanged, in old SHR. In contrast, relaxation and SF were only slightly altered in old WKY rats, suggesting that pressure-related changes in LV function were the dominant features in the SHR.