Pragmatic diagnostic and therapeutic algorithms to optimize new potassium binder use in cardiorenal disease.

BACKGROUND: Pivotal randomized trials demonstrating efficacy, safety and good tolerance, of two new potassium binders (patiromer and sodium zirconium cyclosilicate) led to their recent approval. A major hurdle to the implementation of these potassium-binders is understanding how to integrate them safely and effectively into the long-term management of cardiovascular and kidney disease patients using renin angiotensin aldosterone system inhibitors (RAASi), the latter being prone to induce hyperkalaemia. METHODS: A multidisciplinary academic panel including nephrologists and cardiologists was convened to develop consensus therapeutic algorithm(s) aimed at optimizing the use of the two novel potassium binders (patiromer and sodium zirconium cyclosilicate) in stable adults who require treatment with RAASi and experience(d) hyperkalaemia in a non-emergent setting. RESULTS: Two dedicated pragmatic algorithms are proposed. The lowest intervention threshold (i.e. 5.1 mmol/L or greater) was the one used in the patiromer and sodium zirconium cyclosilicate) pivotal trials, both drugs being indicated to treat hyperkalaemia in a non -emergent setting. Acknowledging the heterogeneity across specialty guidelines in hyperkalaemia definition and thresholds to intervene when facing hyperkalaemia, we have been mindful to use soft language i.e. "it is to consider", not necessarily "to do". CONCLUSIONS: Providing the clinical community with pragmatic algorithms may help optimize the management of high-risk patients by avoiding the risks of both hyper and hypokalaemia and of suboptimal RAASi therapy.

[General recommendations for medical treatment after heart transplantation]. / Aspects médicaux autour de la transplantation cardiaque en 2014.

Heart transplantation remains the treatment of choice in selected patients with severe heart failure (HF) despite optimal medical therapy. Since long-term survival after HTX is improving, there is a growing need for evidence-based strategies that reduce long-term mortality resulting from both immunological and non-immunological risk. This manuscript summarizes recommendations for treatment of transplant vasculopathy, malignancy after transplantation, and prevention of corticosteroid induced bone disease. Based on actual understanding of cardiovascular risk factors in the population, preservation of renal function, prevention and treatment of hyperlipidemia and diabetes, as well as blood pressure control play an important role in the long-term follow-up after heart transplantation.

[Cardiology]. / Cardiologie.

The present review provides a selected choice of clinical research in the field of interventional cardiology, heart failure and cardiac imaging. We also focused on the new guidelines published by the European society of cardiology in 2012.

[Long-term mechanical circulatory support: where do we stand in 2013?]. / Assistance circulatoire chronique: le point en 2013.

With the advent of new technologies, experience with long-term mechanical circulatory support (MCS) is rapidly growing. Candidates to MCS are selected based on concepts, strategies and classifications that are specific to this indication. As results drastically improve, supported by stronger scientific evidence, the trend is towards earlier implantation. An adequate pre-implant follow-up is mandatory in order to avoid missing the best window of opportunity for implantation. While on chronic support, the hemodynamic profile of patients with continuous-flow ventricular assist devices is unique and remarkably influenced by the hydration status. Optimal management of these patients from the pre-implant phase to the long-term support phase requires a multidisciplinary approach that is similar to that already long validated for organ transplantation.

Already low drug dose antagonism of the renin-angiotensin aldosterone system decreases 1-year mortality and rehospitalization in old heart failure patients.

AIMS: Hospitalization for heart failure treatment (HHF) is an incisive event in the course of HF. Today, the large majority of HHF patients is ≥ 65 years and discharge HF drugs are most often not applied at dose levels acknowledged to provide prognostic benefit. This study therefore aims to investigate the treatment effect size of discharge HF drugs in old HHF patients. METHODS: Drugs are analyzed according to pharmacological class. Individual discharge HF drug dose is reported as percentage of guidelines-recommended target dose. Primary endpoint was 1-year all-cause mortality (ACM) after discharge; the secondary endpoint combined 1-year ACM and first cardiovascular hospitalization within 1 year after discharge. Comparison between 65-80 years and > 80 years old study participants tested the relative treatment effect size as a function of respective age group. RESULTS: The 875 consecutive HHF patients had a median age of 82 years [76-87 years]; 48.6 % were females. Betablocker and diuretic treatment did not change the incidence of endpoints. Inhibition of the renin-angiotensin system (RASi), when compared to no treatment, decreased the incidence of endpoints both at the 1-25 % and the > 25 % target dose level. Antagonists of the mineralocorticoid receptor (MRA), when compared to no treatment, decreased the secondary endpoint at the 1-25 % target dose level but not at the > 25 % target dose level. The relative treatment effect size of RASi or MRA corresponded between the age strata for both endpoints. CONCLUSION: Low-dose RASi and MRA had beneficial effects in these old HHF patients.

[Selection and preoperative follow-up of heart transplantation candidates in the French part of Switzerland]. / Sélection et suivi prétransplantation des patients candidats à la greffe cardiaque en Suisse romande.

Heart transplantation (HTx) started in 1987 at two university hospitals (CHUV, HUG) in the western part of Switzerland, with 223 HTx performed at the CHUV until December 2010. Between 1987 and 2003, 106 HTx were realized at the HUG resulting in a total of 329 HTx in the western part of Switzerland. After the relocation of organ transplantation activity in the western part of Switzerland in 2003, the surgical part and the early postoperative care of HTx remained limited to the CHUV. However, every other HTx activity are pursued at the two university hospitals (CHUV, HUG). This article summarizes the actual protocols for selection and pre-transplant follow-up of HTx candidates in the western part of Switzerland, permitting a uniform structure of pretransplant follow-up in the western part of Switzerland.

[What is new in the medical management of acute heart failure?]. / Ouoi de neuf dans to prise en charge médicale de l'insuffisance cardiaque aiguë?

Acute heart failure (AHF) is a frequent medical condition associated with a poor prognosis. Based on systolic blood pressure at presentation, patients with AHF can be classified into 5 clinical profiles enabling a more targeted use of standard medications including diuretics, vasodilators and inotropes. The most recent guidelines underline the importance of a rapid management and the favorable impact of heart failure programs, which reduce morbidity and mortality after an admission for AHF. New therapeutic perspectives include ultrafiltration, vasopressin and adenosine antagonists, relaxin and new inotropes such as istaroxime.

[Monitoring and adjustment of immunosuppression after heart transplantation]. / Suivi du patient après transplantation cardiaque: monitoring et adaptation de l'immunosuppression.

Heart transplantation remains the best therapeutic option for the treatment of end-stage heart failure. However, good survival rates can be obtained only if patients are closely monitored, particularly for their immunosuppressive regimens. Currently, a triple-drug regimen usually based on calcineurin-inhibitors (cyclosporin A or tacrolimus), anti-proliferative agents and steroids is used in most recipients. New agents such as the mTOR inhibitors, a more recently developed class of immunosuppressive drugs, can also be used in some patients. The aim of this article is to review currently used immunosuppressive regimens after heart transplantation, and to propose some individualized options depending on specific patient characteristics and recent pharmacological developments in the field.

Churg-Strauss syndrome with cardiac involvement: case illustration and contribution of CMR in the diagnosis and clinical follow-up.

This report summarises three cases of Churg-Strauss syndrome (CSS) illustrating the diagnostic challenges associated with the cardiac manifestation of this disease. Here, we illustrate the role of cardiac magnetic resonance (CMR) for diagnosis and follow-up of CSS with a focus on new non-contrast T2-weighted imaging sequences for quantification of myocardial scar tissue and quantitative T2 mapping techniques, which allow the detection of myocardial edema.

Subunit expression of the cardiac L-type calcium channel is differentially regulated in diastolic heart failure of the cardiac allograft.

BACKGROUND: Left ventricular diastolic dysfunction is a major cause of cardiac allograft failure. Multimeric L-type calcium channels (alpha1-, alpha2/delta-, and beta-subunits) are essential for excitation/contraction coupling in the heart. Their gene expression was studied in allografts that developed diastolic heart failure. METHODS AND RESULTS: mRNA levels of calcium channel subunits were measured by competitive reverse transcriptase-polymerase chain reaction in microbiopsy samples from the interventricular septum. Size and tissue variabilities between biopsy samples were assessed by determination of cardiac calsequestrin mRNA levels. In the cardiac allografts studied, mRNA levels in microbiopsy samples were considered to represent left ventricular gene expression, because septal and left ventricular gene expression in Northern blots was equivalent, and left ventricles contracted homogeneously. Biopsy samples (n=72) were taken from allografts with normal left ventricular end-diastolic pressure (LVEDP; 8 to 13 mm Hg; n=30), moderately elevated LVEDP (14 to 18 mm Hg; n=26), and elevated LVEDP (19 to 28 mm Hg; n=16). Increased LVEDP was related to slowed diastolic relaxation determined by the time constant tau (r2=0.86), whereas systolic performance (dP/dt; ejection fraction) was preserved. With increasing LVEDP, mRNA levels of the pore-forming alpha1c-subunit (n=15) and of the regulatory alpha2/delta-subunit (n=17) remained unchanged but decreased exponentially (r2=-0.83) for the regulatory beta-subunit (n=40). Compared with cardiac allografts with normal LVEDP (n=15), beta-subunit mRNA level was reduced by 75% at elevated LVEDP (n=9; P=0.012). In an explanted, diastolically failing cardiac allograft, beta-subunit expression was reduced correspondingly by 72% and 76% on the mRNA level in septal and left ventricular myocardium and by 80% on the protein level. CONCLUSIONS: The downregulated expression of the calcium channel beta-subunit might contribute to altered calcium handling in diastolically failing cardiac allografts.

Pre-eclampsia with acute heart failure postpartum as primary manifestation of systemic lupus erythematosus.

Pre-eclampsia occurs in 2-5% of pregnancies of healthy women. Here, we present a rare case of pre-eclampsia with overt acute heart failure, which was the primary manifestation of systemic lupus erythematosus with cardiac and renal involvement.

Tissue-specific expression of calcium channels.

The high-voltage-activated calcium channel is a multimeric protein complex containing α(1), α(2)/δ, ß, and γ subunits. The α(1) subunit is the ion conduction channel and contains the binding sites for calcium channel blockers and toxins. Three genes code for distinct L-type, dihydropyridine-sensitive α(1) subunits; one gene codes for the neuronal P-type (Purkinje) α(1) subunit; and one gene codes for the neuronal N-type α(1) subunit. The smooth and cardiac muscle L-type calcium channel α(1) subunits are splice variants of the same gene. The α(1) subunits are coexpressed with a common α(2)/δ subunit and tissue-specific ß subunits (at least three genes). The γ subunit apparently is expressed only in skeletal muscle. The properties of these cloned and expressed calcium channels are discussed here.

Primary structure and functional expression of a high voltage activated calcium channel from rabbit lung.

The complete amino acid sequence of the receptor for organic calcium channel blockers (CaCB) from rabbit lung has been deduced by cloning and sequence analysis of the cDNA. Synthetic RNA derived from this cDNA induces the formation of a functional CaCB-sensitive high voltage activated calcium channel in Xenopus oocytes.

Primary structure and functional expression of a cyclic nucleotide-gated channel from rabbit aorta.

Sequences specific for cyclic nucleotide-gated channels (CNG channels) have been amplified by PCR from cDNA of heart, aorta, sino-atrial node, cerebellum, C-cells and kidney. The complete amino acid sequence of a CNG channel from rabbit aorta has been deduced by cloning and sequence analysis of the cDNA. Synthetic RNA derived from this cDNA induces the formation of a functional CNG channel in Xenopus oocytes.

Modulation of cardiac Ca2+ channels in Xenopus oocytes by protein kinase C.

L-Type calcium channel was expressed in Xenopus laevis oocytes injected with RNAs coding for different cardiac Ca2+ channel subunits, or with total heart RNA. The effects of activation of protein kinase C (PKC) by the phorbol ester PMA (4 beta-phorbol 12-myristate 13-acetate) were studied. Currents through channels composed of the main (alpha 1) subunit alone were initially increased and then decreased by PMA. A similar biphasic modulation was observed when the alpha 1 subunit was expressed in combination with alpha 2/delta, beta and/or gamma subunits, and when the channels were expressed following injection of total rat heart RNA. No effects on the voltage dependence of activation were observed. The effects of PMA were blocked by staurosporine, a protein kinase inhibitor. beta subunit moderate the enhancement caused by PMA. We conclude that both enhancement and inhibition of cardiac L-type Ca2+ currents by PKC are mediated via an effect on the alpha 1 subunit, while the beta subunit may play a mild modulatory role.

The cause and correction of low blood vitamin C concentrations in the elderly.

Chronically sick elderly women had low intakes and low blood concentrations of vitamin C. Small dietary supplements of vitamin C increased the concentration of vitamin C in their plasma and leucocytes to those found in both the active elderly and the young. These findings confirm that low concentrations of vitamin C in the institutionalized and chronically sick elderly are primarily due to poor intake and can be easily corrected by dietary changes. The case for increasing the intake of vitamin C in these patients is discussed.

Inhibition of aldosterone production in adrenal cell suspensions by serum from patients with manic-depressive psychosis.

A method of preparing a suspension of cells of the zona glomerulosa from rat adrenal capsules treated with crude collagenase is described. The cells responded to ACTH, angiotensin II and serotonin by increased production of aldosterone. Pooled human sera or individual human sera (from healthy normal or non-psychiatric in-patients) to a final concentration of 30% had no effect on ACTH-stimulated production of aldosterone. Many serum samples from five patients with manic-depressive psychosis, however, caused a reduction in aldosterone production; 65% of those samples taken during depression, 44% of the samples taken during manic episodes and 23% of the samples taken when the mood was normal. Sera from manic-depressive patients also reduced the production of aldosterone caused by angiotensin II or serotonin. This effect of serum from manic-depressives in vitro may be related to the abnormalities of aldosterone control in such patients.

Amitriptyline pharmacokinetics. A crossover study with single doses of amitriptyline and nortriptyline.

Six healthy volunteers were given single doses of amitriptyline (AT) and of nortriptyline (NT) separated by at least 10 days. Plasma concentrations of both compounds were measured at intervals for 48 or 72 h. The total areas under the concentration-time curves for the ingested drug were greater for NT, but AT concentrations showed much higher peak values and took more than 12 h to reach the terminal beta phase of elimination. Doses of 50 mg AT produced areas averaging slightly less than half those for 100 mg AT in the same subject, suggesting some saturation of the elimination process. The consumption of a large, fatty meal just before taking the AT tablets had little effect on the plasma drug concentration curves. NT half-lives, measured after ingestion of NT tablets, were used in analysing the production of NT from doses of AT in the same subject. There was a rapid early production, amounting to 30-67% of the total and presumably resulting from the first pass of AT through the liver. NT was then formed continuously at a rate always proportional to the simultaneous rate of AT elimination. The total amount of NT entering the systemic circulation was about one-quarter of the AT dose.

Amitriptyline pharmacokinetics. Single doses of Lentizol compared with ordinary amitriptyline tablets.

Two separate single doses of Lentizol (W. R. Warner, Pontypool, U.K.), a sustained-release preparation of amitriptyline (AT) were taken by each of six healthy subjects. Plasma concentrations of AT and of nortriptyline (NT) were determined at intervals over a period of 48 or 72 h. Faeces were collected and their drug content measured. Results were compared with those obtained when the same subjects took ordinary AT tablets. AT was found in the faeces after the ingestion of Lentizol or of ordinary AT tablets. However, after NT tablets negligible amounts of NT appeared in the faeces. AT was sometimes absorbed slowly from Lentizol, but on other occasions it was absorbed as rapidly as from ordinary tablets. Plasma levels of AT 24 h after the dose were usually not higher after Lentizol than after an equal dose of ordinary tablets. The systemic bioavailability of Lentizol as judged by areas under the plasma concentration-time curves, both for AT and for the NT formed metabolically, was on average lower than that of the ordinary tablets. However, the amounts of AT found in the faeces were not large enough to account for the AT area reduction by simple failure of absorption. Possible explanations of the discrepancy are discussed.

Antidepressive effect of amitriptyline treatment with plasma drug levels controlled within three different ranges.

Seventy-four depressed patients were treated with amitriptyline for 4-6 weeks. Their doses were individually adjusted to maintain the sum of the plasma levels of amitriptyline (AT) and nortriptyline (NT) within one of three different ranges, randomly allocated. Allowance was made for individual plasma binding of the drugs. In the 50 patients between 25 and 65 years of age, the antidepressive response at low plasma drug levels was somewhat poorer than at medium or high levels, which were equally effective. In this age group an association was found between outcome and the individual rate of AT metabolism, expressed as "reciprocal clearance" (RC), the steady-state plasma concentration of AT plus NT divided by the daily AT dose. Good antidepressive outcome was associated with high RC. The implications of these findings for patient treatment and for the interpretation of other studies are discussed. The 18 patients between 65 and 80 years of age showed no significant differences between the effectiveness of treatment at different plasma drug levels, and no significant associations between outcome and RC.