Nasrien E. Ibrahim

Incident Type 2 Myocardial Infarction in a Cohort of Patients Undergoing Coronary or Peripheral Arterial Angiography

Background: Despite growing recognition of type 2 myocardial infarction (T2MI; related to supply/demand mismatch), little is known about its risk factors or its association with outcome. Methods: A single-center cohort of patients undergoing coronary or peripheral angiography with or without intervention was prospectively enrolled and followed for incident type 1 and T2MI, and major adverse cardiovascular events (MACE, a composite of all-cause death, nonfatal myocardial infarction [MI], heart failure, stroke, transient ischemic attack, peripheral arterial complication, and cardiac arrhythmia), as well. T2MI was adjudicated using criteria from the Third Universal Definition of MI. Baseline characteristics, blood samples, and angiography information were obtained. Major end points subsequent to first MI were assessed using landmark analyses to compare the rates of first events only where everyone with a prior history of any MACE before MI were censored and adjusted for follow-up times. Cox proportional hazard models were used for time-to-event analyses with age and sex forced into all models and additional covariates evaluated by using the stepwise option for the selection. Results: One thousand two hundred fifty-one patients were enrolled and followed for a median of 3.4 years. Of these patients, 152 (12.2%) had T2MI during follow-up; T2MI was frequently recurrent. Multivariable predictors of T2MI were older age, lower systolic blood pressure, history of coronary artery disease, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, nitrate use, and elevated concentrations of glucose, N-terminal pro-B type natriuretic peptide, and cystatin C. Patients with T2MI had higher rates of subsequent adverse events than those without T2MI (per 100 person-years: MACE, 53.7 versus 21.1, P<0.001; all-cause death, 23.3 versus 3.3, P<0.001; cardiovascular death, 17.5 versus 2.6, P<0.001; heart failure events, 22.4 versus 7.4, P<0.001); these rates are similar to those seen in patients with type 1 MI. Incident diagnosis of T2MI strongly predicted risk for subsequent MACE (adjusted hazard ratio, 1.90; 95% confidence interval, 1.46–2.48; P<0.001), all-cause death (adjusted hazard ratio, 2.96; 95% confidence interval, 2.01–4.36; P<0.001), and cardiovascular death (adjusted hazard ratio, 2.16; 95% confidence interval, 1.36–3.43; P=0.001). Conclusions: T2MI is common and associated with poor prognosis. Studies evaluating treatment strategies for management of T2MI are needed. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842868.

2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction

James L. Januzzi, Jr, MD, FACC, Chair Luis C. Afonso, MBBS, FACC Brendan Everett, MD, FACC Adrian F. Hernandez, MD, MHS, FACC William Hucker, MD, PhD Hani Jneid, MD, FACC Joseph Edward Marine, MD, FACC Pamela Bowe Morris, MD, FACC Robert N. Piana, MD, FACC Karol E. Watson, MD, FACC Dharam

Established and Emerging Roles of Biomarkers in Heart Failure Clinical Trials

The role of circulating biomarkers in heart failure clinical trials has evolved in recent decades. Increasing evidence behind the use of natriuretic peptides, emergence of novel biomarkers, and increased emphasis on targeting therapies toward physiological basis of disease (so-called precision medicine) have all contributed to the continued expansion of biomarker use in heart failure clinical trials. We will explore the advantages and pitfalls encountered through the use of biomarkers in clinical trials as an inclusion criterion, toxicity marker, and end point. We will also review their role in providing insights into the mechanism of action of therapeutics and guiding therapy in the management of patients with heart failure.

The potential role of natriuretic peptides and other biomarkers in heart failure diagnosis, prognosis and management

Heart failure (HF) is a complex disease process that is challenging to diagnose and manage. For more than 15 years, biomarkers have been used to diagnose and the guide the management of patients with this disease. The gold standard biomarkers for HF are B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP); both are used for diagnosis and prognosis. More recently, there has been an interest in use of BNP and NT-proBNP for HF management as well. Important aspects regarding production and clearance of BNP and NT-proBNP exist, which are vital for the clinician to understand. Beyond BNP or NT-proBNP, other newer biomarkers such as mid-regional pro-atrial natriuretic peptide, soluble ST2, highly sensitive troponin and renal biomarkers may add value for prognostication and possibly, patient management. In this article, the authors will discuss the established and evolving role of BNP and NT-proBNP in HF, along with consideration of select newer biomarkers in this setting.

Beyond Natriuretic Peptides for Diagnosis and Management of Heart Failure.

BACKGROUND Heart failure (HF) is a complex syndrome with an enormous societal burden in terms of cost and morbidity and mortality. Natriuretic peptide (NP) testing is now widely used to support diagnosis, prognostication, and management of patients with HF, but NPs come with limitations, including vulnerability to the presence of obesity, atrial fibrillation, and renal dysfunction, for example. Beyond the NPs, novel biomarkers may supplement traditional clinical and laboratory testing to improve understanding of the complex disease process of HF, and possibly to personalize care for those affected through better individual phenotyping. CONTENT In this review we discuss novel biomarkers by dividing them into categories based on major pathophysiologic pathways they represent including myocardial stretch/stress, cardiac extracellular matrix remodeling, cardiomyocyte injury/death, oxidative stress, inflammation, neurohumoral activation, and renal dysfunction. SUMMARY Given the limitations of NPs, along with the complex physiology in HF, it is logical to consider utilization of novel biomarkers providing orthogonal biological and clinical information. Several novel HF biomarkers have shown promise but have substantial expectations to meet before being used clinically. Nonetheless, it is reasonable to expect the future lies in the application of multibiomarker panels for the improvement in management of HF and the personalization of care.

Renin-Angiotensin System Blockade in Heart Failure: More to the Picture Than Meets the Eye

T he renin-angiotensin system (RAS) is activated in heart failure (HF) and has been a well-established therapeutic target for the treatment of HF for decades. Conventional teaching holds that following activation of the RAS, renal juxtaglomerular cells produce renin, which in turn cleaves angiotensinogen into angiotensin I (Ang-[1–10]). Widely held understanding of the RAS teaches that at this point, Ang-(1–10) is converted by the effects of angiotensin-converting enzyme (ACE) into an octapeptide, angiotensin II (Ang-[1–8]), a potent vasoconstrictor whose effects stimulate a cascade of events such as systemic and renal vasoconstriction, cardiomyocyte remodeling, and stimulation of aldosterone secretion. The sum total of the deleterious effects of Ang-(1–8) have thus formed the basis for therapeutic targeting of this abnormal cascade in HF, and landmark trials have shown use of RAS inhibitors produces a survival benefit in chronic HF with reduced ejection fraction (1); in this regard, treatment of HF with reduced ejection fraction with ACE inhibitors, angiotensin II receptor blockers (ARB), or the recently released angiotensin receptor/neprilysin inhibitor (ARNI) sacubitril/valsartan is a Class I recommendation in current clinical practice guidelines (2).

Worsening Renal Function during Management for Chronic Heart Failure with Reduced Ejection Fraction: Results From the Pro-BNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) Study.

OBJECTIVES To assess prognostic meaning of worsening renal failure (WRF) occurring during management of chronic heart failure (HF) with reduced ejection fraction. BACKGROUND When WRF develops during titration of HF medical therapy, it commonly leads to less aggressive care. METHODS A total of 151 patients enrolled in a prospective, randomized study of standard of care (SOC) HF therapy versus SOC plus a goal N-terminal pro-B type natriuretic peptide (NT-proBNP) < 1000 pg/mL were examined. Cardiovascular (CV) event (defined as worsening HF, hospitalization for HF, significant ventricular arrhythmia, acute coronary or cerebral ischemia, or CV death) at 1 year relative to WRF (defined as any reduction in estimated glomerular filtration rate) 90 days postenrollment were tabulated. RESULTS Those developing WRF by 3 months had an average 14% reduction in estimated glomerular filtration rate. There was no difference in incidence of WRF between study arms (43% in SOC, 57% in NT-proBNP, P = .29). During the first 3 months of therapy titration, incident WRF was associated with numerically fewer CV events at 1 year compared with those without WRF (mean 0.81 vs 1.16 events, P = .21). WRF was associated trend toward fewer CV events in the SOC arm (hazard ratio 0.45, 95% confidence interval 0.16-1.24, P = .12); the NT-proBNP-guided arm had numerically lower CV event rates regardless of WRF. Subjects with NT-proBNP <1000 pg/mL and WRF received higher doses of guideline directed medical therapies, lower doses of loop diuretics, and had significantly lower CV event rates (P < .001). CONCLUSIONS Modest degrees of WRF are common during aggressive HF with reduced ejection fraction management, but we found no significant association with CV outcomes. HF care guided by NT-proBNP was not associated with more WRF compared with SOC, and led to benefit regardless of final renal function.

Heart rate, beta-blocker use, and outcomes of heart failure with reduced ejection fraction

Aims High resting heart rate (HR ≥70 b.p.m.) is associated with worse clinical outcomes in heart failure with reduced ejection fraction (HFrEF). Heart rate, guideline-directed medical therapy (GDMT) with beta-blocker (BB), and cardiovascular outcomes were evaluated in a large integrated health network. Methods and results Using electronic health records we examined patients with chronic HFrEF (ejection fraction ≤35%) in sinus rhythm with at least 1 year of follow-up and available serial HR and medication data between 1 January 2000 and 31 December 2014. Among 6071 patients followed for median of 1330 days across 73 586 total visits, median HR remained stable over time with 61.2% of the follow-up period with HR  ≥70 b.p.m. At baseline, 27.9% of patients were on ≥ 50% GDMT target BB dose, 16.2% subjects at baseline, and 19.4% at the end of follow-up had HR ≥70 b.p.m. despite receiving ≥50% of target BB dose. In adjusted analyses, baseline HR was associated with all-cause mortality/heart failure (HF) hospitalization (hazard ratio 1.28 per 15 b.p.m. Heart rate increase; P < 0.001). In comparison, hazard ratio for BB dose was 0.97 (per 77.2 mg increase; P = 0.36). When evaluating patients based on HR and BB dose there was a significant difference in the cumulative hazard for all-cause mortality or HF hospitalization (P < 0.001). For HF hospitalization, hazard appeared to be more closely associated with HR rather than BB dose (P = 0.01). Conclusion In a real-world analysis, high resting HR was common in HFrEF patients and associated with adverse outcomes. Opportunities exist to improve GDMT and achieve HR control.

The Future of Biomarker-Guided Therapy for Heart Failure After the Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) Study

Purpose of ReviewBiomarker-guided management of patients with chronic heart failure with reduced ejection fraction (HFrEF) remains controversial.Recent FindingsBiomarkers have established roles for diagnosis and prognostication in HF. Pilot data suggested that use of natriuretic peptides might be helpful to guide HF care. The recent Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) randomized–controlled trial did not find therapy guided by NT-proBNP to be more effective than usual care in improving the primary endpoint of HF hospitalization or cardiovascular mortality amongst patients with chronic HFrEF. Patients in GUIDE-IT received similar care and had similar NT-proBNP lowering regardless of treatment allocation.SummaryThough biomarkers retain important standing for diagnosis and prognosis in HF, the GUIDE-IT trial results suggest carefully managed patients may not benefit from a biomarker-guided strategy. Future studies focusing this intervention on patients treated in a more real-world setting are needed.

Serial Heart Rates, Guideline-Directed Beta Blocker Use, and Outcomes in Patients With Chronic Heart Failure With Reduced Ejection Fraction

A single heart rate (HR) measurement may inform future prognosis in chronic heart failure with reduced ejection fraction (HFrEF). The importance of elevated HR across serial assessment is uncertain, particularly with well-applied guideline-directed medical therapy (GDMT) with beta blockers (BBs). In this post hoc analysis of 129 patients with chronic HFrEF in sinus rhythm, who had aggressive medication titration over 10.6 months, HR and BB use were assessed at each visit (average of 6 visits per patient). All-cause mortality was assessed. At baseline, 81 subjects (62.8%) had HR ≥70 beats/min; 40 subjects (31.0%) had high HR despite being on ≥50% of GDMT BB dose. At final visit, 30.4% of the subjects still had high HR despite achieving ≥50% target BB dose. There were no significant baseline differences in demographics or BB doses in patients with HR <70 vs HR ≥70 beats/min. In adjusted model in which HR was treated as time-dependent covariate, an increase in HR of 10  beats/min was associated with an increased hazard of all-cause mortality during follow-up (adjusted hazard ratio per 10 beats/min = 2.46; 95% confidence interval 1.46-4.16, p <0.001). In conclusion, in well-managed patients with HFrEF, high HR was frequent even after aggressive medication titration, and often despite being on at least 50% of GDMT BB dose. An increase in HR was associated with worse clinical outcomes (Clinicaltrials.gov NCT#00351390).