Neprilysin Inhibitors: Emerging Therapy for Heart Failure.

Biologically active natriuretic peptides (NPs) are an integral part of cardiac homeostasis as they help to maintain sodium and fluid balance. When homeostasis is perturbed by neurohormonal activation in heart failure, levels of NPs rise in response. Neprilysin (NEP) is a naturally occuring enzyme that breaks down NPs. Scientists have recently discovered a novel pharmacologic agent that combines a NEP inhibitor and an angiotensin receptor blocker. In a large clinical trial, this new drug was found to reduce hospitalization and mortality in systolic heart failure. The challenges of implementing this therapy include patient selection, cost, and risk of side effects including angioedema and Alzheimer's disease.

New Management Strategies in Heart Failure.

Despite >100 clinical trials, only 2 new drugs had been approved by the US Food and Drug Administration for the treatment of chronic heart failure in more than a decade: the aldosterone antagonist eplerenone in 2003 and a fixed dose combination of hydralazine-isosorbide dinitrate in 2005. In contrast, 2015 has witnessed the Food and Drug Administration approval of 2 new drugs, both for the treatment of chronic heart failure with reduced ejection fraction: ivabradine and another combination drug, sacubitril/valsartan or LCZ696. Seemingly overnight, a range of therapeutic possibilities, evoking new physiological mechanisms, promise great hope for a disease that often carries a prognosis worse than many forms of cancer. Importantly, the newly available therapies represent a culmination of basic and translational research that actually spans many decades. This review will summarize newer drugs currently being used in the treatment of heart failure, as well as newer strategies increasingly explored for their utility during the stages of the heart failure syndrome.

Guidelines for the management of heart failure: differences in guideline perspectives.

The development of clinical or practice guidelines is thought to be a successful strategy for improving quality of care. Accordingly, many professional organizations, societies, institutions of health care or policy, and even countries have published practice guidelines on a variety of topics, including heart failure.

Transcatheter aortic valve replacement for bicuspid aortic stenosis 13years post heart transplant.

Despite the widespread use of transcatheter aortic valve replacement (TAVR) for moderate and high-risk patients with severe aortic stenosis, it is utilized less frequently in patients with bicuspid aortic valves (BAV). Orthotopic heart transplant (OHT) donors tend to be younger and may have undiagnosed BAV. We present a case of successful TAVR in a patient with BAV thirteen years after OHT.

Case report: Placement of a coronary sinus lead in a patient with dextrocardia and situs inversus.

Situs inversus with dextrocardia is a congenital condition in which the heart is a mirror image of the anatomically normal heart on the right side. Patients with this condition are increasingly surviving into adulthood and may present with heart failure. Several of such patients may benefit from atriobiventricular pacing which may be technically challenging. This case report describes techniques and equipment used to successfully place a coronary sinus lead in a patient with this congenital condition.

Detection of cardiac allograft rejection and response to immunosuppressive therapy with peripheral blood gene expression.

BACKGROUND: Assessment of gene expression in peripheral blood may provide a noninvasive screening test for allograft rejection. We hypothesized that changes in peripheral blood expression profiles would correlate with biopsy-proven rejection and would resolve after treatment of rejection episodes. METHODS AND RESULTS: We performed a case-control study nested within a cohort of 189 cardiac transplant patients who had blood samples obtained during endomyocardial biopsy (EMB). Using Affymetrix HU133A microarrays, we analyzed whole-blood expression profiles from 3 groups: (1) control samples with negative EMB (n=7); (2) samples obtained during rejection (at least International Society for Heart and Lung Transplantation grade 3A; n=7); and (3) samples obtained after rejection, after treatment and normalization of the EMB (n=7). We identified 91 transcripts differentially expressed in rejection compared with control (false discovery rate <0.10). In postrejection samples, 98% of transcripts returned toward control levels, displaying an intermediate expression profile for patients with treated rejection (P<0.0001). Cluster analysis of the 40 transcripts with >25% change in expression levels during rejection demonstrated good discrimination between control and rejection samples and verified the intermediate expression profile of postrejection samples. Quantitative real-time polymerase chain reaction confirmed significant differential expression for the predictive markers CFLAR and SOD2 (UniGene ID No. 355724 and No. 384944). CONCLUSIONS: These data demonstrate that peripheral blood expression profiles correlate with biopsy-proven allograft rejection. Intermediate expression profiles of treated rejection suggest persistent immune activation despite normalization of the EMB. If validated in larger studies, expression profiling may prove to be a more sensitive screening test for allograft rejection than EMB.

Risk stratification of women with peripartum cardiomyopathy at initial presentation: a dobutamine stress echocardiography study.

OBJECTIVES: We sought to determine the prognostic use of inotropic contractile reserve on risk stratification and prognostication of women with peripartum cardiomyopathy. BACKGROUND: Peripartum cardiomyopathy is a rare disorder effecting women in their prime years of life. There appears to be an initial high-risk period with 25% to 50% of women dying within the first 3 months postpartum. Early risk stratification and prognostication are, thus, crucial. However, only limited data are available. METHODS: In all, 7 women (mean age 31.8 years) with peripartum cardiomyopathy and severe left ventricular (LV) dysfunction (mean LV ejection fraction [LVEF] 25.3 +/- 9.5%) were studied. Of these, 6 underwent dobutamine stress echocardiography at baseline and a follow-up resting echocardiogram at a mean of 4.7 +/- 0.9 months after initial presentation. Resting and peak inotropic contractile reserve, and follow-up LVEF, were computed. RESULTS: The mean LVEF improved significantly from baseline (25.3 +/- 9.5%) to maximal inotropic contractile reserve (53.8 +/- 12.6%) (P = .0004) and at follow-up (53.0 +/- 16.4%) (P = .006). Importantly, LVEF at maximal inotropic contractile reserve and at follow-up (5.6 months) did not differ significantly (P = .5). The mean LVEF at maximal inotropic contractile reserve correlated well with the follow-up (LVEF R = 0.79). However, the baseline LVEF did not correlate with follow-up LVEF (P = not significant). CONCLUSIONS: In patients presenting with peripartum cardiomyopathy, inotropic contractile reserve during dobutamine stress echocardiography accurately correlates with subsequent recovery of LV function and confers a benign prognosis.

Conversion to tacrolimus for the treatment of cyclosporine-associated nephrotoxicity in heart transplant recipients.

Many heart transplant recipients experience nephrotoxicity caused by cyclosporine. Tacrolimus has been associated with similar efficacy and safety in heart transplant recipients compared with cyclosporine. It is unknown whether there is any benefit to switching calcineurin inhibition from cyclosporine to tacrolimus in heart transplant recipients with presumed cyclosporine nephrotoxicity. We report five such cases in which this approach was used successfully. In these cases, the heart transplant recipients had bland urine sediments, low urinary sodium concentrations, adequate cardiovascular and systemic hemodynamics, and cyclosporine levels within or below the therapeutic range as defined by heart transplant criteria. The mechanism of renal failure in these patients was believed to be consistent with renal hypoperfusion secondary to cyclosporine-induced renal vasoconstriction. Conversion to tacrolimus resulted in a prompt and significant improvement in serum creatinine concentrations in these patients (P = 0.002). This report shows that conversion to tacrolimus may represent a useful therapeutic strategy to reduce cyclosporine-associated renal failure in recipients of orthotopic heart transplants.

A prospective study of continuous intravenous milrinone therapy for status IB patients awaiting heart transplant at home.

BACKGROUND: We performed a prospective study to determine the feasibility and safety of continuous intravenous milrinone therapy administered at home in patients listed as Status IB for heart transplant. METHODS: Patients who were Status IB could participate if they met specific criteria including an optimal dose of milrinone < or =0.5 microg/kg/min, presence of an implantable cardioverter-defibrillator (ICD), and no other serious comorbidity. The primary end-point of the study was survival to transplant. Hospitalizations, quality of life and cost comparisons were assessed. RESULTS: From May 1999 through October 2002, a total of 60 patients (51 men, 9 women), aged 55.5 +/- 8.4 years, entered the study. Before milrinone therapy, cardiac index was 1.98 +/- 0.66 liters/min/m2 and peak oxygen consumption was 11.4 +/- 2.6 ml/kg/min. Mean time in the study was 160.1 +/- 151.8 days. Fifty-three patients (88.3%) underwent heart transplant. There were only 2 deaths during the study. There were 89 hospital admissions in 46 patients over the 43-month follow-up period; 58 of these admissions were for heart failure. There were 6 episodes of ICD firing for ventricular tachycardia. Quality-of-life measures in a sub-group of patients significantly improved 1 month after discharge. Substantial estimated cost savings occurred. CONCLUSIONS: Continuous intravenous milrinone therapy can be safely administered at home in selected patients with advanced heart failure who are listed for transplant. This strategy may be an acceptable alternative to prolonged hospitalization for patients dependent on continuous inotropic support. Re-hospitalization is to be expected. An implantable cardioverter-defibrillator should be present due to the incidence of ventricular tachycardia.

Epilogue: support devices for end stage heart failure.

The present approach to circulatory assist/replacement devices is to use them as rescue for a patient in shock while awaiting transplant. In the next decade, the paradigm will shift to a more widespread use of such devices in patients without subsequent transplantation. Achievement of the ultimate goals of improved survival and quality of life for patients with advanced heart disease may depend on the strategic use of support devices more frequently than on the total replacement heart.

The new staging system for heart failure. What every primary care physician should know.

The primary care physician is in a unique position to have a major impact on the prevention of heart failure. Using the new system of classifying heart failure, the primary care physician can better evaluate and treat patients in the primary care setting. The new American College of Cardiology/American Heart Association staging system for heart failure emphasizes the structural condition of the heart as well as the prevention, evolution, and progression of heart failure. It is meant to complement the NYHA classification system, which has been used to describe functional limitations, not structural abnormalities.

Asymmetric bilateral demyelinating optic neuropathy from tacrolimus toxicity.

OBJECTIVE: To report the first histopathologic description of optic nerve demyelination from tacrolimus (FK 506) toxicity in the absence of toxic levels of tacrolimus in a patient presenting with asymmetric bilateral visual loss after 5 years of tacrolimus therapy. PATIENTS: We report a patient status post cardiac and renal transplantation who developed severe, progressive and asynchronous bilateral visual loss after prolonged treatment with tacrolimus. Orbital MRI showed an enlarged left optic nerve that enhanced with gadolinium. CONCLUSION: After extensive negative work up, biopsy of one optic nerve was performed. Microscopic analysis showed extensive demyelination in the absence of vasculitis, neoplastic or infectious etiologies. Our patient illustrates that demyelination of the optic nerve causing asynchronous vision loss can be associated with tacrolimus toxicity in the absence of toxic drug levels.

Cardiac resynchronization with sequential biventricular pacing for the treatment of moderate-to-severe heart failure.

OBJECTIVES: The InSync III study evaluated sequential cardiac resynchronization therapy (CRT) in patients with moderate-to-severe heart failure and prolonged QRS. BACKGROUND: Simultaneous CRT improves hemodynamic and clinical performance in patients with moderate-to-severe heart failure (HF) and a wide QRS. Recent evidence suggests that sequentially stimulating the ventricles might provide additional benefit. METHODS: This multicenter, prospective, nonrandomized, six-month trial enrolled a total of 422 patients to determine the effectiveness of sequential CRT in patients with New York Heart Association (NYHA) functional class III or IV HF and a prolonged QRS. The study evaluated: whether patients receiving sequential CRT for six months experienced improvement in 6-min hall walk (6MHW) distance, NYHA functional class, and quality of life (QoL) over control group patients from the reported Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial; whether sequential CRT increased stroke volume compared to simultaneous CRT; and whether an increase in stroke volume translated into greater clinical improvements compared to patients receiving simultaneous CRT. RESULTS: InSync III patients experienced greater improvement in 6MHW, NYHA functional class, and QoL at six months compared to control (all p < 0.0001). Optimization of the sequential pacing increased (median 7.3%) stroke volume in 77% of patients. No additional improvement in NYHA functional class or QoL was seen compared to the simultaneous CRT group; however, InSync III patients demonstrated greater exercise capacity. CONCLUSIONS: Sequential CRT provided most patients with a modest increase in stroke volume above that achieved during simultaneous CRT. Patients receiving sequential CRT had improved exercise capacity, but no change in functional status or QoL.

Serum protein electrophoresis abnormalities in adult solid organ transplant patients with post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is an Epstein-Barr virus (EBV) associated malignancy that occurs in the setting of pharmacologic immunosuppression used after organ transplantation. The presence of monoclonal gammopathy (MG) after organ transplantation is a risk factor for the development of PTLD. We retrospectively explored the characteristics of serum protein electrophoresis (SPEP) in 38 adult solid organ transplant patients with biopsy proven PTLD and SPEP. Twenty-three (61%) had MG with nine (24%) showing multiple MG. Background gammaglobulin levels were abnormal in 13 (34%) patients with five (13%) and eight (21%) having polyclonal hypergammaglobulinemia or hypogammaglobulinemia, respectively. Hypogammaglobulinemia was correlated with the presence of MG (p = 0.01) and polymorphic B-cell hyperplasia histology (p = 0.01). No correlation between SPEP findings and overall survival were noted. With median follow-up of 116 wk (range 2-261 wk), 21 (55%) patients are alive with 20 (53%) in complete remission. Response to reduction in immunosuppression was correlated with improved overall survival (262 wk vs. 68 wk, p = 0.003). Persistence of MG after complete response of the PTLD did not predict relapse. There is a high incidence of MG and gammaglobulin abnormalities in patients with PTLD.

Accidental intravenous colchicine poisoning.

Colchicine is a commonly used drug for the treatment of gout and other indications. Toxicity from intentional oral overdoses of colchicine has been reported. Two cases are reported here in which colchicine was given by intravenous injection, and patients presented with multiorgan toxicity. The authors tested plasma and urine colchicine levels in these patients and found them significantly elevated. Testing of the vial from which the colchicine injections were given showed that the vial was mislabeled and contained 10-fold greater concentration of drug than the labeling indicated. These patients thus received a bolus dose of 20 mg of intravenous colchicine rather than the intended 2-mg dose. An intravenous dose of this magnitude has not previously been reported.