Cardiology

Packer, M. (2018). “Augmentation of glucagon-like peptide-1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure.” Eur J Heart Fail Mar 30. [Epub ahead of print].

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Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP-1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.

Packer, M. (2018). “Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications.” Eur J Heart Fail Mar 22. [Epub ahead of print].

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Most treatments for chronic heart failure are effective both in preventing its onset and reducing its progression. However, statins prevent the development of heart failure, but they do not decrease morbidity and mortality in those with established heart failure. This apparent discordance cannot be explained by an effect to prevent interval myocardial infarctions. Instead, it seems that the disease that statins were preventing in trials of patients with a metabolic disorder was different from the disease that they were treating in trials of chronic heart failure. The most common phenotype of heart failure in patients with obesity and diabetes is heart failure with a preserved ejection fraction (HFpEF). In this disorder, the anti-inflammatory effects of statins might ameliorate myocardial fibrosis and cardiac filling abnormalities, but these actions may have little relevance to patients with heart failure and a reduced ejection fraction (HFrEF), whose primary derangement is cardiomyocyte loss and stretch. These distinctions may explain why statins were ineffective in trials that focused on HFrEF, but have been reported to produce with favourable effects in observational studies of HFpEF. Similarly, selective cytokine antagonists were ineffective in HFrEF, but have been associated with benefits in HFpEF. These observations may have important implications for our understanding of the effects of antihyperglycaemic medications. Glucagon-like peptide-1 receptor agonists have had neutral effects on heart failure events in people at risk for HFpEF, but have exerted deleterious actions in HFrEF. Similarly, sodium-glucose co-transporter 2 inhibitors, which exert anti-inflammatory effects and reduce heart failure events in patients who are prone to HFpEF, may not be effective in HFrEF. The distinctions between HFrEF and HFpEF may explain why the effects of drugs on heart failure events in diabetes trials may not be relevant to their use in patients with systolic dysfunction.

Chandra, A., E. F. Lewis, B. L. Claggett, A. S. Desai, M. Packer, M. R. Zile, K. Swedberg, J. L. Rouleau, V. C. Shi, M. P. Lefkowitz, T. Katova, J. J. V. McMurray and S. D. Solomon (2018). “Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial.” JAMA Cardiol. Apr 4. [Epub ahead of print].

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Importance: Health-related quality of life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities. In the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, sacubitril/valsartan improved overall HRQL compared with enalapril, as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Objective: To examine the effects of sacubitril/valsartan on physical and social activities. Design, Setting, and Participants: The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled clinical trial performed from December 8, 2009, to March 31, 2014, in 8399 patients with New York Heart Association class II to IV disease and a left ventricular ejection fraction of 40% or less at 1043 centers in 38 countries. Data analysis was performed from August 1, 2017, to December 25, 2017. Interventions: Sacubitril/valsartan, 200 mg twice daily, or enalapril, 10 mg twice daily. Main Outcomes and Measures: Patients completed HRQL assessments using the KCCQ at randomization, 4-month, 8-month, and annual visits. The effect of sacubitril/valsartan on components of the physical and social limitation sections of the KCCQ at 8 months and longitudinally and related biomarkers and clinical outcomes were studied. Results: At baseline, 7618 of 8399 patients (90.7%) (mean [SD] age, 64 [11] years; 5987 [78.6%] male and 1631 [21.4%] female) completed the initial KCCQ assessment. Patients reported the greatest limitations at baseline in jogging and sexual relationships. Patients receiving sacubitril/valsartan had significantly better adjusted change scores in most physical and social activities at 8 months and during 36 months compared with those receiving enalapril. The largest improvement over enalapril was in household chores (adjusted change score difference, 2.35; 95% CI, 1.19-3.50; P < .001) and sexual relationships (adjusted change score difference, 2.72; 95% CI, 0.97-4.46; P = .002); both persisted through 36 months (overall change score difference, 1.69 [95% CI, 0.78-2.60], P < .001; and 2.36 [95% CI, 1.01-3.71], P = .001, respectively). Conclusions and Relevance: In patients with heart failure with reduced ejection fraction, sacubitril/valsartan significantly improved nearly all KCCQ physical and social activities compared with enalapril, with the largest responses in household chores and sexual relationships. In addition to reduced likelihood of cardiovascular death, all-cause mortality, and heart failure hospitalization, sacubitril/valsartan may improve limitations in common activities in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01035255.

Carey, S. A., K. M. Tecson, A. K. Jamil, J. Felius, T. K. Wolf-Doty and S. A. Hall (2018). “Gene expression profiling scores in dual organ transplant patients are similar to those in heart-only recipients.” Transpl Immunol. Mar 26. [Epub ahead of print].

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BACKGROUND: Serial gene expression profiling (GEP) may reduce the need for endomyocardial biopsies for detecting acute cellular rejection (ACR) after transplantation, but its performance in dual organ transplant recipients is currently unknown. METHODS: We analyzed 18months of follow-up in a national cohort of 27 dual organ recipients (18 heart-kidney, 8 heart-liver, 1 heart-lung) matched to 54 heart-only recipients for gender, age, and time to first GEP (AlloMap(R)) test. ACR, antibody-mediated rejection (AMR), cytomegalovirus infections, biopsies, and longitudinal GEP scores were evaluated. RESULTS: During the first 90days post-transplant, the mean GEP score for dual organ recipients was 25.2+/-9.1, vs. 23.5+/-7.7 for heart-only recipients (P=0.48), with final GEP scores being 29.1+/-6.1 and 32.3+/-3.4, respectively (P=0.34). GEP scores increased over time (P<0.001) at a similar rate (P=0.33) for both groups. One heart-only recipient had treated ACR (GEP score=17). Fourteen subjects had cytomegalovirus infection, 8 of whom were dual-organ. During follow-up, mean GEP score among patients with cytomegalovirus infection was 32.3, compared to 26.7 (p<0.001) in patients without cytomegalovirus. Only 4 (2%) of 233 biopsies were positive for mild AMR; all occurring in 2 heart-only recipients (GEP scores=18-33). CONCLUSIONS: This largest cohort to date suggests that dual organ transplantation alone should not be reason to omit GEP testing from post-transplant medical management, as the two groups' scores did not differ significantly. Confirming that GEP scores increase over time for heart-only and dual organ recipients and in the presence of cytomegalovirus infection, our work shows promise for the use of serial GEP testing in dual organ recipients.

Bertisch, S. M., B. D. Pollock, M. A. Mittleman, D. J. Buysse, L. A. Bazzano, D. J. Gottlieb and S. Redline (2018). “Insomnia with Objective Short Sleep Duration and Risk of Incident Cardiovascular Disease and All-Cause Mortality: Sleep Heart Health Study.” Sleep. Mar 7. [Epub ahead of print].

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Study Objectives: To quantify the association between insomnia/poor sleep with objective short sleep and incident cardiovascular disease (CVD) and mortality in the general population. Methods: We conducted a time-to-event analysis of Sleep Heart Health Study data. Questionnaires and at-home polysomnography were performed between 1994 -1998. Participants were followed for a median 11.4 years (Q1-Q3, 8.8-12.4 years) until death or last contact. The primary exposure was insomnia or poor sleep with short sleep defined as: difficulty falling asleep, difficulty returning to sleep, early morning awakenings, or sleeping pill use, 16-30 nights/month; and total sleep <6 hours on polysomnography (PSG). We used proportional hazards models to estimate the association between insomnia/poor sleep with short sleep and CVD, as well as all-cause mortality. Results: Among 4,994 participants (mean age 64.0 +/- 11.1 years), 14.1% reported insomnia or poor sleep, of which 50.3% slept <6 hours. Among 4,437 CVD-free participants at baseline, we observed 818 incident CVD events. After propensity-adjustment, there was a 29% higher risk of incident CVD in the insomnia/poor sleep with short sleep group compared with the reference group (HR, 1.29, 95% CI, 1.00, 1.66), but neither the insomnia/poor sleep only nor short sleep only groups were associated with higher incident CVD. Insomnia/poor sleep with objective short sleep was not significantly associated with all-cause mortality (HR, 1.07, 95% CI, 0.86, 1.33). Conclusions: Insomnia/poor sleep with PSG-short sleep was associated with higher risk of incident CVD. Future studies should evaluate the impact of interventions to improve insomnia with PSG-short sleep on CVD.