Cardiology

Kavinsky, C. J., M. F. Poulin and M. J. Mack (2018). “Training in Structural Heart Disease: Call to Action.” Circulation 138(3): 225-228.

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Catheter-based therapies for congenital and structural heart diseases (SHDs) have come a long way since the pioneering work of Terry King in 1976 with the first percutaneous atrial septal defect closure, the first mitral balloon valvuloplasty by Kanji Inoue in 1984, and the first percutaneous valve replacements by Philipp Bonhoeffer and Alain Cribier in the early 2000s. More than 100 000 transcatheter aortic valve replacements (TAVRs) have been performed in the United States, and the yearly number of TAVR implants now exceeds that of isolated surgical aortic valve replacements. If the ongoing TAVR trials for low-risk patients demonstrate equivalence with surgery, we can expect another surge in demand for TAVR procedures. Similarly, percutaneous mitral valve repair procedures have now climbed to >15 000 in the United States.1 In addition, several percutaneous therapies for tricuspid and mitral valve repair and replacement are currently in the pipeline and will fuel continued growth in percutaneous therapies for SHD in the coming years. Recent Food and Drug Administration approvals of devices to close the left atrial appendage and patent foramen ovale further highlight this point. Furthermore, the number of adults with congenital heart disease (CHD) now exceeds the number of affected children, and many of these patients will require additional catheterization procedures. It is paradoxical that this nascent field has been devoid of formalized training paradigms. There is a clear and unmet need for defining the training requirements of physicians intending to perform SHD interventions. We need to ensure that future proceduralists will possess the appropriate cognitive and technical skill sets required to safely and effectively perform these interventions. (Excerpt from text, p. 225; no abstract available.)

Chen, S., R. A. Bastarrachea, J. S. Shen, A. Laviada-Nagel, E. Rodriguez-Ayala, E. J. Nava-Gonzalez, P. Huang, R. A. DeFronzo, J. W. Kent, Jr. and P. A. Grayburn (2018). “Ectopic BAT mUCP-1 overexpression in SKM by delivering a BMP7/PRDM16/PGC-1a gene cocktail or single PRMD16 using non-viral UTMD gene therapy.” Gene Ther Aug 2. [Epub ahead of print].

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Here we present our progress in inducing an ectopic brown adipose tissue (BAT) phenotype in skeletal muscle (SKM) as a potential gene therapy for obesity and its comorbidities. We used ultrasound-targeted microbubble destruction (UTMD), a novel targeted, non-viral approach to gene therapy, to deliver genes in the BAT differentiation pathway into rodent SKM to engineer a thermogenic BAT phenotype with ectopic mUCP-1 overexpression. In parallel, we performed a second protocol using wild-type Ucp-1-null knockout mice to test whether the effects of the gene therapy are UCP-1 dependent. Our main findings were a robust cellular presence of mUCP-1 immunostaining (IHC), significantly higher expression levels of mUCP-1 measured by qRT-PCR, and highest temperature elevation measured by infrared thermography in the treated thigh, achieved in rats after delivering the UTMD-PRDM16/PGC-1a/BMP7/hyPB gene cocktail. Interestingly, the weight loss obtained in the treated rats with the triple gene delivery, never recovered the levels observed in the controls in spite of food intake recovery. Our results establish the feasibility of minimally invasive UTMD gene-based therapy administration in SKM, to induce overexpression of ectopic mUCP-1 after delivery of the thermogenic BAT gene program, and describe systemic effects of this intervention on food intake, weight loss, and thermogenesis.

Kandzari, D. E., M. Bohm, F. Mahfoud, R. R. Townsend, M. A. Weber, S. Pocock, K. Tsioufis, D. Tousoulis, J. W. Choi, C. East, S. Brar, S. A. Cohen, M. Fahy, G. Pilcher and K. Kario (2018). “Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial.” Lancet 391(10137): 2346-2355.

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BACKGROUND: Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients with uncontrolled hypertension on antihypertensive medications with drug adherence testing. METHODS: In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20-80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing. FINDINGS: Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure -7.0 mm Hg, 95% CI -12.0 to -2.1; p=0.0059, 24 h diastolic blood pressure -4.3 mm Hg, -7.8 to -0.8; p=0.0174, office systolic blood pressure -6.6 mm Hg, -12.4 to -0.9; p=0.0250, and office diastolic blood pressure -4.2 mm Hg, -7.7 to -0.7; p=0.0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference -6.8 mm Hg, 95% CI -12.5 to -1.1; p=0.0205), 24 h systolic blood pressure (difference -7.4 mm Hg, -12.5 to -2.3; p=0.0051), office diastolic blood pressure (difference -3.5 mm Hg, -7.0 to -0.0; p=0.0478), and 24 h diastolic blood pressure (difference -4.1 mm Hg, -7.8 to -0.4; p=0.0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group. INTERPRETATION: Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common. FUNDING: Medtronic.

Packer, M., B. Claggett, M. P. Lefkowitz, J. J. V. McMurray, J. L. Rouleau, S. D. Solomon and M. R. Zile (2018). “Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial.” Lancet Diabetes Endocrinol 6(7): 547-554.

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BACKGROUND: Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of neprilysin inhibition on the course of renal function in patients with type 2 diabetes. METHODS: In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255. FINDINGS: eGFR decreased by 1.1 mL/min per 1.73 m(2) per year (95% CI 1.0-1.2) in patients without diabetes, but by 2.0 mL/min per 1.73 m(2) per year (1.9-2.1) in those with diabetes (p<0.0001). Compared with patients treated with enalapril, those treated with sacubitril/valsartan had a slower rate of decline in eGFR (-1.3 vs -1.8 mL/min per 1.73 m(2) per year; p<0.0001), and the magnitude of the benefit was larger in patients with versus those without diabetes (difference 0.6 mL/min per 1.73 m(2) per year [95% CI 0.4-0.8] in patients with vs 0.3 mL/min per 1.73 m(2) per year [0.2-0.5] in those without diabetes; pinteraction=0.038). The greater effect of neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA1c. The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0.41). INTERPRETATION: In patients in whom the renin-angiotensin system is already maximally blocked, the addition of neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure. FUNDING: Novartis.

Vaduganathan, M., B. Claggett, M. Packer, J. J. V. McMurray, J. L. Rouleau, M. R. Zile, K. Swedberg and S. D. Solomon (2018). “Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure.” JACC Heart Fail 6(7): 564-569.

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OBJECTIVES: This study sought to determine whether treatment-related changes in natriuretic peptides (NPs) predict longer-term therapeutic effects in clinical trials of heart failure (HF). BACKGROUND: The lack of reliable predictors of efficacy of drugs and devices in HF has presented a major hurdle to the development and evaluation of novel therapies. METHODS: The study conducted a trial-level analysis of 16 phase III chronic HF trials completed between 1987 and 2013 studying 18 therapeutic comparisons in 48,844 patients. Weighted Pearson correlation coefficients were calculated between average control- or placebo-corrected changes in NPs and longer-term treatment effects on clinical endpoints (expressed as log-transformed hazard ratios). RESULTS: Median follow-up for clinical endpoints was 28 (25th to 75th percentile range: 18 to 36) months. NPs were available in a median of 748 (25th to 75th percentile range: 270 to 1,868) patients and measured at a median of 4 (25th to 75th percentile range: 3 to 6) months after randomization. Treatment-related changes in NPs were not correlated with longer-term treatment effects on all-cause mortality (r = 0.12; p = 0.63), but were correlated with HF hospitalization (r = 0.63; p = 0.008). Correlation with HF hospitalization improved when analyses were restricted to trials completed in the last decade (>2010; r = 0.92; p = 0.0095), using N-terminal pro-B-type NP assays (r = 0.65; p = 0.06), and evaluating inhibitors of the renin-angiotensin-aldosterone system (r = 0.97; p = 0.0002). CONCLUSIONS: When examining a broad range of interventions, therapy-related changes in NPs appeared modestly correlated with longer-term therapeutic effects on hospitalization for HF, but not with effects on all-cause mortality. These observations raise important caveats regarding the use of NPs in phase II trials for decision making regarding phase III trials.