**3. Micronutrient effects and metabolism-targeting drug effects**

Micronutrient deficiency is associated with heart failure and is a potential cause of cardiomyopathy. Low vitamin D levels are known to be associated with cardiomyopathy though the mechanism by which vitamin D affects the heart is not fully understood. Vitamin D is known to have an antihypertrophic effect. Vitamin D deficient rats have been shown to have smaller myofibrils than vitamin D sufficient rats. Additionally, vitamin D helps to regulate the expression of MMP's and tissue inhibitors of metalloproteinases (TIMP's). Imbalance in their expression is associated with diastolic and systolic dysfunction [72]. Vitamin D levels are also thought to regulate heart energy metabolism and intracellular calcium handling [73]. Of note, Vitamin D deficits have been strongly identified with morbidity and mortality associated with SARS-2 COVID19 [74]. While COVID19 mortality is not exclusively a cardiovascular event, neither can substantial cardiovascular compromise be excluded as a significant contributing factor, simply suggesting that at least some micronutrient deficiencies likely are emerging as cardiovascular risk factors of note for the future. Consistent with that impression, thiamine deficiency deprives the heart of ATP and can lead to heart failure. Thiamine is an essential cofactor for aerobic metabolism, for example, as a cofactor for the pyruvate dehydrogenase complex.

CoQ10 deficiency may also be capable of causing cardiomyopathy, as it is involved in energy metabolism, stabilization of the cellular membrane, and has antioxidant effects [75]. Blood levels of CoQ10 have been reported to be low in patients taking statin class drugs. Statins are some of the most commonly prescribed drugs to manage risk of ischemic cardiovascular disease, and a recent meta-analysis indicated that

CoQ10 supplementation reduces the risk of Statin-induced peripheral myopathies (muscle weakness, muscle cramp, muscle tiredness) but without changes in creatine kinase levels [76]. Interestingly, while the peripheral myopathies are a known complication of statin therapy, there are few studies specifically questioning whether a cardiomyopathy could also develop in a subset of patients on statins. A recent study examined the potential relationship between heart failure and long-term statin use and reported a statin-associated cardiomyopathy that responded to discontinuation of the statin combined with CoQ10 supplementation. After a mean follow-up of 2.8 years, 34% had normalized diastolic dysfunction, and 25% showed improvement [77]. While encouraging that the adverse outcomes were somewhat reversible, the results also indicate that over 40% of the patients did not improve and had lasting deleterious cardiac effects at least partially attributable to statin therapy originally prescribed to prevent cardiovascular disease [77].

In a similar vein, thiazolidinediones (TZDs) are PPARg agonists used in the treatment of type II diabetes mellitus (DMTII). To the extent that DMTII is one of strongest predictors of cardiovascular risk overall, it makes sense that these would be beneficial drugs for reducing the risk, especially for ischemic heart diseases, and the drugs are effective in that regard. However, in the event an ischemic event occurs anyway, therapeutic doses of TZDs are associated with impaired recovery and increased mortality [78]. Experimental studies indicate that excess stimulation of fatty acid metabolism by upregulating PPAR signaling restricts the heart from transitioning away from fatty acid as a substrate in the setting of ischemia, augmenting injury and subsequent dysfunction [79]. In addition to findings associated with therapeutic doses, there also can be a direct cardiotoxicity associated with TZDs at supratherapeutic levels. At least some of the cardiotoxicity is not PPAR related but remains metabolic/mitochondrial in origin [78]. Thiazolidinediones also bind off-target sites that contribute to the cardiotoxic effects. These off-target sites include mitoNEET, mitochondrial pyruvate carrier 2 (Mpc-2), mitochondrial and cytoplasmic dehydrogenases, ion channels, and enzymes and modulators involved in glucose homeostasis and energy production. MitoNEET is an iron–sulfur cluster transporter on the outer mitochondrial membrane that inhibits mitochondrial iron transport. Altering expression of mitoNEET has been shown to affect ROS levels and damage induced by ROS [78].

Similarly, Rosiglitazone, another DMTII drug, also causes myocardial energy deficiency and oxidative stress in a PPARg-independent mechanism via inhibition of complex I and complex IV of the electron transport chain, resulting in an increase in the NADH/NAD ratio and a reduction in ATP synthesis. Additionally, rosiglitazone potentially decreases mitochondrial ROS-scavenging capacity and increases phosphorylation of p38-MAPK via a PPARg-independent mechanism, as well as inhibiting NF-κB activity, which all can contribute to cardiac hypertrophy [78].

Together, these findings suggest that a host of mechanisms can contribute to adverse cardiovascular outcomes. Many of them impact mitochondrial function, with consequences including excess ROS oxidative stress, decreased capacity to buffer the oxidative stress, energy depletion, and increased apoptosis. In some cases, the cardiovascular risks are unavoidable, but if they could be managed better, the therapeutic efficacy of the drugs might be improved. While managing dosing based on known toxicities and the emergence of symptoms works in some cases, in many cases the emergence of symptoms can be quite delayed, or in some cases, associated with beneficial outcomes in some other aspect of cardiovascular risk. What is increasingly clear is an appreciation that a need for a more sophisticated approach to anticipation and surveillance of cardiovascular risk is emerging.
