Emilia D'Elia

Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use

Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome characterized by cardiovascular, metabolic, and pro‐inflammatory diseases associated with advanced age and extracardiac comorbidities. All of these conditions finally lead to impairment of myocardial structure and function. The large phenotypic heterogeneity of HFpEF from pathophysiological underpinnings presents a major hurdle to HFpEF therapy. The new therapeutic approach in HFpEF should be targeted to each HF phenotype, instead of the ‘one‐size‐fits‐all’ approach, which has not been successful in clinical trials. Unless the structural and biological determinants of the failing heart are deeply understood, it will be impossible to appropriately differentiate HFpEF patients, identify subtle myocardial abnormalities, and finally reverse abnormal cardiac function. Based on evidence from endomyocardial biopsies, some of the specific cardiac structural phenotypes to be targeted in HFpEF may be represented by myocyte hypertrophy, interstitial fibrosis, myocardial inflammation associated with oxidative stress, and coronary disease. Once the diagnosis of HFpEF has been established, a potential approach could be to use a panel of biomarkers to identify the main cardiac structural HFpEF phenotypes, guiding towards more appropriate therapeutic strategies. Accordingly, the purpose of this review is to investigate the potential role of biomarkers in identifying different cardiac structural HFpEF phenotypes and to discuss the merits of a biomarker‐guided strategy in HFpEF.

NGF and heart: Is there a role in heart disease?

The review emphasizes the role of NGF, the most representative member of the neurotrophins family, in cardiac physiopathology with a particular focus on healing and sprouting processes occurring after tissue damage. Cardiac and circulating NGF levels dramatically increase following myocardial injury (MI). A very early rise of this neurotrophin is indeed observed soon after MI (hours). Such a rise may lead to sympathetic nerve sprouting which may underlie the later genesis of arrhythmias but may also favor the healing process. At later times (months after), when heart failure develops, the opposite is detected and NGF tissue levels are below the normal range, an event that may in turn participate to defective innervation and cardiac failure. Through a careful analysis of preclinical and clinical studies, this review proposes that time is the key variable when studying these opposite changes in NGF expression observed following MI and attempting to interpret and correlate them with cardiac physiopathology. The examination of the results leads to the speculation that NGF modulation may be a pharmacological target for interventions in specific stages of heart dysfunction following MI.

Prognostic scores in heart failure — Critical appraisal and practical use

Survival in patients with heart failure in the last two decades has significantly improved, owing to availability of new drugs, devices, and technologies. However, these new therapeutic tools are often costly and not without attendant risks. Thus, accurate and reproducible risk stratification is required to assess appropriateness of therapy. Although a growing body of evidence has characterized various predictors of poor outcomes, the application of comprehensive prognostic models in clinical practice remains limited. Herein, we critically evaluate the utility of prognostic scores in heart failure, discussing the strategies to select the most efficient and appropriate risk estimator in the individual patient.

Determinants of functional capacity after mitral valve annuloplasty or replacement for ischemic mitral regurgitation

OBJECTIVE To identify the exercise echocardiographic determinants of long-term functional capacity, in patients with chronic ischemic mitral regurgitation, after restrictive mitral valve annuloplasty (RMA) or mitral valve replacement (MVR). METHODS We retrospectively analyzed 121 patients with significant chronic ischemic mitral regurgitation, who underwent RMA (n = 62) or MVR (n = 59), between 2005 and 2011. Preoperatively, all patients underwent a resting echocardiographic examination, and a 6-minute walking test (6-MWT) to measure distance. Resting and exercise stress echocardiography, and the 6-MWT were repeated at 41 ± 16.5 months. RESULTS After surgery, the 6-MWT distance significantly improved in the MVR group, and decreased in the RMA group (+37 ± 39 m vs -24 ± 49 m, respectively; P < .0001). Exercise indexed effective orifice area was significantly higher in the MVR, versus the RMA, group (MVR: change from 1.3 ± 0.2 cm(2)/m(2) to 1.5 ± 0.3 cm(2)/m(2); RMA: change from 1.1 ± 0.3 cm(2)/m(2) to 1.2 ± 0.3 cm(2)/m(2); P = .001). The mean mitral gradients significantly increased from rest to exercise, in both groups, but to a greater extent in the RMA group (change from 4.4 ± 1.4 to 11 ± 3.6 mm Hg; MVR: change from 4.3 ± 1.8 to 9 ± 3.5 mm Hg; P = .006). On multivariate analysis, MVR and exercise indexed effective orifice area were the main independent determinants of postoperative 6-MWT. In the RMA group, 25 patients experienced late mitral regurgitation recurrence, severe in 9 (14%) of them. The rate of postoperative cardiovascular events was significantly higher in the RMA group (21% vs MVR: 8%; P = .03). Follow-up survival was 83% in the RMA group and 88% in the MVR group (P = .54). CONCLUSIONS For chronic ischemic mitral regurgitation, MVR versus RMA was associated with better postoperative exercise hemodynamic performance and long-term functional capacity.

Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides

The autonomic nervous system, the renin–angiotensin–aldosterone system, and the natriuretic peptide system represent critical regulatory pathways in heart failure and as such have been the major targets of pharmacological development. The introduction and approval of angiotensin receptor neprilysin inhibitors (ARNi) have broadened the available drug treatments of patients with chronic heart failure with reduced ejection fraction. Neprilysin catalyses the degradation of a number of vasodilator peptides, including the natriuretic peptides, bradykinin, substance P, and adrenomedullin, as well as vasoconstrictor peptides, including endothelin‐1 and angiotensin I and II. We review the multiple, potentially competing, substrates for neprilysin inhibition, and the resultant composite clinical effects of ARNi therapy. A mechanistic understanding of this novel therapeutic class may provide important insights into the expected on‐target and off‐target effects when this agent is more widely prescribed.

Novel approaches to the post-myocardial infarction/heart failure neural remodeling

The review aims to discuss the role of nerve growth factor (NGF) as a potential novel biomarker in post-myocardial infarction (MI) and in heart failure (HF), with a specific focus on neural remodeling and sprouting processes occurring after tissue damage. Many experimental data show that MI induces nerve sprouting, leading to increased sympathetic outflow and higher risk of ventricular arrhythmias and sudden cardiac death. In this framework, cardiac and circulating NGF might be an indicator of the innervation process and neural remodeling: it dramatically increases after MI, while it declines along with advanced HF and ventricular dysfunction. The bimodal behavior of NGF in acute and chronic settings leads to the speculation that NGF modulation may be a pharmacological target for intervention in different stages of the ischemic heart disease. Specifically, a fascinating possibility is to support or to inhibit NGF receptors, in order to prevent negative cardiac remodeling after MI and consequent ventricular dysfunction.

Ranolazine in Heart Failure With Preserved Left Ventricular Ejection Fraction and Microvascular Dysfunction: Case Report and Literature Review

Heart failure with a normal or nearly preserved left ventricular (LV) ejection fraction (HFpEF) may represent more than 50% of heart failure cases. Despite HFpEF is being increasingly recognized, there is still a lack of information regarding of its potential pharmacological treatment. Patients with HFpEF are more frequently elderly, female, hypertensive and diabetic. Microvascular dysfunction (MVD) may be involved during the development of HFpEF mainly because of comobidities including hypertension and diabetes. Diastolic dysfunction is seen in 30–70% of patients with type 2 diabetes: the likely mechanisms include altered endothelial function, defective energy metabolism, and microvascular disease. MVD is also estimated to be more common in women. Women with angina, evidence of ischemia by stress testing, and no obstructive coronary artery disease (CAD) by angiography frequently have MVD which carries an adverse prognosis for cardiovascular events including myocardial infarction, stroke, heart failure, and sudden cardiac death. There are an estimated 2–3 million women in the United States with MVD: in this patient population persistent angina, despite treatment with nitrates, beta‐ blockers, and calcium channel blockers, remains a therapeutic challenge. MVD and myocardial ischemia are known to be associated with reduced adenosine triphosphate fluxes and decreased energy supply, resulting in disturbances of intracellular ion homeostasis of cardiac myocites. Disruption of this electrolyte balance leads to abnormally elevated intracellular levels of sodium and calcium, which are thought to contribute to the discrepancy between myocardial oxygen demand and supply. The increase of intracellular sodium concentrations is mediated by either late activation or failing channel closure of the inward sodium current (INa), which mainly happen in pathological states, such as ischemia, oxidative stress, myocardial stretch, and left ventricular hypertrophy. Previous studies demonstrated that the increase of sodium current is mainly associated to a reduced net cytosolic calcium efflux, leading to higher degree of diastolic stiffness, diastolic coronary vascular compression and, consequently, diastolic dysfunction. Ranolazine reduces the sodium‐dependent calcium overload via inhibition of the late INa and thus improves diastolic tone and oxygen handling during myocardial ischemia. This molecular mechanism is associated to a symptomatic relief of chronic angina without affecting heart rate or systolic blood pressure, therefore ranolazine has been widely used for ischemic patients not only as an add‐on therapy. New experimental studies in mouse models documented a potential role of ranolazine in reversing diastolic dysfunction oxidative stress‐mediated, showing a direct effect on myofilaments and contractile apparatus. So far, no data have been published on the influence of ranolazine in HFpEF and MVD. In this case report, we describe the beneficial effect of ranolazine in an ischemic HFpEF patient symptomatic for dyspnea. The Journal of Clinical Pharmacology 53(6) 665–669

Global Longitudinal Strain in master athletes and in hypertensive patients with the same degree of septal thickness.

Athletes may have electrocardiogram (ECG) repolarization abnormalities during stress test suggestive for ischemia in the absence of ischemic coronary artery disease, often in a setting of myocardial septum hypertrophy. Global longitudinal strain (GLS) might be altered in these athletes compared to hypertensive patients with the same degree of septal thickness. About 735 consecutive athletes were screened for mandatory assessment of fitness to participate in competitive sports. At the stress test, 23 (19 M, 4 F) were found to have ECG repolarization abnormalities suggestive for ischemia in the presence of normal coronary vessels. They were matched to a control group of 23 hypertensive patients with no ECG abnormalities during stress test and the same degree of septal thickness. A transthoracic echocardiography for evaluation of global longitudinal strain (GLS) was performed. Interventricular septum thickness (IST) and relative wall thickness (RWT) were also calculated. A preserved ventricular function was seen in both groups (64 ± 8% in cases vs 60 ± 6% in controls, P = 0.42). IST and RWT were not significantly different. GLS was significantly lower in athletes vs hypertensive patients (−18.7 ± 2.5 vs −21.67 ± 0.27, P = 0.001). In athletes with septal hypertrophy and a positive stress test not associated to coronary disease, GLS is lower with respect to a population of hypertensive patient with the same degree of septal hypertrophy. Further investigations in a larger population are required to better define the potentiality of GLS in differentiating pathological vs physiological septum hypertrophy.

Echocardiographic outflow pump ramp test in centrifugal-flow left ventricular assist device

This study sought to develop a novel echocardiogram outflow ramp test to detect device malfunctions in centrifugal-flow left ventricular assist devices (LVADs). This new ramp pump test is based on the direct analyses of systolic and diastolic ratio (S/D) Doppler velocity in the outflow cannula in the HeartWare LVAD during progressive increases in speed. The results showed that in patients with normal pump function, the Doppler velocity S/D ratio gradually decreased during LVAD speed increases. This test is easily performed and seems promising to detect normal pump function in patients assisted by a centrifugal flow LVAD.

Leadless pacemaker implantation in a patient with complex congenital heart disease and limited vascular access

Management of rhythm related issues might be particularly challenging in patients with congenital heart disease due to complex anatomy and restricted vascular access. The leadless technology appears a suitable and attractive alternative for this population. We describe a patient with single ventricle physiology who successfully underwent implantation of a leadless pacemaker.