Dr Dalby attended the Cardiology, Nephrology and Diabetes at the Limits meeting in London and reports back:
Notes from the Front
“At the Limits”
London, 24 – 27 April 2014
An “At the Limits” meeting in Cardiology, Diabetes and Nephrology was held at the Royal College of Physicians in London this year. All 15 previous meetings had been held in Cape Town. The meeting was organised by Prof Lionel Opie and Prof Derek Yellon assisted by Prof John Cunningham, Prof Peter Libby, Prof Marc Pfeffer and Prof Brian Rayner The meeting was held under the auspices of the Hatter Institute of University College London and the University of Cape Town. Participating organisations were the the British Cardiovascular Society, the South African Heart Association, The Renal Association, the National Institute for Health Research and the Brigham and Womens’ Hospital. The meeting was endorsed and supported by The Lancet. Sponsorship was provided by Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Pfizer, Amgen, Servier, Boehringer-Ingelheim, Bayer HealthCare, Daiichi-Sankyo, The Coca-Cola Company, MSD and Roche. The meeting received Continuing Medical Education accreditation from the European Board for Accreditation in Cardiology (EBAC).
As has been the case at every previous meeting, an exceptionally high academic standard was maintained by all the presenters throughout the 4 days. Lively audience participation after each presentation enhanced the learning experience.
Prof M Pfeffer: Surprising findings from clinical trials
Prof Pfeffer reviewed a outcomes of trials in hypertension, dyslipidaemia (LDLc and HDLc), arrhythmias (CAST), LV dysfunction (with flosequinan and other positive inotropes) and HRT that have altered therapy. These changes occurred because the clinical outcomes were made clear. Unwarranted dependence on surrogate endpoints has misled treatment in the past. Randomised controlled trials are needed to be able reach reasonable conclusions. He remarked on the responsibility of the DSMB to be aware of the specific therapy being given to each group and not being blinded to the treatment allocation. Treatment is adversely affected at times by direct to consumer advertising and clinical bias. As an example, the refusal of regulators and investigators to accept placebo control in TREAT (darbopoeitin alpha) was based on the premise that raising hemoglobin had to be beneficial. Biomarkers and surrogate endpoints are aids to research but do not conclusively indicate the need to treat. Although certain treatments do not require randomised trials to prove their worth, in 1981 Braunwald wrote about not letting the genie out of the bottle (releasing new therapies for patient use) before outcomes research has been completed.
Prof E Braunwald: Heart failure at the limits (The Lancet Lecture).
Prof Braunwald spoke about the “war on heart failure.” Although survival and quality of life have improved in chronic heart failure, heart failure with preserved ejection fraction (HeFPEF) and acute heart failure (AHF) remain a problem. AHF has an 11% 30 day mortality. Overall heart failure (HF) results in 1 million hospitalisation / year in the USA.
He discussed 5 novel promising treatment modalities in heart failure treatment:
1. MicroRNA binds to RNA and can suppress protein production. MicroRNA’s may be useful biomarkers of heart failure and possible targets for treatment. Inhibition of miR-25 (which is up-regulated in HF) improves cardiac contractility in the failing heart (Wahlquist, Nature, 2014).
2. Calcium cycling is involved in excitation-contraction coupling. The ryanodine receptor facilitates Ca entry into the sarcoplasm whereas the SERCA pump facilitates entry into sarcoplasmic reticulum. Phospholamban also important. Calmodulin kinase II inhibition can reduce the increase in heart weight.
3. Gene therapy to incorporate DNA. Adeno-associated viruses are of most interest. It has been shown that calcium can be up-regulated in severe heart failure via SERCA with gene therapy. Persistent gene expression was noted up to 31 months after treatment.
4. Cell therapy using stem cells or progenitor cells. REPAIR AMI showed improved LVEF and wall thickening at 2 years. In this research there is a lack of evidence of long term clinical benefit. The BAMI trial is looking at post-reperfusion administration in patients with a left ventricular ejection fraction (LVEF) <45%, assessing survival at 2 years.
5. Left ventricular assist devices (LVAD): In the USA more than 75% of devices are used now as destination therapy and no longer as a bridge to transplant. Research is proceeding on the HeartWare intrapericardial device that pumps 10 L/min. Reverse remodeling has been documented over time with LVAD: some of the beneficial changes involve neurohormones, hypertrophy and calcium cycling. Survival after explantation of LVAD may be excellent in many cases. Braunwald suggested intervention with an LVAD might be beneficial at an earlier stage in the development of heart failure. It will be necessary to explore how to eliminate transcutaneous leads to make the devices safer.
Finally he also noted the announcement of a trial involving an ARB (valsartan) and neprolysin that improved outcomes in chronic HF. Neprolysin (LCZ696) inhibits BNP.
Prof Matthias Frick: Anti-platelet therapy
The focus of his talk was on acute coronary syndrome (ACS). Clopidogrel’s disadvantages include variability in response, delayed onset of action, polymorphisms and delayed offset of action. Newer P2Y12 inhibitors have a more homogenous response. In PLATO ticagrelor was effective but also associated with an increase in bleeding. In STEMI with the new agents, results with the newer agents have been better than with clopidogrel and without increased bleeding. His concerns with the TRILOGY trial which compared prasugrel to clopidogrel in ACS patients not undergoing revascularisation included the high percentage of hypertensives and smokers and the low incidence of angiography. The ongoing ISAR REACT trial is studying ticagrelor vs. prasugrel. He proposed risk stratifying NSTEMI patients to choose the best P2Y12 for them according to their assessed bleeding risk.
Prof Vincente Torres: Aquaretics
Torres drew parallels between the humoral and intracellular responses in polycystic renal disease (vasopressin) and heart failure (catecholamines). The neurohypophysis receives preprovasopressin which is broken into a number of active substances. Vasopressin is secreted in low concentration to which CD Principal Cells are highly sensitive. With low BP a high concentration of vasopressin is secreted to which the receptors have a low sensitivity. Vaptans reduce water and salt retention, reduce cardiomyocyte senescence, reduce diuretic requirements, reduce natriuretic peptides and may be renal protective. Vaptans may not produce the neurohormonal response seen with furosemide. Vaptans may reduce myocardial fibrosis. However to date the clinical trials have been discouraging. Mortality and HF hospitalisation were not improved. Post-marketing survey of tolvaptan in Japan has shown reduction in oedema, dyspnoea with sustained weight reduction and a stable serum sodium and creatinine. Thirst may be a limiting factor when using this treatment.
In polycystic kidney disease (PCKD), inhibition of vasopressin by tolvaptan has reduced the development of PCKD. It reduced the rate of decline in kidney function and reduced kidney pain. The effect size was bigger in those with worse kidney function at randomization. The problem was the higher incidence of adverse events, including liver dysfunction which appeared to be restricted to the first 15 months of treatment.
Prof Lionel Opie: Are there cardiac benefits to red wine?
Modest alcohol is beneficial but the quantity required to achieve the effect is not definitely determined. Women are more susceptible to adverse effects of alcohol than men. The sex difference may relate to females’ HDLc level. A Danish study indicated that the alcohol benefit was confined to wine, not beer or spirits. Red wine intake inhibited tissue factor in pigs. Phasic thrombosis in dogs is inhibited by red wine (Circulation 2006). De-alcoholised red wine decreased ssystolic blood pressure (sBP) and diastolic blood pressure (dBP) through a nitric oxide (NO) mediated mechanism (Circ Res 2012). Resveratrol and melatonin in similar concentrations to those found in red wine protect against myocardial infarction (MI) and ischaemic reperfusion injury. He postulates that SAFE pathway is activated. Melatonin is active in very small concentrations. In an experimental situation melatonin protected against ischaemia. It is possible to block the effect of melatonin with luzindole (receptors 1 and 2). Both resveratrol and melatonin act through STAT-3 phosphorylation.
Prof del Prato: The link between diabetes and cancer
There is plausible evidence to support a higher incidence of cancer in diabetes, especially liver cancer and T cell lymphoma (HR about 2.5X). It should be regarded as a long term complication of diabetes. There is a link between fasting blood glucose and cancer (as with vascular deaths) (Emerging Risk Factors Collaboration. N Engl J Med, 2011, 364). Hyperglycaemia affects a number of pathways promoting cell proliferation and survival and activate pro-inflammatory pathways. Hyperglycaemic memory facilitates breast cancer growth. Hyperglycaemia can induce resistance to chemotherapy in prostate cancer cells. Insulin aggravates the tendency; there are suggestions that longer acting insulins may be worse. Subjects in the ORIGIN trial did not show an increased cancer risk. Gerstein commented that the absolute risk of cancer in ORIGIN was higher than the risk of CVD.
Prof Sir Rory Collins: LDL cholesterol – how low can we go? (The South African Heart Association and British Cardiovascular Society Lecture)
The importance of cholesterol was initially underestimated due to lack of a global perspective on population lipid levels. Statin treatment vs. control yields approximately 20% reduction in CV events. There is a lag phase after starting treatment (50% of total effect) with incremental improvement year-on-year (about ¼). There is a potential for greater benefit with early intervention. The allegations of unacceptable % of side-effects from statins is a misrepresentation. Statin side effects were reviwed by Kashoni (Circulation, 2006). There has been no emergence of cancer over longer term observation. New onset diabetes is increased (HR 1.09). There is no evidence of memory loss nor evidence for cataract development (HR 1.01) in the Health Protection Study. Trials of more vs. less potent statin therapy showed a greater benefit for the more potent treatment arm. The IMPROVE IT trial result comparing simvastatin + ezetimibe to simvastatin in patients after ACS awaited. Trials with cholesterol ester transfer protein (CETP) inhibitors that raise HDL are in progress as are outcome trials of PCSK9 inhibitors.
Prof Hertzel Gerstein: Vasculopaenia in diabetes
Diabetes mellitus (DM) is a disease of accelerated aging; there are legion complications of diabetes. The risk of complications increases below the glucose threshold at which diabetes is diagnosed. Tighter control of glucose reduces eye disease, albuminuria, MI (but no overall effect on major cardiovascular events). In T2DM the presence of retinopathy increases the risk of death 2.4X. In ACCORD progressive retinopathy predicted higher mortality. Diabetes rarifies the vasa vasorum. Albuminuria may not be specific to DM. Yaqoob noted that while the blood glucose is persistently elevated in glucose 6 phosphate deficiency, it does not result in vascular complications.
Prof N Morrell: Pulmonary hypertension
PHT may be due to “idiopathic” PAH or may accompany left heart disease, lung disease, PTED or rarer causes such as sarcoidosis or histiocytosis. IPAH may be truly idiopathic, familial, drug-induced, related to HIV or autoimmune disorder. Endothelin (ET) antagonists, NO pathway activation (by PDE5 inhibition) and prostacyclin derivatives have been used in treating the condition. These agents have provided symptomatic relief and possibly improve survival but mortality remains high.
The familial condition is an autosomal dominant with poor penetrance (about 20%). A bone morphogenic protein BMPR2 encodes a tissue growth factor- beta (TGF-beta) receptor. Numerous forms of mutation leading to loss of function. 15-26% of cases are sporadic mutations. Mutations have been found in 19% of idiopathic PAH and 77% in the familial group. BMPR2 has been shown to be reduced in lung tissue in familial and idiopathic PHT.Inflammation in BMPR2 deficient individuals leads to breakdown of endothelium and smooth muscle cell proliferation. BMP9 reverses pulmonary hypertension in experimental mice. Chloroquine inhibits the lysosomal degradation of BMPR2.
Patients who have heart or lung disease with disproportionate PHT may have an underlying genetic predisposition.
Prof D Raal: The future beyond statins: novel lipid-lowering drugs (The Hatter Award Lecture)
There is an unmet need in the treatment of familial hypercholesterolaemic (FH) patients because maximised statin therapy fails to lower LDL cholesterol sufficiently. Although the mortality of FH patients has improved since the introduction of statins, FH patients still suffer cardiovascular events and die prematurely. Prof Raal explored the alternatives to statin therapy which might overcome this problem.
1. Mipomersin is an antisense which blocks ApoB production inhibits VLDL and thus LDL production. In a trial mipomersin reduced LDL by 25%. However there were problems with injection site reactions and ‘flu-like symptoms.
2. Microsomal triglyceride transfer protein (MTP) inhibition with lopitamide also inhibits VLDL production. LDL was reduced up to 50% but liver enzymes were increased.
3. PCSK9 regulates cellular LDL uptake. Currently all the front runners in this area are injectable monoclonal antibodies. These agents produce a significant sustained reduction in LDLc and Lp(a) in heterozygous FH. His patients with homozygous FH showed a variable but significant response in LDLc. Theoretically, the side effects of PCSK9 inhibition might include hepatic, pancreatic, neurocognitive and glycaemic problems.
4. Raal was not optimistic about the prospects for CETP inhibitors.
Prof G Mancia: Micro- and macrovascular events in diabetes and hypertension
BP control in DM (BMJ 1998; 317, 703) reduces cardiovascular events. The variety of drugs were used in the various trials in hypertensive diabetics all achieved the same result. There were no significant differences in outcome between various agents used to control BP. There is a linear relationship between magnitude of BP reduction and reduction in cardiovascular (CV) events. A beneficial effect has been noted in only one trial in DM that reduced BP below 130 mm Hg. In a post-hoc analysis of VALUE, reducing BP <130 mm Hg showed no benefit. Benefit has been demonstrated only in the range <140 mm Hg >130 mm Hg. Mancia recommends using 140/85 as a target in diabetics. In ACCORD serious adverse events were 3X higher with aggressive BP reduction (<120 mm Hg). Adherence to prescription was associated with reduction in both coronary and cerebrovascular events (Lombardy study). It is difficult to get sBP controlled in DM. The totality of evidence supporting reduction in the frequency of MI with antihypertensive treatment is not convincing. Angiotensin receptor blockers (ARBs) provide better protection against progression of nephropathy. In ADVANCE there was no effect in DM on deterioration in vision, neuropathy, dementia and cognitive decline. The optimal BP target may vary between and within patients. The coronary perfusion in patients with LVH may be more sensitive to reduction in BP than patients without LVH. It was proposed that borderline BP elevations be treated only if significant global risk is present. Even sub-optimal BP control provides substantial CV protection. A wide pulse pressure is a marker of risk, but there is no convincing evidence to support specific management.
Prof M Yaqoob: Uraemic LVH
Myocardial disease is the major cause of death in uraemia, accounting for around a third of the mortality. When presenting for dialysis only 10% of patients have a normal echocardiogram. 90% have HT when starting dialysis and most have poor BP control. However the histology of uraemic left ventricular hypertrophy (LVH) is different to that encountered in HT. Histology reveals more fibrosis and more capillary drop-out. These changes are akin to the senescent heart or the findings in progeria. The CV mortality of young patients on haemodialysis is equivalent to that of octogenarians. Yaqoob considers the process to be that of premature aging. Progerin (prelamin A) is implicated. Autophagy allows for recycling of damaged cells and its inhibition leads to premature aging. In normotensive uraemia there is downreglation of genes promoting autophagy. The arterial stiffness present in normotensive uraemic patients is reversed by angiotensin converting enzyme inhibition (ACEI) but unresponsive to NO. Uraemia per se (without HT or anaemia) results in LVH. Calpain which hydrolyses the cell skeleton is increased in uraemia. It may be the cause of low grade myonecrosis and the reason for the elevation of troponin seen in kidney failure. Uraemic patients sustain larger MI’s and higher mortality. Ouabain is elevated in uraemia and promotes calpain activity. FGF23 is phosphaturic and is secreted even in earlier stages of kidney injury and promotes LVH.
Prof C Granger: Atrial fibrillation
Only 50-60% of patients with AF are anti-coagulated.
The LA appendage occluder may offer an alternative to anticoagulation in patients unable to or unwilling to take an anticoagulant. However, less than 40 strokes were observed in the Watchman trials and though there were fewer strokes with than without the device the numbers are too few to draw firm conclusions about its effectiveness.
The meta-analysis by Ruff (Lancet 2013) of the results with NOAC’s showed a 50% reduction in haemorrhagic stroke and 10% reduction in mortality. Treatment effects across the age range were consistent. NOAC’s are better tolerated than aspirin and cause less intracranial haemorrhage than aspirin (AVERROES).
Prof V Fuster: Imaging and screening of sub-clinical diseases: is multimodality exceeding the limits? (The NIHR-UCLH Biomedical Research Centre Lecture)
Fuster spoke of the need for the profession to transition from the treatment of disease to the maintenance of health. His group has used carotid 3D ultrasound and coronary calcium to study 6 000 healthy middle-aged patients. These studies demonstrated a close interaction between carotid and coronary disease. Carotid IMT was not highly as predictive. They found that a significant number with a low Framingham risk score had established disease. Multimodal imaging identified patients at a higher short term risk than their Framingham score indicated although their longer term risk may be equivalent to their risk calculted with Framingham. Fuster holds that the concept of “vulnerable plaque” is not valid. In his study, patients knowing their findings did not improve their treatment adherence. In the Spanish study of a younger group of patients, ilio-femoral changes were more sensitive than carotid changes in detecting disease. Over time rapid progression of disease from single to multiple sites was documented. Once again, in this younger group of patients, disease was found in around 40% of subjects who had a low Framingham risk score. MRI scans identified lacunar infarcts due to small vessel occlusion in patients with identifiable disease. The CARDIA study showed that eventual cognitive dysfunction relates to risk factors that are present in young middle age. Telomere function affects the aging process. As the telomere shortens cell renewal decreases. Senescence associated factors promote many of the features associated with advanced age.
Prof P McCullough: Pathogenesis of acute cardiorenal syndrome
There are 5 subdivisions of the cardiorenal syndrome (CRS). 1. Acute cardiac failure, 2. Chronic heart failure determining progressive kidney injury, 3. Acute kidney dysfunction, 4. Chronic kidney injury, 5. Combination disorders. 50-78% of acute kidney injury (AKI) is community acquired. The calcium disorder in AKI also leads to calcium deposition in the myocardium. Albuminuria is pathogenic in AKI; urinary protein impairs repair of the glomerular injury. Also renal venous congestion plays an important role in the deterioration of kidney function. 30% of AKI results in permanent dysfunction. TIMP-2 and IGFBP7 are cell cycle arrest markers that appear in the urine with early kidney injury. Renal resistance to diuretics is occurring at multiple levels in the kidney. None of the clinical trials have demonstrated an effective general strategy to manage CRS Type 1. McCullough recommends identifying the patient phenotype according to the wet-dry and warm-cold 2X2 division previously proposed by Warner Stevenson.
Prof. L Warner Stevenson: Therapy of acute CRS
Patients are living longer with HF today. Consequently there has been a concomitant increase in kidney failure. Over time the diuretic doses used in HF have increased also. Most HF symptoms are improved when the LVEDP <25 mm Hg. Aggravated kidney dysfunction is almost never associated with a fall in cardiac output. CRS is equally common in HeFPEF and heart failure with reduced ejection fraction (HeFREF). Diuretics decrease the incidence of HF in HT. Neither dopamine or neseritide improved diuresis. Ultrafiltration in UNLOAD reduced 90 day hospitalisation (Constanzo, JACC, 2009). However in CARESS (Bart, NEJM, 2012) there was no difference in 60 day mortality with more adverse effects. Acute worsening of kidney function is probably a reflection of underlying chronic kidney injury. Haemoconcentration worsened kidney function but had better outcomes. In-hospital decongestion results in only 33% staying decongested at 30 days. The outcome of left venricular assist device (LVAD) implantation is influenced by baseline kidney function. The CHAMPION trial showed reduced hospitalisation by adjusting diuretic therapy according to haemodynamic monitoring (Ritzema, Circulation, 2010) – 2/3 of adjustments were to reduce diuretic dose and was accompanied by increase in neurohormonal therapy. She advised against trying to shorten the length of stay by using ultrafiltration.