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The isoprenoid biosynthetic pathway leading from the production of mevalonate by HMGCoA reductase (Hmgcr) to the geranylation of the G protein subunit, Gγ1, plays an important role in cardiac development in the fly. Hmgcr has also been implicated in the release of the signaling molecule Hedgehog (Hh) from hh expressing cells and in the production of an attractant that directs primordial germ cells to migrate to the somatic gonadal precursor cells (SGPs). The studies reported here indicate that this same hmgcr→Gγ1 pathway provides a novel post-translational mechanism for modulating the range and activity of the Hh signal produced by hh expressing cells. We show that, like hmgcr, gγ1 and quemao (which encodes the enzyme, geranylgeranyl diphosphate synthetase, that produces the substrate for geranylation of Gγ1) are components of the hh signaling pathway and are required for the efficient release of the Hh ligand from hh expressing cells. We also show that the hmgcr→Gγ1 pathway is linked to production of the germ cell attractant by the SGPs through its ability to enhance the potency of the Hh signal. We show that germ cell migration is disrupted by the loss or gain of gγ1 activity, by trans-heterozygous combinations between gγ1 and either hmgcr or hh mutations, and by ectopic expression of dominant negative Gγ1 proteins that cannot be geranylated.

Background The fluoropyrimidines, 5‐fluorouracil (5‐FU) and capecitabine, are commonly used chemotherapeutic agents that have been associated with coronary vasospasm. Methods In this retrospective case‐control study, we identified patients at our institution who received 5‐FU or capecitabine in 2018. We compared characteristics of patients who experienced cardiotoxicity with controls. We described phenotypes and outcomes of cardiotoxic cases. Results We identified 177 patients who received fluoropyrimidines. After adjudication, 4.5% of the cohort met the criteria for cardiovascular toxicity. Coronary artery disease was more common among cases than controls (38% vs. 7%, p < .05). There was also a trend toward increased prevalence of cardiovascular risk factors in cases compared with controls. Most cardiotoxic cases had chest pain, although a minority of cases presented with nonischemic cardiomyopathy. Conclusion Cardiotoxicity phenotypes associated with fluoropyrimidine use are not limited to coronary vasospasm. Cardiac risk factors and ischemic heart disease were highly prevalent among patients with cardiotoxicity.

The current arsenal of cancer chemotherapy is broad and rapidly expanding and includes conventional cytotoxic agents and targeted and immune-based therapies. As cancer survival rates have improved, the acute and latent cardiotoxicities of chemotherapy have emerged as important contributors to morbidity and mortality in cancer survivors. All chemotherapeutic agents have the potential for cardiac complications, with manifestations ranging from subclinical left ventricular dysfunction and asymptomatic QT prolongation, to congestive heart failure, myocardial ischemia, myocarditis, arrhythmia, and sudden cardiac death. Efforts are ongoing to identify patients at high risk of cardiac complications and to develop evidence-based approaches to cardioprotection. In this review, we describe antitumor agents commonly associated with cardiotoxicity, with a focus on risk assessment, surveillance strategies, and pharmacologic and nonpharmacologic interventions aimed at preventing and mitigating chemotherapy-induced myocardial dysfunction.