We studied the reaction mechanism of dopamine autoxidation using quantum chemical methods. Unlike other biogenic amines important in the central nervous system, dopamine and noradrenaline are capable of undergoing a non-enzymatic autoxidative reaction giving rise to a superoxide anion that further decomposes to reactive oxygen species. The reaction in question, which takes place in an aqueous solution, is as such not limited to the mitochondrial membrane where scavenging enzymes such as catalase and superoxide dismutase are located. With the experimental rate constant of 0.147 s−1, the dopamine autoxidation reaction is comparably as fast as the monoamine oxidase B catalyzed dopamine decomposition with a rate constant of 1 s−1. By using quantum chemical calculations, we demonstrated that the rate-limiting step is the formation of a hydroxide ion from a water molecule, which attacks the amino group that enters intramolecular Michael addition, giving rise to a pharmacologically inert aminochrome. We have shown that for dopamine stability on a time scale of days, it is essential that the pH value of the synaptic vesicle interior is acidic. The pathophysiologic correlates of the results are discussed in the context of Parkinson's disease as well as the pathology caused by long-term amphetamine and cocaine administration.

Background: Our goal was to evaluate the ability of cardiovascular magnetic resonance for detecting and predicting cardiac dysfunction in patients receiving cancer therapy. Left ventricular ejection fraction, global and regional strain utilizing fast-strain-encoded, T1 and T2 mapping, and cardiac biomarkers (troponin and BNP [brain natriuretic peptide]) were analyzed. Methods: Sixty-one patients (47 with breast cancer, 11 with non-Hodgkin lymphoma, and 3 with Hodgkin lymphoma) underwent cardiovascular magnetic resonance scans at baseline and at regular intervals during 2 years of follow-up. The percentage of all left ventricular myocardial segments with strain ≤−17% (normal myocardium [%]) was analyzed. Clinical cardiotoxicity (CTX) and sub-CTX were defined according to standard measures. Results: Nine (15%) patients developed CTX, 26 (43%) had sub-CTX. Of the 35 patients with CTX or sub-CTX, 24 (69%) were treated with cardioprotective medications and showed recovery of cardiac function. The amount of normal myocardium (%) exhibited markedly higher accuracy for the detection of CTX and sub-CTX compared with left ventricular ejection fraction, T1, and T2 mapping as well as troponin I (Δareas under the curve=0.20, 0.24, and 0.46 for normal myocardium (%) versus left ventricular ejection fraction, troponin I, and T1 mapping, P <0.001 for all). In addition, normal myocardium (%) at baseline accurately identified patients with subsequent CTX ( P <0.001), which was not achieved by any other markers. Conclusions: Normal myocardium (%) derived by fast-strain-encoded cardiovascular magnetic resonance, is an accurate and sensitive tool that can establish cardiac safety in patients with cancer undergoing cardiotoxic chemotherapy not only for the early detection but also for the prediction of those at risk of developing CTX. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03543228.

Background Cardiotoxicity during cancer treatment has become an acknowledged problem of chemotherapy medications and radiation therapy. Limitations of biomarkers and imaging tests such as echocardiography left ventricular ejection fraction (LVEF) hinder early detection of cardiotoxicity and proactive cardioprotective therapy. Once the heart is unable to compensate for subclinical dysfunction, systemic damage and remodeling occurs increasing the potential for heart failure. Fast-SENC segmental intramyocardial strain (fSENC) is a unique cardiac magnetic resonance imaging (CMR) test that regionally detects subclinical intramyocardial dysfunction in 1 heartbeat. This study evaluates the ability of fSENC to detect subclinical cardiotoxicity and manage cardioprotective therapy in cancer patients. Methods This single center, prospective Prefect Study was used to evaluate cardiotoxicity and the impact of cardioprotective therapy in Breast Cancer and Lymphoma patients (NCT03543228). fSENC was acquired with a 1.5T MRI and processed with the MyoStrain software to quantify intramyocardial strain. Segmental strain was measured in three short axis scans (basal, midventricular & apical) with 16LV/6RV longitudinal segments & three long axis scans (2-, 3-, 4-chamber) with 21LV/5RV circumferential segments. fSENC CMR was performed before chemotherapy, during and after anthracycline/taxan therapy, at 1 year follow-up, and as needed in between designated follow-up periods. Cardioprotective therapy was offered to patients meeting the definition of cardiotoxicity by the ESC Guidelines on Cardiotoxicity and/or ESMO Clinical Practice Guidelines or those observing a substantial decline in cardiac function. Comparisons were made with paired t-Test with a 95% confidence interval. Results Two hundred eight (208) CMRs were performed in fifty-two (52) patients (44 female). Patients had an average (± stdev) age of 53 (15) yrs, BMI of 26 (5) kg/m2; 77% had breast cancer, 23% had Lymphoma. fSENC CMRs required 11 (2) min total exam time. Figure 1 shows bar graphs of the % of normal LV myocardium (e.g. % LV MyoStrain Segments <−17%) at baseline and sequential follow-ups for patients without cardiotoxicity and with cardiotoxicity requiring cardioprotective therapy. Patients observing cardiotoxicity had a statistically significant decline in cardiac function measured by segmental fSENC (p=0.0002) which resolved after cardioprotective therapy. Figure 1 Conclusion Segmental fSENC intramyocardial strain detects subclinical cardiotoxicity during chemotherapy and impact of cardioprotective therapy. The ability to serve as a surrogate safety endpoint for chemotherapy or other pharmacological agents, and aid management of cardiotoxicity by serving as a surrogate efficacy endpoint for cardioprotection agents, dosage, and patient compliance may help physicians detect subclinical cardiac dysfunction, and proactively manage cancer patients to avoid early or late heart failure.

Background The incidence of cardiotoxicity during cancer therapy is underestimated due to limitations of current diagnostic tests. Current biomarkers (BNP, NT-pro-BNP, hs-Troponin, etc.) and imaging calculations (e.g. echocardiography) such as left ventricular ejection fraction (LVEF) are currently included in the guidelines to designate cardiotoxicity during cancer therapy. Unfortunately, these diagnostics identify systemic damage in symptomatic patients after the heart is unable to compensate for regional dysfunction. Fast-SENC segmental intramyocardial strain (fSENC) is a unique cardiac magnetic resonance imaging (CMR) test that regionally detects subclinical intramyocardial dysfunction in 1 heartbeat. Methods This single center, prospective Prefect Study was used to evaluate cardiotoxicity and the impact of cardioprotective therapy in Breast Cancer and Lymphoma patients (NCT03543228). fSENC was acquired with a 1.5T MRI and processed with the software to quantify intramyocardial strain. Segmental strain was measured in three short axis scans (basal, midventricular, apical) with 16 LV/6 RV longitudinal segments & three long axis scans (2-, 3-, 4-chamber) with 21 LV/5 RV circumferential segments. fSENC CMR was performed before chemotherapy, during and after anthracycline/taxane therapy, at 1 year follow-up, and as needed in between designated follow-up periods. Cardioprotective therapy was offered to patients meeting the definition of cardiotoxicity by the ESC Guidelines on Cardiotoxicity and/or ESMO Clinical Practice Guidelines or those observing a substantial decline in cardiac function. Results Two hundred eight (208) CMRs were performed in fifty-two (52) patients (44 female). Patients had an average (± stdev) age of 53 (15) yrs, BMI of 26 (5) kg/m2; 77% had breast cancer, 23% had Lymphoma. fSENC CMRs required 11 (2) min total exam time. The % of normal fSENC (segmental stain <−17%) with a threshold of 65% showed a sensitivity of 87% and specificity of 89% in detecting cardiotoxicity while echocardiography GLS with a threshold of −17% observed a sensitivity of 20% and specificity of 88%. Figure 1 shows receiver operating characteristic curves for fSENC based on the percent of normal myocardium, and echocardiography global longitudinal strain (GLS) respectively. Global fSENC had substantially lower sensitivity than segmental fSENC despite having higher accuracy than the other global metrics. Figure 1 Conclusion Segmental fSENC intramyocardial strain detects subclinical dysfunction due to cardiotoxic response of chemotherapy before other biomarkers and imaging modalities. The ability to detect the subclinical cardiotoxicity of chemotherapy agents, or other pharmacological agents that cause or worsen heart failure, enables proactive prescription of cardioprotective medications to avoid tissue remodeling that precedes systemic cardiac dysfunction and worsening of global measures such as LVEF and current biomarkers.