Platelet-derived growth factor-AB improves scar mechanics and vascularity after myocardial infarction

2020 ◽  
Vol 12 (524) ◽  
pp. eaay2140 ◽  
Author(s):  
Sujitha Thavapalachandran ◽  
Stuart M. Grieve ◽  
Robert D. Hume ◽  
Thi Yen Loan Le ◽  
Kalyan Raguram ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Ventricular Arrhythmias ◽  
Wound Repair ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Balloon Occlusion ◽  
Platelet Derived Growth Factor ◽  
Functional Improvement ◽  
Ventricular Compliance

Therapies that target scar formation after myocardial infarction (MI) could prevent ensuing heart failure or death from ventricular arrhythmias. We have previously shown that recombinant human platelet-derived growth factor-AB (rhPDGF-AB) improves cardiac function in a rodent model of MI. To progress clinical translation, we evaluated rhPDGF-AB treatment in a clinically relevant porcine model of myocardial ischemia-reperfusion. Thirty-six pigs were randomized to sham procedure or balloon occlusion of the proximal left anterior descending coronary artery with 7-day intravenous infusion of rhPDGF-AB or vehicle. One month after MI, rhPDGF-AB improved survival by 40% compared with vehicle, and cardiac magnetic resonance imaging showed left ventricular (LV) ejection fraction improved by 11.5%, driven by reduced LV end-systolic volumes. Pressure volume loop analyses revealed improved myocardial contractility and energetics after rhPDGF-AB treatment with minimal effect on ventricular compliance. rhPDGF-AB enhanced angiogenesis and increased scar anisotropy (high fiber alignment) without affecting overall scar size or stiffness. rhPDGF-AB reduced inducible ventricular tachycardia by decreasing heterogeneity of the ventricular scar that provides a substrate for reentrant circuits. In summary, we demonstrated that rhPDGF-AB promotes post-MI cardiac wound repair by altering the mechanics of the infarct scar, resulting in robust cardiac functional improvement, decreased ventricular arrhythmias, and improved survival. Our findings suggest a strong translational potential for rhPDGF-AB as an adjunct to current MI treatment and possibly to modulate scar in other organs.

scholarly journals Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy

2021 ◽  
Vol 10 (13) ◽  
pp. 2968
Author(s):  
Alessandro Bellis ◽  
Giuseppe Di Gioia ◽  
Ciro Mauro ◽  
Costantino Mancusi ◽  
Emanuele Barbato ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Reperfusion Injury ◽  
Therapeutic Strategy ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
St Elevation Myocardial Infarction ◽  
Ischemic Time ◽  
St Elevation

The significant reduction in ‘ischemic time’ through capillary diffusion of primary percutaneous intervention (pPCI) has rendered myocardial-ischemia reperfusion injury (MIRI) prevention a major issue in order to improve the prognosis of ST elevation myocardial infarction (STEMI) patients. In fact, while the ischemic damage increases with the severity and the duration of blood flow reduction, reperfusion injury reaches its maximum with a moderate amount of ischemic injury. MIRI leads to the development of post-STEMI left ventricular remodeling (post-STEMI LVR), thereby increasing the risk of arrhythmias and heart failure. Single pharmacological and mechanical interventions have shown some benefits, but have not satisfactorily reduced mortality. Therefore, a multitarget therapeutic strategy is needed, but no univocal indications have come from the clinical trials performed so far. On the basis of the results of the consistent clinical studies analyzed in this review, we try to design a randomized clinical trial aimed at evaluating the effects of a reasoned multitarget therapeutic strategy on the prevention of post-STEMI LVR. In fact, we believe that the correct timing of pharmacological and mechanical intervention application, according to their specific ability to interfere with survival pathways, may significantly reduce the incidence of post-STEMI LVR and thus improve patient prognosis.

scholarly journals Myocardial Connective Tissue Growth Factor (CCN2/CTGF) Attenuates Left Ventricular Remodeling after Myocardial Infarction

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e52120 ◽  
Author(s):  
Jørgen Gravning ◽  
Stein Ørn ◽  
Ole Jørgen Kaasbøll ◽  
Vladimir N. Martinov ◽  
Cord Manhenke ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Tissue Growth

Abstract 5362: Inhibition Of The Epidermal Growth Factor Receptor Transactivation By The Angiotensin II Type I Receptor Prevents Compensatory Cardiac Hypertrophy And Worsens Cardiac Function Following Myocardial Infarction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jonathan Galeotti ◽  
Chiao Po Hsu ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Myocardial Infarction ◽  
Epidermal Growth Factor Receptor ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Cardiac Function ◽  
Growth Factor Receptor ◽  
Left Ventricular ◽  
Type I ◽  
Epidermal Growth ◽  
Tibia Length

The angiotensin II type I receptor (AT1R) has been shown to activate the epidermal growth factor receptor (EGFR). However, the downstream effects of this activation have not yet been elucidated in the heart. To examine the function of the AT1R-EGFR pathway, we have created an AT1R mutant in which amino acid 319 is mutated from tyrosine to phenylalanine (Y319F). The Y319F mutant lacks the ability to transactivate the EGFR. We generated transgenic lines overexpressing either wild type AT1R (Tg-WT) or Y319F (Tg-Y319F) only in the heart with similar levels of overexpression, and evaluated the contribution of the AT1R-EGFR pathway to cardiac responses against stress. Under baseline conditions at 3 months of age, cardiac function of Tg-WT and Tg-Y319F was not significantly different from non-transgenic mice (NTg) except that Tg-WT showed mild left ventricular hypertrophy. To examine the role of the AT1R-EGFR pathway under stress, we induced myocardial infarction (MI) by permanently ligating the left anterior descending coronary artery. Four weeks after MI, increases in heart weight/tibia length (Tg-WT, Tg-Y319F, NTg: 12.57, 10.11, 9.96, p<0.05 vs Tg-WT) and left ventricular myocyte cross sectional area (35, 5, 29% vs sham, p<0.05) were significantly attenuated in Tg-Y319F compared to Tg-WT. Fibrosis was also milder in Tg-Y319F than in Tg-WT (10.7% vs 22.9%). These results suggest that the AT1R-EGFR pathway plays an important role in mediating LV hypertrophy and fibrosis after MI. Interestingly, however, echocardiographic measurement showed that Tg-Y319F have impaired LV ejection fraction (Tg-WT, Tg-Y319F, NTg: 51, 19, 44%, p<0.05) and %fractional shortening (21.4, 6.7, 17.7%, p<0.05) compared with Tg-WT or NTg. Tg-Y319F showed an increase in mortality in days 0–28 following MI, when compared to Tg-WT and NTg (35, 67, 30%, p<0.5). Additionally, lung weight/tibia length was increased in Tg-Y319F (11.3, 24.7, 16.1, p<0.05) These results suggest that the lack of EGFR activation causes cardiac dysfunction after MI. In summary, transactivation of the EGFR following MI may play a compensatory role, thereby protecting the heart from further deterioration of cardiac function. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

Psychological factors and survival in the cardiac arrhythmia suppression trial (CAST): a reexamination

1997 ◽  
Vol 6 (2) ◽  
pp. 116-126 ◽  
Author(s):  
SA Thomas ◽  
E Friedmann ◽  
F Wimbush ◽  
E Schron
Keyword(s):  
Myocardial Infarction ◽  
Life Events ◽  
Cardiac Arrhythmia ◽  
Ventricular Arrhythmias ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Physiological Status ◽  
Cardiac Arrhythmia Suppression Trial ◽  
Past Life

BACKGROUND: Evaluating the independent effects of psychosocial and physiological factors on survival of cardiac patients is difficult because it requires obtaining extensive physiological and psychosocial data and long-term follow-up of high-risk patients. OBJECTIVES: To examine the independent contributions of psychosocial and physiological status to survival of patients who had had myocardial infarction. METHODS: The sample consisted of 348 patients in the Cardiac Arrhythmia Suppression Trial who had asymptomatic ventricular arrhythmias after myocardial infarction. Psychosocial status was assessed with the Social Support Questionnaire-6, Social Readjustment Rating Scale, State-Trait Anxiety Inventory, Self-Rating Depression Scale, Jenkins Activity Survey, and Expression of Anger Scale. Physiological data included measurement of left ventricular ejection fraction; history of previous myocardial infarction, congestive heart failure, and diabetes; and results of Holter monitoring. RESULTS: At the first follow-up, after the effect of the physiological predictors was controlled for, psychosocial factors were significant independent predictors of survival. Among men in the nonactive medication group (n = 263), higher state anxiety, lower anger outward, more past life events, and lower expectations of future life events were predictors of mortality. Data suggested that the relationship of anger to mortality might differ for men and women. Increases in past life events and depression from baseline to first follow-up were greater among those who died than among those who lived. CONCLUSION: Among patients who had asymptomatic ventricular arrhythmias after myocardial infarction, psychological status during the period after infarction contributed to mortality beyond the effect of physiological status. The results reaffirm the critical interrelationship between mind and body for cardiovascular health.

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