The autonomic nervous system regulates all aspects of normal cardiac function, and is recognized to play a critical role in the pathophysiology of many cardiovascular diseases. As such, the value of ...neuroscience‐based cardiovascular therapeutics is increasingly evident. This White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology, pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.
The neural cardiac therapy for heart failure (NECTAR-HF) was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac ...remodelling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy.
Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LV end systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers.
Of the 96 implanted patients, 87 had paired datasets for the primary endpoint. Change in LVESD from baseline to 6 months was -0.04 ± 0.25 cm in the therapy group compared with -0.08 ± 0.32 cm in the control group (P = 0.60). Additional echocardiographic parameters of LV end diastolic dimension, LV end systolic volume, left ventricular end diastolic volume, LV ejection fraction, peak V02, and N-terminal pro-hormone brain natriuretic peptide failed to show superiority compared to the control group. However, there were statistically significant improvements in quality of life for the Minnesota Living with Heart Failure Questionnaire (P = 0.049), New York Heart Association class (P = 0.032), and the SF-36 Physical Component (P = 0.016) in the therapy group.
Vagal nerve stimulation as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodelling and functional capacity in symptomatic heart failure patients, but quality-of-life measures showed significant improvement.
Chronic pressure-overload induces right ventricular (RV) adaptation to maintain RV–pulmonary arterial (PA) coupling. RV remodeling is frequently associated with secondary tricuspid regurgitation (TR) ...which may accelerate uncoupling. Our aim is to determine whether the non-invasive analysis of RV–PA coupling could improve risk stratification in patients with secondary TR. A total of 1,149 patients (median age 72IQR, 63 to 79 years, 51% men) with moderate or severe secondary TR were included. RV–PA coupling was estimated using the ratio between two standard echocardiographic measurements: tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP). The risk of all-cause mortality across different values of TAPSE/PASP was analyzed with a spline analysis. The cut-off value of TAPSE/PASP to identify RV–PA uncoupling was based on the spline curve analysis. At the time of significant secondary TR diagnosis the median TAPSE/PASP was 0.35 (IQR, 0.25 to 0.49) mm/mm Hg. A total of 470 patients (41%) demonstrated RV–PA uncoupling (<0.31 mm/mm Hg). Patients with RV–PA uncoupling presented more frequently with heart failure symptoms had larger RV and left ventricular dimensions, and more severe TR compared to those with RV–PA coupling. During a median follow-up of 51 (IQR, 17 to 86) months, 586 patients (51%) died. The cumulative 5-year survival rate was lower in patients with RV–PA uncoupling compared to their counterparts (37% vs 64%, p < 0.001). After correcting for potential confounders, RV–PA uncoupling was the only echocardiographic parameter independently associated with all-cause mortality (HR 1.462; 95% CI 1.192 to 1.793; p < 0.001). In conclusion, RV–PA uncoupling in patients with secondary TR is independently associated with poor prognosis and may improve risk stratification.
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes the angiotensin-converting enzyme-2 (ACE-2) receptor to enter human cells. Angiotensin-converting enzyme inhibitors ...(ACEI) and angiotensin II receptor antagonists (ARB) are associated with ACE-2 upregulation. We hypothesized that antecedent use of ACEI/ARB may be associated with mortality in coronavirus disease 2019 (COVID-19). Methods and Results We used the Coracle registry, which contains data of patients hospitalized with COVID-19 in 4 regions of Italy, and restricted analyses to those ≥50 years of age. The primary outcome was in-hospital mortality. Among these 781 patients, 133 (17.0%) used an ARB and 171 (21.9%) used an ACEI. While neither sex nor smoking status differed by user groups, patients on ACEI/ARB were older and more likely to have hypertension, diabetes mellitus, and congestive heart failure. The overall mortality rate was 15.1% (118/781) and increased with age (
<0.0001). The crude odds ratios (ORs) for death for ACEI users and ARB users were 0.98, 95% CI, 0.60-1.60,
=0.9333, and 1.13, 95% CI, 0.67-1.91,
=0.6385, respectively. After adjusting for age, hypertension, diabetes mellitus, and congestive heart failure, antecedent ACEI administration was associated with reduced mortality (OR, 0.55; 95% CI, 0.31-0.98,
=0.0436); a similar, but weaker trend was observed for ARB administration (OR, 0.58; 95% CI, 0.32-1.07,
=0.0796). Conclusions In those aged ≥50 years hospitalized with COVID-19, antecedent use of ACEI was independently associated with reduced risk of inpatient death. Our findings suggest a protective role of renin-angiotensin-aldosterone system inhibition in patients with high cardiovascular risk affected by COVID-19.
In chronic heart failure (CHF), reduced vagal activity correlates with increased mortality and acute decompensation. Experimentally, chronic vagus nerve stimulation (VNS) improved left ventricular ...(LV) function and survival; clinically, it is used for the treatment of drug-refractory epilepsy. We assessed safety and tolerability of chronic VNS in symptomatic CHF patients, using a novel implantable nerve stimulation system. The secondary goal was to obtain preliminary data on clinical efficacy.
This multi-centre, open-label phase II, two-staged study (8-patient feasibility phase plus 24-patient safety and tolerability phase) enrolled 32 New York Heart Association (NYHA) class II-IV patients age 56 ± 11 years, LV ejection fraction (LVEF) 23 ± 8%. Right cervical VNS with CardioFit (BioControl Medical) implantable system started 2-4 weeks after implant, slowly raising intensity; patients were followed 3 and 6 months thereafter with optional 1-year follow-up. Overall, 26 serious adverse events (SAEs) occurred in 13 of 32 patients (40.6%), including three deaths and two clearly device-related AEs (post-operative pulmonary oedema, need of surgical revision). Expected non-serious device-related AEs (cough, dysphonia, and stimulation-related pain) occurred early but were reduced and disappeared after stimulation intensity adjustment. There were significant improvements (P < 0.001) in NYHA class quality of life, 6-minute walk test (from 411 ± 76 to 471 ± 111 m), LVEF (from 22 ± 7 to 29 ± 8%), and LV systolic volumes (P = 0.02). These improvements were maintained at 1 year.
This open-label study shows that chronic VNS in CHF patients with severe systolic dysfunction may be safe and tolerable and may improve quality of life and LV function. A controlled clinical trial appears warranted.
Sympathetic–parasympathetic interaction plays a major role in the evolution and outcome of many cardiovascular disorders. Nonetheless, a thorough understanding of this relationship and of its ...potential implications for prognosis and management still escapes many cardiologists. This article reviews the background of sympathetic–parasympathetic interactions focusing on the best direct evidence available, namely direct neural recordings of the activity of single vagal and sympathetic fibers directed to the heart. It examines indirect but highly reliable markers of this interaction as they can be studied in the clinical setting of ischemic heart disease and of heart failure, focusing primarily on the experimental and clinical studies of baroreflex sensitivity. It concludes by drawing inferences likely to lead to a novel approach to the management of heart failure, resulting from the knowledge gained about the vagal control of the heart and based on electrical vagal stimulation.
A novel tricuspid regurgitation (TR) grading system, using vena contracta (VC) width and effective regurgitant orifice area (EROA), was proposed and validated based on its prognostic usefulness.
The ...clinical need of a new grading system for TR has recently been emphasized to depict the whole spectrum of TR severity, particularly beyond severe TR (massive or torrential).
TR severity was characterized in 1,129 patients with moderate or severe secondary TR (STR). Recently proposed cutoff values of VC width were more effective in differentiating the prognosis of patients with moderate STR, whereas EROA cutoff values performed better in characterizing the risk of patients with more severe STR. Therefore, these 2 parameters were combined into a novel grading system to define moderate (VC <7 mm), severe (VC ≥7 mm and EROA <80 mm2), and torrential (VC ≥7 mm and EROA ≥80 mm2) STR.
A total of 143 patients (13%) showed moderate STR, whereas 536 patients (47%) had severe STR, and 450 (40%) had torrential STR. Patients with torrential STR had larger right ventricular (RV) dimensions, lower RV systolic function, and were more likely to receive diuretics. The cumulative 10-year survival rate was 53% for moderate, 45% for severe, and 35% for torrential STR (p = 0.007). After adjusting for potential confounders, torrential STR retained an association with worse prognosis compared with other STR grades (hazard ratio: 1.245; 95% confidence interval: 1.023 to 1.516; p = 0.029).
A novel STR grading system was able to capture the whole range of STR severity and identified patients with torrential STR who were characterized by a worse prognosis.
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Background
The impact of atrial fibrillation catheter ablation (AFCA) on hard clinical endpoints remains controversial.
Objective
Our aim was to conduct a random‐effect model meta‐analysis on ...efficacy data from high‐quality large matched database/registry studies and randomized clinical trials. We compared long‐term all‐cause mortality, stroke, and hospitalization for heart failure in patients undergoing AFCA vs patients treated with medical therapy alone (rhythm and/or rate control medications) in a general AF population.
Methods and Results
PubMed/MEDLINE and Embase databases were screened and a total of nine studies were selected (one randomized clinical trial—CABANA—and eight large matched population studies). A total of 241 372 patients (27 711 in the ablation group, 213 661 in the nonablation group) were included. After a median follow‐up of 3.5 years, AFCA decreased the risk of mortality (hazard ratio HR, 0.62; 95% confidence interval CI, 0.54‐0.72; I2 = 54%; number needed to treat NNT = 28), stroke (HR, 0.63; 95% CI, 0.56‐0.70; I2 = 23%; NNT = 59) and hospitalization for heart failure (HR, 0.64; 95% CI, 0.51‐0.80; I2 = 28%; NNT = 33) compared with AF patients treated with medical therapy alone.
Conclusion
Based on the currently available efficacy and effectiveness evidence, AFCA significantly reduces the risk of death, stroke, and hospitalization compared with medical therapy alone.
Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety ...in the long term remains unknown.
In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels.
In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted
<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years.
In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns.
URL: https://www.
gov; Unique identifier: NCT01764633.
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