Clinical studies of the renin-angiotensin-aldosterone system and cardiac autonomic regulation in man

The work embodied in this thesis was designed to explore the interaction between the renin -angiotensin -aldosterone system (RAAS) and the autonomic nervous system. It was stimulated by the observations that the neurohormonal suppression of the RAAS by ACE inhibitors in chronic heart failure (CHF) is inadequate, and that high residual levels of circulating aldosterone have been shown to have detrimental autonomic modulating effects independent of angiotensin II in experimental models.The effects of aldosterone blockade with spironolactone therapy were examined in CHF patients already established on ACE inhibitors. It was observed that spironolactone has beneficial parasympathomimetic properties, improving heart rate variability and reducing heart rate, particularly during the early morning hours of the day when ACTH -induced aldosterone secretion is maximal. The interaction between the RAAS and the parasympathetic tone was explored further in a series of normal volunteer studies. Although the effects of ACE inhibitors are well recognised, not much is known about the parasympathomimetic properties of direct angiotensin II or aldosterone receptor antagonism. In this thesis, it was demonstrated that losartan, an angiotensin II receptor antagonist, and enalapril, an ACE inhibitor, were equally effective in improving the vagally-mediated baroreflex response in salt depleted normotensive subjects. It was also demonstrated that direct intravenous aldosterone administration impaired the baroreflex response to vasopressor agents in healthy subjects.The observed vagomimetic effects of aldosterone blockade may have important therapeutic implications, suggesting the possibility that spironolactone may have anti -ischaemic or anti -arrhythmic properties. However, aldosterone blockade did not appear to have any significant impact on either autonomic tone or ischaemic events when administered to patients with ischaemic heart disease but preserved LV function. The reasons for the latter remain unclear but may reflect differences in disease -state (less neurohormonal activation, and a larger proportion of these patients was established on beta -blockers -which may influence autonomic tone - and only a minority was taking concomitant ACE inhibitors, compared to the CHF cohort). In CHF however, spironolactone was shown to improve QT dispersion, a surrogate marker of arrhythmic activity and sudden cardiac death. Mechanisms in which aldosterone may contribute towards dispersion of the QT intervals on the electrocardiogram are probably multifactorial. Aldosterone increases cardiac afterload (by increasing vascular tone and potentiating vascular smooth muscle hypertrophy) and it is demonstrated that cardiac afterload would increase QT dispersion through mechano- electrical feedback. Vagal tone modulation itself however did not contribute towards QT dispersion.These studies demonstrate how inextricably linked the RAAS and the autonomic nervous system is. In particular, the detrimental autonomic effects of aldosterone in CHF have been highlighted. The findings of these studies highlight possible mechanisms and provide valuable insights as to why further therapeutic mileage is gained by the addition of an aldosterone antagonist in CHF patients who have already been established on ACE inhibitors

Treatment for ascites in adults with decompensated liver cirrhosis:a network meta-analysis

BACKGROUND:Approximately 20% of people with cirrhosis develop ascites. Several different treatments are available; including, among others, paracentesis plus fluid replacement, transjugular intrahepatic portosystemic shunts, aldosterone antagonists, and loop diuretics. However, there is uncertainty surrounding their relative efficacy. OBJECTIVES:To compare the benefits and harms of different treatments for ascites in people with decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for ascites according to their safety and efficacy. SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until May 2019 to identify randomised clinical trials in people with cirrhosis and ascites. SELECTION CRITERIA:We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and ascites. We excluded randomised clinical trials in which participants had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS:We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS:We included a total of 49 randomised clinical trials (3521 participants) in the review. Forty-two trials (2870 participants) were included in one or more outcomes in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies, without other features of decompensation, having mainly grade 3 (severe), recurrent, or refractory ascites. The follow-up in the trials ranged from 0.1 to 84 months. All the trials were at high risk of bias, and the overall certainty of evidence was low or very low. Approximately 36.8% of participants who received paracentesis plus fluid replacement (reference group, the current standard treatment) died within 11 months. There was no evidence of differences in mortality, adverse events, or liver transplantation in people receiving different interventions compared to paracentesis plus fluid replacement (very low-certainty evidence). Resolution of ascites at maximal follow-up was higher with transjugular intrahepatic portosystemic shunt (HR 9.44; 95% CrI 1.93 to 62.68) and adding aldosterone antagonists to paracentesis plus fluid replacement (HR 30.63; 95% CrI 5.06 to 692.98) compared to paracentesis plus fluid replacement (very low-certainty evidence). Aldosterone antagonists plus loop diuretics had a higher rate of other decompensation events such as hepatic encephalopathy, hepatorenal syndrome, and variceal bleeding compared to paracentesis plus fluid replacement (rate ratio 2.04; 95% CrI 1.37 to 3.10) (very low-certainty evidence). None of the trials using paracentesis plus fluid replacement reported health-related quality of life or symptomatic recovery from ascites. FUNDING:the source of funding for four trials were industries which would benefit from the results of the study; 24 trials received no additional funding or were funded by neutral organisations; and the source of funding for the remaining 21 trials was unclear. AUTHORS' CONCLUSIONS:Based on very low-certainty evidence, there is considerable uncertainty about whether interventions for ascites in people with decompensated liver cirrhosis decrease mortality, adverse events, or liver transplantation compared to paracentesis plus fluid replacement in people with decompensated liver cirrhosis and ascites. Based on very low-certainty evidence, transjugular intrahepatic portosystemic shunt and adding aldosterone antagonists to paracentesis plus fluid replacement may increase the resolution of ascites compared to paracentesis plus fluid replacement. Based on very low-certainty evidence, aldosterone antagonists plus loop diuretics may increase the decompensation rate compared to paracentesis plus fluid replacement

City-wide Analysis of Electronic Health Records Reveals Gender and Age Biases in the Administration of Known Drug-Drug Interactions

The occurrence of drug-drug-interactions (DDI) from multiple drug dispensations is a serious problem, both for individuals and health-care systems, since patients with complications due to DDI are likely to reenter the system at a costlier level. We present a large-scale longitudinal study (18 months) of the DDI phenomenon at the primary- and secondary-care level using electronic health records (EHR) from the city of Blumenau in Southern Brazil (pop. $\approx 340,000$). We found that 181 distinct drug pairs known to interact were dispensed concomitantly to 12\% of the patients in the city's public health-care system. Further, 4\% of the patients were dispensed drug pairs that are likely to result in major adverse drug reactions (ADR)---with costs estimated to be much larger than previously reported in smaller studies. The large-scale analysis reveals that women have a 60\% increased risk of DDI as compared to men; the increase becomes 90\% when considering only DDI known to lead to major ADR. Furthermore, DDI risk increases substantially with age; patients aged 70-79 years have a 34\% risk of DDI when they are dispensed two or more drugs concomitantly. Interestingly, a statistical null model demonstrates that age- and female-specific risks from increased polypharmacy fail by far to explain the observed DDI risks in those populations, suggesting unknown social or biological causes. We also provide a network visualization of drugs and demographic factors that characterize the DDI phenomenon and demonstrate that accurate DDI prediction can be included in healthcare and public-health management, to reduce DDI-related ADR and costs

Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study.

OBJECTIVE: To determine if trimethoprim use for urinary tract infection (UTI) is associated with an increased risk of acute kidney injury, hyperkalaemia, or sudden death in the general population. DESIGN: Cohort study. SETTING: UK electronic primary care records from practices contributing to the Clinical Practice Research Datalink linked to the Hospital Episode Statistics database. PARTICIPANTS: Adults aged 65 and over with a prescription for trimethoprim, amoxicillin, cefalexin, ciprofloxacin, or nitrofurantoin prescribed up to three days after a primary care diagnosis of UTI between April 1997 and September 2015. MAIN OUTCOME MEASURES: The outcomes were acute kidney injury, hyperkalaemia, and death within 14 days of a UTI treated with antibiotics. RESULTS: Among a cohort of 1 191 905 patients aged 65 and over, 178 238 individuals were identified with at least one UTI treated with antibiotics, comprising a total of 422 514 episodes of UTIs treated with antibiotics. The odds of acute kidney injury in the 14 days following antibiotic initiation were higher following trimethoprim (adjusted odds ratio 1.72, 95% confidence interval 1.31 to 2.24) and ciprofloxacin (1.48, 1.03 to 2.13) compared with amoxicillin. The odds of hyperkalaemia in the 14 days following antibiotic initiation were only higher following trimethoprim (2.27, 1.49 to 3.45) compared with amoxicillin. However, the odds of death within the 14 days following antibiotic initiation were not higher with trimethoprim than with amoxicillin: in the whole population the adjusted odds ratio was 0.90 (95% confidence interval 0.76 to 1.07) while among users of renin-angiotensin system blockers the odds of death within 14 days of antibiotic initiation was 1.12 (0.80 to 1.57). The results suggest that, for 1000 UTIs treated with antibiotics among people 65 and over, treatment with trimethoprim instead of amoxicillin would result in one to two additional cases of hyperkalaemia and two admissions with acute kidney injury, regardless of renin-angiotensin system blockade. However, for people taking renin-angiotensin system blockers and spironolactone treatment with trimethoprim instead of amoxicillin there were 18 additional cases of hyperkalaemia and 11 admissions with acute kidney injury. CONCLUSION: Trimethoprim is associated with a greater risk of acute kidney injury and hyperkalaemia compared with other antibiotics used to treat UTIs, but not a greater risk of death. The relative risk increase is similar across population groups, but the higher baseline risk among those taking renin-angiotensin system blockers and potassium-sparing diuretics translates into higher absolute risks of acute kidney injury and hyperkalaemia in these groups

Diabetic nephropathy: early detection and therapeutic strategies

The increasing global prevalence of diabetes poses a huge challenge to health services. The diagnosis is accompanied by a reduction in life expectancy, primarily due to cardiovascular disease which is inextricably linked to microvascular complications such as diabetic nephropathy (DN). Microalbuminuria (MA) is generally accepted as the primary clinical hallmark of DN, but despite widespread prescribing of agents blocking the renin angiotensin aldosterone system (RAAS) in these patients many continue to progress towards end-stage renal disease (ESRD). Clinical trials evaluating early initiation of RAAS blocking agents in untargeted, nonalbuminuric diabetic patients have shown potential for delaying disease progression but these effects are generally counterbalanced by side effects and adverse events associated with these therapies. Discovery of novel biomarkers to identify individuals at highest risk of DN who would stand to benefit most from targeted preclinical intervention would be a significant step towards implementation of personalised medicine in this population. One technique which shows promise is proteomics, based on the concept of separation and quantification of peptides in a biological sample to produce a disease-specific pattern. A panel of 273 urinary peptides (CKD273) has been shown to have potential for identification of nonalbuminuric diabetic patients who are at risk of progression to overt DN. However, many such novel biomarkers are described in the literature and to date none have successfully made the transition from research studies to routine clinical practice. In order to be considered for clinical implementation novel biomarkers are required to be subject to a rigorous evaluation process. In brief there are several key steps beginning with proof-of-concept studies; progressing through validation in independent populations to demonstration of incremental value beyond the current guideline-endorsed tests; thereafter proof of clinical applicability in determining treatment strategies and cost-effectiveness are required. The work contained within this thesis is designed to address each of these aspects with regard to use of the CKD273 proteomic panel as a biomarker for early detection of DN

Hypertension Guideline 2003 Update

Outcomes. Extensive data from many randomised controlled trials have shown the benefit of treating hypertension. The target blood pressure (BP) for antihypertensive management should be systolic BP < 140 mmHg, diastolic < 90 mmHg, with minimal or no drug side-effects. However, a lesser reduction will elicit benefit although this is not optimal. The reduction of BP in the elderly and in those with severe hypertension should be achieved gradually over 6 months. Stricter BP control is required for patients with end organ damage, co-existing risk factors and co-morbidity, e.g. diabetes mellitus. Co-existent risk factors should also be controlled.Benefits. Reduction in risk of stroke, cardiac failure, renal insufficiency and probably coronary artery disease. The major precautions and contraindications to each antihypertensive drug recommended are listed.Recommendations. Correct BP measurement procedure is described. Evaluation of cardiovascular risk factors and recommendations for antihypertensive therapy are stipulated. The total cardiovascular disease risk profile should be determined for all patients and this should inform management strategies. 'Lifestyle modification and patient education plays an essential role in the management strategy. Drug therapy: First line -low dose thiazide-like diuretics; second line -add one of the following: reserpine or β-blockers or ACE inhibitors or calcium channel blockers; third line - add another second line drug or hydralazine or α-blocker. The guideline includes management of specific situations, i.e. hypertensive emergency and urgency, severe hypertension with target organ damage and refractory hypertension (BP >160/95 mmHg on triple therapy), hypertension in diabetes mellitus, etc.Validity. Developed by the Working Groups established by the Executive Committee of the Southern African Hypertension Society with broader consensus meeting endorsement. The 2001 version was endorsed by the South African Medical Association Guideline Committee. The 2003 revisions were endorsed by the Executive Committee and a wider Working Group

Resurgence of interest in the hemodynamic alterations of advanced heart failure

Historically, cardiac insufficiency has always being allocated to be the culprit lesion of the heart failure syndrome. However, contemporary heart failure pharmacotherapy solely focuses on preservation of neurohormonal homeostasis. The research described in this manuscript is the result of thorough investigation of the hemodynamic alterations of hundreds of patients admitted for advanced decompensated heart failure (ADHF). Firstly, our data suggest that progressive cardiac insufficiency and hemodynamic derangements assessed through invasive hemodynamic monitoring, are still contributing to short- and long-term compromise, and this independent of race or gender. In addition, we demonstrated that restoring an optimal hemodynamic balance with add-on afterload reduction provides incremental intermediate- and long-term benefits over evidence based neurohormonal blockade alone. Indeed parental vasodilator therapy with sodium nitroprusside can be safely administered to achieve more hemodynamic improvement in patients presenting with ADHF. In addition, the institution of a more aggressive oral vasodilator regimen with isosorbide diniatrate / hydralazine over standard neurohormonal antagonists at the time of discharge after an episode of ADHF can safely maintain these hemodynamic improvements leading to improved outcomes. Another novel insight comes from the notice that venous congestion and raised intra-abdominal pressure, more than impaired cardiac output, seem to be related to the development of worsening renal function in patients admitted with ADHF. Treatment strategies with the aim of better renal preservation should therefore focus how to safely reduce this renal venous congestion with diuretic therapy, ultrafiltration or paracentesis whenever indicated. Finally, we demonstrated that cardiac resynchronization therapy (CRT) really acts as a novel "hemodynamic therapy" for advanced heart failure patients even in the patient population previously categorized as "non-responders". Moreover, we have proven that the phenotypic improvement in heart failure status after prolonged CRT is paralleled by a reversed left ventricualr remodeling and recovery of left ventricular contractility. Thus, prolonged (hemodynamic) unloading of the heart will lead to physiological changes on the myocyte level in hearts once destined to only further deteriorate

Pharmacologic Management of Pediatric Hypertension

Hypertension in children is common, and the prevalence of primary hypertension is increasing with the obesity epidemic and changing dietary choices. Careful measurement of blood pressure is important to correctly diagnose hypertension, as many factors can lead to inaccurate blood pressure measurement. Hypertension is diagnosed based on comparison of age-, sex-, and height-based norms with the average systolic and diastolic blood pressures on three separate occasions. In the absence of hypertensive target organ damage (TOD), stage I hypertension is managed first by diet and exercise, with the addition of drug therapy if this fails. First-line treatment of stage I hypertension with TOD and stage II hypertension includes both lifestyle changes and medications. First-line agents include angiotensin-converting enzyme (ACE) inhibitors, thiazide diuretics, and calcium-channel blockers. Hypertensive emergency with end-organ effects requires immediate modest blood pressure reduction to alleviate symptoms. This is usually accomplished with IV medications. Long-term reduction in blood pressure to normal levels is accomplished gradually. Specific medication choice for outpatient hypertension management is determined by the underlying cause of hypertension and the comparative adverse effect profiles, along with practical considerations such as cost and frequency of administration. Antihypertensive medication is initiated at a starting dose and can be gradually increased to effect. If ineffective at the recommended maximum dose, an additional medication with a complementary mechanism of action can be added