Henry Krum

We have previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) in part via the reduction of renal sympathetic activity. The aim of this study was to examine the effect of RDN on adipokines. In particular, whether BP reduction, associated with RDN treatment, has a favorable outcome on adipokine profile in patients with resistant hypertension (RH).Fifty seven patients with RH undergoing RDN have been recruited for the study (65% males, age 60.8 ± 1.5 years, BMI 32.6 ± 0.7 kg/m, mean ± SEM). At recruitment the patients were on an average of 4.8 ± 2.1 antihypertensive drugs and were asked o refrain from the changing their medication regimen for the duration of the study. Automated seated office BP measurements were taken with an Omron HEM-705 monitor at baseline and 3 months follow up visit. Leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were measured in plasma at baseline and 3 months after RDN.There was a significant reduction in mean office systolic (168.75 ± 2.57 vs 155.2 ± 3.2 mmHg, p < 0.001) and diastolic (90.7 ± 2.3 vs 83.7 ± 2.4 mmHg, p < 0.001) BP 3 months after RDN. Body weight and heart rate remained unchanged. There were no significant differences in plasma leptin levels post RDN. Fasting insulin concentration significantly increased 3 months after the procedure (20.05 ± 1.46 vs 29.70 ± 2.51 uU/ml, p = 0.002). There was a significant drop in circulating NEFA at follow up (1.01 ± 0.07 vs 0.47 ± 0.04 mEq/l, p < 0.001). While there were no changes in resistin, adiponectin concentration was significantly higher after RDN (5654 ± 800 vs 6644 ± 967ng/ml, p = 0.024).Our findings confirm previous reports of the effects of RDN on the reduction of BP. In addition, this is the first study to demonstrate that RDN is associated with potentially beneficial effects on the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via metabolic pathways.

Background—: Angiotensin receptor neprilysin inhibitors (ARNi), beyond blocking angiotensin II signaling, augment natriuretic peptides by inhibiting their breakdown by neprilysin. The myocardial effects of ARNi have been little studied until recently. We hypothesized that LCZ696 attenuates left ventricular (LV) remodeling after experimental myocardial infarction (MI), and that this may be contributed to by inhibition of hypertrophy and fibrosis in cardiac cells. Methods and Results—: One week after MI, adult male Sprague–Dawley rats were randomized to treatment for 4 weeks with LCZ696 (68 mg/kg body weight perorally; MI-ARNi, n=11) or vehicle (MI-vehicle, n=6). Five weeks after MI, MI-ARNi versus MI-vehicle demonstrated lower LV end-diastolic diameter (by echocardiography; 9.7±0.2 versus 10.5±0.3 mm), higher LV ejection fraction (60±2 versus 47±5%), diastolic wall strain (0.23±0.02 versus 0.13±0.02), and circular strain (−9.8±0.5 versus −7.3±0.5%; all P P <0.01) and markedly reduced fibrosis in peri-infarct and remote myocardium. Angiotensin II–stimulated incorporation of 3[H]leucine in cardiac myocytes and 3[H]proline in cardiac fibroblast was used to evaluate hypertrophy and fibrosis, respectively. The neprilysin inhibitor component of LCZ696, LBQ657, inhibited hypertrophy but not fibrosis. The angiotensin receptor blocker component of LCZ696, valsartan inhibited both hypertrophy and fibrosis. Dual valsartan+LBQ augmented the inhibitory effects of valsartan and the highest doses completely abrogated angiotensin II–mediated effects. Conclusions—: LCZ696 attenuated cardiac remodeling and dysfunction after MI. This may be contributed to by superior inhibition of LCZ696 on cardiac fibrosis and cardiac hypertrophy than either stand-alone neprilysin inhibitor or angiotensin receptor blocker.

Summary: Background: Heart failure (HF) remains a condition with high morbidity and mortality. We tested a telephone support strategy to reduce major events in rural and remote Australians with HF, who have limited healthcare access. Telephone support comprised an interactive telecommunication software tool (TeleWatch) with follow‐up by trained cardiac nurses.Methods: Patients with a general practice (GP) diagnosis of HF were randomized to usual care (UC) or UC and telephone support intervention (UC+I) using a cluster design involving 143 GPs throughout Australia. Patients were followed up for 12 months. The primary endpoint was the Packer clinical composite score. Secondary endpoints included hospitalization for any cause, death or hospitalization, as well as HF hospitalization.Results: Four hundred and five patients were randomized to CHAT. Patients were well matched at baseline for key demographic variables. The primary endpoint of the Packer score was not different between the two groups (P = 0.98), although more patients improved with UC+I. There were fewer patients hospitalized for any cause (74 vs. 114, adjusted HR 0.67 [95% CI 0.50–0.89], P = 0.006) and who died or were hospitalized (89 vs. 124, adjusted HR 0.70 [95% CI 0.53–0.92], P = 0.011), in the UC+I vs. UC group. HF hospitalizations were reduced with UC+I (23 vs. 35, adjusted HR 0.81 [95% CI 0.44–1.38]), although this was not significant (P = 0.43). There were 16 deaths in the UC group and 17 in the UC+I group (P = 0.43).Conclusions: Although no difference was observed in the primary endpoint of CHAT (Packer composite score), UC+I significantly reduced the number of HF patients hospitalized among a rural and remote cohort. These data suggest that telephone support may be an efficacious approach to improve clinical outcomes in rural and remote HF patients.

Cardiovascular diseases in general and heart failure (HF) in particular are major contributors to death and morbidity in the Western world, where they are also recognized as important drivers of healthcare expenditure. The health and economic burden of these disorders is projected to increase with the aging of populations around the world.1–3 On the basis of accumulating evidence that chronic overactivity of the renin–angiotensin–aldosterone system (RAAS) plays a fundamental role in HF pathophysiology, drugs inhibiting key components of the RAAS have become a cornerstone of contemporary cardiovascular drug therapy.4–6 For example, angiotensin-converting enzyme inhibitors (ACEi) reduce biosynthesis of angiotensin-II (Ang-II), 1 of the strongest vasoconstrictors, prohypertrophic and profibrotic hormones in man. Moreover, ACEi may prevent proteolysis of bradykinin, thus enhancing bradykinin-mediated vasodilatory effects that may counteract the profound vasoconstriction seen in patients with HF.7 Excessive levels of Ang-II have been implicated in many cardiovascular diseases, and in addition to ACEi, the detrimental actions of Ang-II can be abrogated by direct angiotensin-receptor blockers (ARB). However, despite encouraging results from many clinical trials, ACEi- and ARBs-based pharmacotherapy is still far from optimal. ACEi may lose their efficacy over time because of redundant Ang-II–generating pathways and the so-called aldosterone escape,8 whereas conventional ARBs do not possess the bradykinin-enhancing properties of ACEi and are considered less effective in HF compared with ACEi.4,5 The natriuretic peptides (NPs), consisting of atrial NP (ANP), B-type NP (BNP), C-type NP (CNP), and urodilatin, are predominantly generated by the heart, vasculature, kidney, and central nervous system in response to wall stress and number of other stimuli. Importantly the NPs, particularly ANP and BNP, represent the body’s own blood pressure (BP)–lowering system. Besides promoting vasodilation, NPs counteract pathological growth, fibrosis, and dysfunction of heart, kidneys, brain, and the vasculature. Current NP-augmenting strategies include …

Hypertension, coronary artery disease and heart failure affect over half of the adult population in most Western societies, and are prime causes of CV morbidity and mortality. With the ever-increasing worldwide prevalence of CV disease due to ageing and the “diabetes” pandemic, guideline groups have recognized the importance of achieving cardioprotection in affected individuals as well as in those at risk for future CV events. The renin-angiotensin-aldosterone system (RAAS) is the most important system controlling blood pressure (BP), cardiovascular and renal function in man. As our understanding of the crucial role of RAAS in the pathogenesis of most, if not all, CV disease has expanded over the past decades, so has the development of drugs targeting its individual components. Angiotensin-converting enzyme inhibitors (ACEi), Ang-II receptor blockers (ARB), and mineralcorticoid receptor antagonists (MRA) have been evaluated in large clinical trials for their potential to mediate cardioprotection, singly or in combination. Direct renin inhibitors are currently under scrutiny, as well as novel dual-acting RAAS-blocking agents. Herein, we review the evidence generated from large-scale clinical trials of cardioprotection achieved through RAAS-blockade.

Transthoracic echocardiography (TTE) is commonly used for the evaluation of suspected or known cardiac disease. This article discusses the impact of TTE findings on patient management using seven case studies as examples. Any abnormality on echocardiography should be carefully considered as to its severity, cause and potential to account for the patient's symptoms. Evidence based therapies should be instituted in the setting of a reduced left ventricular ejection fraction and previously unrecognised myocardial infarction. Other abnormalities such as left ventricular hypertrophy or diastolic abnormalities suggest the need for more aggressive risk factor control. Patients should be referred to a cardiologist for further evaluation if the cause of TTE abnormalities or overall diagnosis is uncertain or the patient needs ongoing monitoring and treatment.