The Intra-Aortic Balloon Pump

Cardiogenic shock remains one of the most challenging clinical syndromes in modern medicine. Mechanical support is being increasingly used in the ...

University of Nebraska Medical Center

Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1β isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7-14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans.

Effects of neuregulin GGF2 (cimaglermin alfa) dose and treatment frequency on left ventricular function in rats following myocardial infarction.

Pulmonary Hypertension in Left Ventricular Dysfunction: Still Numerous Unanswered Questions.

Inflammation is an increasingly recognized hallmark of pulmonary hypertension (PH). Statins have been shown to attenuate key pathologic mechanisms via pleiotropic effects in animal models. However, clinical benefit of statins in patients with PH is unknown and their effect on mortality has not been studied. We performed a retrospective analysis of patients between January 2002 to January 2012, with severe PH (pulmonary artery systolic pressure ≥60 mmHg) and preserved left ventricular function (ejection fraction ≥50%), defined by transthoracic echocardiograms. Patients were divided into two groups based on statin therapy for 12 consecutive months after diagnosis of PH. Propensity score matching was performed. Subgroup analysis was done based on COPD status. Study endpoint was 1-year all-cause mortality and hospitalization. 2363 patients (age 71 ± 16; 31% male) were included; 140 (6%) were on statin therapy. Overall 1-year mortality was 34%. Following propensity score matching, 138 patients were included in the statin group and 624 patients in the no-statin group; all-cause mortality was significantly lower in the statin group compared with the no-statin group [15.2 vs. 33.8%, HR 0.42 (95% CI 0.27, 0.66), p < 0.001], but hospitalization was comparable between two groups. After stratifying patients based on COPD status, patients with COPD showed a marginally significant survival benefit from statins [HR 0.53 (95% CI 0.26, 1.10), p = 0.09]; and statins significantly reduced 1-year all-cause mortality in patients without COPD [HR 0.36 (95% CI 0.19, 0.67), p = 0.001]. We found no significant difference in the effect of statins on patients with COPD compared to those without (p = 0.16). Statin therapy is associated with reduced mortality risk in patients with severe PH and preserved left ventricular function. This beneficial effect was not found to be dependent on COPD status. These novel findings should be confirmed in large randomized trials.

Statin therapy improves survival in patients with severe pulmonary hypertension: a propensity score matching study.

Left ventricular assist device (LVAD) deactivation may be considered in cases of left ventricular recovery, pump thrombosis, infection, and end-of-life palliation. Surgical pump explantation remains the principal method, but percutaneous deactivation presents a safe and effective alternative. We have developed a formal program for percutaneous LVAD deactivation within our advanced heart failure program including patient selection criteria, preprocedure testing, a procedural algorithm, and a postprocedure care plan. Patient selection for percutaneous LVAD deactivation required review by an interdisciplinary heart transplant team including reason for deactivation, cardiac function, surgical risk, and patient preference. All candidates underwent LVAD ramp studies with both transthoracic echocardiography and right heart catheterization assessment. Deactivation was performed under general anesthesia with transesophageal echocardiography guidance. Three Amplatzer Vascular Plug IIs (Abbott, St. Paul, MN) were deployed in the LVAD outflow cannula with the proximal edge of the third plug aligned with the aortic anastomosis of the graft as guided by angiography and 3-dimensional transesophageal echocardiography. In a separate procedure, the LVAD drive line was transected below the skin, which was closed surgically over the driveline stump. Anticoagulation was continued for at least 3 months. Since initiation in January 2017, our program has performed 7 percutaneous LVAD deactivation procedures. All procedures have been successful, 5 of the patients remain medically managed, and 2 have proceeded to heart transplant. Percutaneous LVAD deactivation provides an alternative to surgical explantation. A percutaneous LVAD deactivation program is an important component of an advanced heart failure program.

Percutaneous Deactivation of Left Ventricular Assist Devices.

Pulmonary arterial hypertension (PAH) is a vascular disorder associated with high morbidity and mortality rate and is characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in right ventricular failure and death. Over the past few decades, significant advances in the understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary arterial hypertension have occured. This has led to the development of disease specific treatment including prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators. These therapies significantly improve exercise capacity, quality of life, pulmonary hemodynamics, but none of the current treatments are actually curative and long-term prognosis remains poor. Thus, there is a clear need to develop new therapies. Several potential pharmacologic agents for the treatment of pulmonary arterial hypertension are under clinical development and some promising results with these treatments have been reported. These agents include tyrosine protein kinase inhibitors, rho-kinase inhibitors, synthetically produced vasoactive intestinal peptide, antagonists of the 5-HT2 receptors, and others. This article will review several of these promising new therapies and will discuss the current evidence regarding their potential benefit in pulmonary arterial hypertension.

Article	Year
Effects of neuregulin GGF2 (cimaglermin alfa) dose and treatment frequency on left ventricular function in rats following myocardial infarction. European journal of pharmacology\| PubMed ID: 27993643	2017
Pulmonary Hypertension in Left Ventricular Dysfunction: Still Numerous Unanswered Questions. Journal of cardiac failure\| PubMed ID: 28126498	2017
Statin therapy improves survival in patients with severe pulmonary hypertension: a propensity score matching study. Heart and vessels\| PubMed ID: 28303379	2017
Percutaneous Deactivation of Left Ventricular Assist Devices. Seminars in thoracic and cardiovascular surgery\| PubMed ID: 32057968	2020
Pulmonary arterial hypertension specific therapy: The old and the new. Pharmacology & therapeutics\| PubMed ID: 32417272	2020

Ronald L. Zolty

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