Inappropriate sinus tachycardia (IST) is a clinical syndrome lacking formal diagnostic criteria. It is generally defined as an elevated resting heart rate (HR; >90-100 bpm) with an exaggerated response to physical or emotional stress and a clearly sinus mechanism. Clinical manifestations are broad from a complete lack of symptoms to incapacitating incessant tachycardia. Now understood to be relatively prevalent, it is observed to have a generally benign prognosis, though symptoms may persist for years. Whether IST is a single discrete entity or a heterogeneous condition with overlap to other syndromes such as postural orthostatic tachycardia syndrome remains a matter of debate.

OBJECTIVE

Many societies recommend using estimated glomerular filtration rate (eGFR) rather than serum creatinine (sCr) to determine metformin eligibility. We examined the potential impact of these recommendations on metformin eligibility among U.S. adults.

RESEARCH DESIGN AND METHODS

Metformin eligibility was assessed among 3,902 adults with diabetes who participated in the 1999-2010 National Health and Nutrition Examination Surveys and reported routine access to health care, using conventional sCr thresholds (eligible if <1.4 mg/dL for women and <1.5 mg/dL for men) and eGFR categories: likely safe, ≥45 mL/min/1.73 m(2); contraindicated, <30 mL/min/1.73 m(2); and indeterminate, 30-44 mL/min/1.73 m(2)). Different eGFR equations were used: four-variable MDRD, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine (CKD-EPIcr), and CKD-EPI cystatin C, as well as Cockcroft-Gault (CG) to estimate creatinine clearance (CrCl). Diabetes was defined by self-report or A1C ≥6.5% (48 mmol/mol). We used logistic regression to identify populations for whom metformin was likely safe adjusted for age, race/ethnicity, and sex. Results were weighted to the U.S. adult population.

RESULTS

Among adults with sCr above conventional cutoffs, MDRD eGFR ≥45 mL/min/1.73 m(2) was most common among men (adjusted odds ratio [aOR] 33.3 [95% CI 7.4-151.5] vs. women) and non-Hispanic Blacks (aOR vs. whites 14.8 [4.27-51.7]). No individuals with sCr below conventional cutoffs had an MDRD eGFR <30 mL/min/1.73 m(2). All estimating equations expanded the population of individuals for whom metformin is likely safe, ranging from 86,900 (CKD-EPIcr) to 834,800 (CG). All equations identified larger populations with eGFR 30-44 mL/min/1.73 m(2), for whom metformin safety is indeterminate, ranging from 784,700 (CKD-EPIcr) to 1,636,000 (CG).

CONCLUSIONS

The use of eGFR or CrCl to determine metformin eligibility instead of sCr can expand the adult population with diabetes for whom metformin is likely safe, particularly among non-Hispanic blacks and men.

The surface electrocardiogram (ECG) holds many clues with regard to the etiology of bradycardia and site of atrioventricular (AV) block. Bedside maneuvers may prove helpful in cases of 2:1 AV block or situations where the data is not all concordant. Wenckebach conduction may occur in any region of the heart, and there are nonpathologic mimickers of Mobitz II AV block as well. The surface ECG may aid in the inference of etiology for better than expected or slowed rather than blocked AV conduction. Sinus node dysfunction may present in several forms and often accompanies other conduction system disease. On occasion invasive studies may be required to help elucidate the mechanism of bradycardia.

Ischemia-reperfusion injury (IRI) occurs when blood returns to tissues following a period of ischemia. Reintroduction of blood flow results in the production of free radicals and reactive oxygen species that damage cells. Skeletal muscle IRI is commonly seen in orthopedic trauma patients. Experimental studies in other organ systems have elucidated the importance of extracellular and intracellular matrix metalloproteinase-2 (MMP-2) isoforms in regulating tissue damage in the setting of oxidant stress resulting from IRI. Although the extracellular full-length isoform of MMP-2 (FL-MMP-2) has been previously studied in the setting of skeletal muscle IRI, studies investigating the role of the N-terminal truncated isoform (NTT-MMP-2) in this setting are lacking. In this study, we first demonstrated significant increases in FL- and NTT-MMP-2 gene expression in C2C12 myoblast cells responding to re-oxygenation following hypoxia in vitro. We then evaluated the expression of FL- and NTT-MMP-2 in modulating skeletal muscle IRI using a previously validated murine model. NTT-MMP-2, but not FL-MMP-2 expression was significantly increased in skeletal muscle following IRI. Moreover, the expression of toll-like receptors (TLRs) -2 and -4, IL-6, OAS-1A, and CXCL1 was also significantly up-regulated following IRI. Treatment with the potent anti-oxidant pyrrolidine dithiocarbamate (PDTC) significantly suppressed NTT-MMP-2, but not FL-MMP-2 expression and improved muscle viability following IRI. This data suggests that NTT-MMP-2, but not FL-MMP-2, is the major isoform of MMP-2 involved in skeletal muscle IRI.