Vittorio Emanuele Bianchi, MD

Abstract: The metabolic sources of energy for myo- cardial contractility include mainly free fatty acids (FFA) for 95%, and in lesser amounts for 5% from glucose and minimal contributions from other sub- strates such lactate, ketones, and amino acids. How- ever, myocardial efficiency is influenced by metabolic condition, overload, and ischemia. During cardiac stress, cardiomyocytes increase glucose oxidation and reduce FFA oxidation. In patients with ischemic coro- nary disease and heart failure, the low oxygen avail- ability limits myocardial reliance on FFA and glucose utilization must increase. Although glucose uptake is fundamental to cardiomyocyte function, an excessive intracellular glucose level is detrimental. Insulin plays a fundamental role in maintaining myocardial effi- ciency and in reducing glycemia and inflammation; this is particularly evident in obese and type-2 diabetic patients. An excess of F availability increase fat deposi- tion within cardiomyocytes and reduces glucose oxida- tion. In patients with high body mass index, a restricted diet or starvation have positive effects on cardiac metabolism and function while, in patients with low body mass index, restrictive diets, or starva- tion have a deleterious effect. Thus, weight loss in obese patients has positive impacts on ventricular  mass and function, whereas, in underweight heart fail- ure patients, such weight reduction adds to the risk of heart damage, predisposing to cachexia. Nutrition

Conflict of interest: The author declares no conflict of interest and no funding support to this work.

plays an essential role in the evolution of cardiovascu- lar disease and should be taken into account. An energy-restricted diet improves myocardial efficiency but can represent a potential risk of heart damage, particularly in patients affected by cardiovascular dis- ease. Micronutrient integration has a marginal effect on cardiovascular efficiency. (Curr Probl Cardiol 2020;45:100391.)Curr Probl Cardiol 2020;45:100391 0146-2806/$ see front matter

Energy Metabolism and Heart Function

he  cardiomyocyte  is  a  unique muscle  cell  which  possesses  the

tions, the contractile function is sustained by the production of adenosine

triphosphate (ATP), predominantly derived from the fatty acid oxidation (60%-90%), with the balance derived from glucose (30%-40%)¹ and a lesser contributions from lactate, ketones, amino acids, and pyruvate. Pyruvate production derives mainly from glycolysis and lactate oxidation of 10%.^2-4 The primary energy source for cardiac metabolism is supplied by free fatty acids (FFA) and by chylomicrons which cross the cell mem- brane passively or transported actively by a specific protein.⁵ In the healthy heart, although lipid oxidation represents the principal energy  source, the glucose metabolism is essential to maintain physiological car- diac function.²

Glucose uptake from cardiomyocytes is regulated mainly by Glut-4,  in response to insulin stimulation and increases during  ischemia  or  work demand (overload).⁶ Glut-4 is dependent upon activation of AMP-activated protein kinase (AMPK), nutria-sensors of the cells.⁷ Glycolysis causes the formation of pyruvate, and its oxidation is the  final step of carbohydrate (CHO) oxidation.⁸ Glucose and pyruvate oxi- dation is inhibited by FFA levels, while increased by the reduction of FFA level⁹ This interaction between fatty acids availability and glycol- ysis inhibition was first described by Randle and is called “glucose-fatty acid cycle”.¹⁰ In conditions of cardiac stress and overload, the cardio- myocyte energy source shifts towards higher utilization of glucose.

In normal cardiomyocytes, the ATP production is maintained constant by mitochondrial oxidative phosphorylation, even in the condition of overload, eg, intensive exercise or hypertension.¹¹ The increased contrac- tile force is sustained by a concomitant increase in fatty acid and carbohy- drate utilization¹² and by the nutritional state¹³ as observed during

overnutrition and restricted calorie balance that significantly changes car- diomyocyte energy metabolism.

In patients with ischemic coronary artery disease (CAD), the low oxygen availability of the myocardium is supplied by optimizing glucose utilization with an improved insulin activity and cardiomyocytes glucose sensitivity. In heart failure (HF) the global cardiac efficiency is impaired due to the reduced mitochondrial energy production¹⁷ via oxidative phosphorylation¹⁸ and these conditions favor an evolution from cardiac hypertrophy to HF.¹⁹ Glucose is the most energetically efficient substrate which is preferentially utilized dur- ing conditions of myocardial stress such as overload and HF. In these circum- stances, the increased glucose oxidation protects against acute myocardial ischemic injury.²⁰ Furthermore, in HF the myocardium metabolizes ketone bodies which become an essential fuel source for oxidative ATP production.²¹ Ketone body oxidation is metabolically more efficient than FFA oxidation²² and can acutely improve left ventricular function.²³ In the failing heart, ketones bodies represent a preferential source of energy for energy produc- tion.²¹ Although ketone bodies oxidation is a more competitive energy pathway compared with other substrates in HF, there is a great limitation due to the ketogenic diet characterized by a high fat and high protein with minimal (50 g/day) or absent intake of carbohydrates,²⁴ not at all tolerated by these patients. However, the effect of the ketogenic diet in patients with cardiovascular disease (CVD) remains to be investigated. Thus, the meta- bolic flexibility of cardiomyocyte is considerable and is responsive to changes in substrate availability and nutritional status. (Fig 1).During maximal cardiac demand, the healthy heart progressively utilizes lactate for energy.¹⁴ In the condition of cardiac stress, such as in prolonged overload and the hypertrophied heart, cardiac metabolism changes—spar- ing FFA oxidation, while increasing glucose oxidation.¹⁵ During ischemic heart conditions, glucose becomes the prevalent source of energy for myo- cardial tissue both in chronically hypertrophied and normal hearts.¹⁶ In severely ischemic hypertrophied hearts, glycogen degradation is further accelerated, and the consequent reduced CHO availability accentuates the risk of ischemia and reduced contractile performance.¹⁵

Metabolism in the Heart

FFA

FFA metabolism is less efficient energetically than glucose metabo- lism although it increases the oxygen consumption.²⁵ However, an exces- sive availability of myocardial FFA exceeds the oxidative capacity of the

FIG 1. Fatty acids are prevalently oxidized by adult heart, in diabetes, and fasting. Glucose oxi- dation is prevalent in fetal heart, hypertrophy, cardiac overload, and ischemia. During fasting are oxidized ketone bodies and amino acids.

 

myocardial tissue favoring the FFA accumulation as intramyocardial lip- ids, thus causing a “lipotoxicity,” leading to insulin resistance and impairment of the cardiac function.^26-28 A high intracellular lipids accu- mulation, as observed in type-2 diabetes, inhibits the glucose oxidation via the phosphorylation of pyruvate dehydrogenase kinase.²⁹

 

Glucose Metabolism

Glucose crosses the membrane of cardiomyocytes passively or by glu- cose transporter GLUT4 which regulates the glucose level in the cells. In

 

contrast to skeletal muscle, in cardiomyocytes, there is also a significant expression of GLUT1, which contributes to cardiac glucose uptake under certain circumstances.³⁰ Various hormones and cytokines regulate glu- cose metabolism in the myocardium contributing to the development of insulin resistance.³¹

Glucose is an oxygen sparing substrate that generates more ATP per mole of oxygen compared to fatty acids, and when the availability of oxygen is decreased, it can produce energy through glycolysis. Imaging studies using the fluorodeoxyglucose-positron emission tomography FDG-PET have shown that the ischemic myocardium in the fasting state changes the energy source switching from fatty acids to glucose. Preserving myocardial viability,³² and the degree of elevation in myocardial glucose uptake is predictive of cardiac function recovery after revascularization.³²

In patients with a nonischemic CAD, whole body substrate oxida-  tion rates did not differ from that observed in the no-CAD group.³³        In ischemic CAD patients, their myocardium will adapt to the condi-  tion of limited oxygen  availability,  although  oral  glucose  loading  does not acutely increase myocardial CHO oxidation, evidences lim-  ited metabolic flexibility. These data indicate that there is a remark-   able chronic requirement and utilization of glucose in patients with ischemic CAD.³⁴ The ability of ischemic myocardium to upregulate glucose extraction by overexpressing glucose transporters is  lim-  ited^35,36 and some evidence indicates that physiological plasma  glu-  cose levels and insulin activity are essential  to  increase  glucose delivery to tissues, thereby playing a protective  role.^37-39  In  agree-  ment with this, hypoglycemia has been shown to extend the area of necrosis in the ischemic heart,⁴⁰ and recent  trials  addressing  exces-  sive glucose reduction following the  therapy  in  type-2  diabetes patients found an increased rate of cardiovascular  events and mortal-  ity, correlated with the frequency of hypoglycemic episodes.⁴¹ How- ever, the switching from FFA to glucose substrate utilization is not completely benign. In fact, the increased use of glucose changes the glutation-related and mTOR pathways favoring hypertrophy and oxi- dative stress.⁴² Activation of mTORC1, a major regulator of  cell  growth, promotes protein synthesis and responds to  stress,  and nutrients, particularly amino acids and glucose.⁴³ AMPK is low and activated by exercise overload and ischemia and regulates the glucose uptake with an insulin-independent mechanism⁴⁴ (Fig 2).

FIG 2. Caloric restriction improves insulin sensitivity that inhibits directly the Akt/NF-kB and increase the AMPK in the cell. NF-kB inhibits phosphorylation of mTOR and reverses left ventricu- lar remodeling and cardiac function The activation of both signaling act directly on mitochondria in the cardiomyocytes. AMPK and PGC1 increase mitochondrial biogenesis and autophagy. The increased efficiency of mitochondria reduces the ROS production and improvement of cell survival and apoptosis. Prolonged starvation reduces the muscle mass and strength favoring cachexia.

 

Protein and Amino Acids

In chronic heart failure (CHF) patients, a reduced circulating level of amino acids was observed, that is correlated with HF severity.⁴⁵ Amino acids have a regulatory effect on myocardium protein turnover^46,47 and raise the oxygen consumption and glucose oxidation.⁴⁸ Amino acids have the physiological function to stimulate mitochondrial energy production under anaerobic conditions⁴⁸ and activate the protein synthesis in cardio- myocytes⁴⁷ in the presence of glucose and insulin that accelerates the for- mation of peptides chains.⁴⁹ A higher amino acid levels, more specifically branched chain amino acids (BCAA), are oxidized by the heart, and a 7% of O₂  consumption  is  required  proceeding  through  the formation of CoA derivative⁴⁹ suggesting a role as metabolic fuels and a primary anabolic effect on the human heart.⁴⁶ Amino acids avail- ability is crucial for heart and depends solely on serum amino acids lev- els.⁵⁰ Myocardial tissue uses amino acids for protein synthesis which is regulated by the availability of the circulating amino acids, by the avail- ability of oxidative substrates, by the oxygen delivery, and the availability of anabolic hormones.⁴⁷

However, recent reports found that an abnormal amino acids metabo- lism (included BCAA) were correlated with pathologic remodeling after myocardial infarction⁵¹ and a higher concentration of serum level of BCAAs was correlated with increased risk of CVD, especially stroke, in a population with high cardiovascular risk.⁵² A high level of BCAAs was correlated with cardiac diseases⁵³ and that a defect in the catabolism of BCAA is implicated in the pathogenesis of HF⁵⁴ associated with elevated oxidative stress, and profound metabolic changes in the heart. BCAA catabolism in the myocardium is an underconsidered part of metabolic dysfunction and could explain therapeutic target for the disease.

3.6 g/kg/day and lipids 1.2 g/kg/day, the level of essential and BCAAs were found extremely reduced compared to healthy (Fig 3). Nutritional intake was not responsible for the low amino acids level. However, these data show that a diet with normal caloric and protein intake in HF patients needs along much time to restore the normal circulating level of amino acids probably due to malabsorption and that protein ingestion should  beIn patients with CHF, Aquilani et al⁴⁵ found a reduced arterial amino acids levels that were correlated with the severity of left ventricular dys- function. In the study NYHA class II, III, and IV have been evaluated, and all class-patients received an adequate nutritional intake. In patients in NYHA class IV group  which  received  the  nutritional  intake  of  kcal 2132     482/day (29.2 kcal/kg/day), protein 1.3 g/kg/day and CHO

FIG 3. Serum level of total amino acids (AA), essential amino acids (essential AA) and branched chain amino acids in healthy (orange) and FH patients (blue) (from Aquilani et al⁴⁵ modified, with permission). (Color version of figure is available online.)

 

supplemented with essential amino acids. Unfortunately, in this study, the plasma level of anabolic hormones such as insulin, testosterone, estradiol, and IGF1 was not detected and this could have explained in part this aspect.

The effect of protein intake on the progression of CVD and HF remains to be fully elucidated. Epidemiologic studies have found that a high intake of protein with the diet had no deleterious effect on CVD and HF^55,56 while the greater incidence of CVD was observed in middle age women.⁵⁷ In rats with HF induced by pressure overload, a high protein intake with the diet did not affect cardiac mass, left ventricular volumes or ejection fraction, or myocardial mitochondrial oxidative capacity, but the survival was significantly reduced.⁵⁸

 

Insulin Effects on the Ischemic Heart

Insulin activity, reducing plasma glucose level, plays an important anti-inflammatory effect on the heart counteracting left ventricular and mitochondrial dysfunction in ischemic myocardial tissue, although, the complexity of insulin signaling within the myocardium is not fully eluci- dated.⁵⁹ Higher plasma glucose levels have a deleterious effect on cardiac function,⁶⁰ impairing cardiomyocytes function at the nuclear level⁶¹ and reducing diastolic and systolic function.⁶² The acute overingestion of glu- cose activates an inflammatory process and the reactive oxygen species generation⁶³ through the NF-kB (nuclear factor kB), the most sensitive transcription factor to redox signaling.⁶⁴ Glycemic control is beneficial to reduce the risk of mortality in type-2⁶⁵ and type-1 diabetes.⁶⁶ Hyperglyce- mia in the acute care setting in HF patients was associated with increased mortality. Improving glucose control and insulin sensitivity in type-1 dia- betes patients significantly reduces the risk of microvascular complications and CVD.⁶⁷ The amount of carbohydrates ingestion is extremely important in the development of the inflammatory process, which is regulated by insulin activity.⁶⁸ Insulin activity, reducing plasma glucose level, plays an important anti-inflammatory effect on the heart counteracting left ventricu- lar and mitochondrial dysfunction in ischemic myocardial tissue, although, the complexity of insulin signaling within the myocardium is not fully elu- cidated.⁵⁹ Insulin has a vasodilator effect, by increasing arterial blood flow at the microcirculatory level and stimulating nitric oxide formation,⁶⁹ which has an anti-inflammatory, antithrombotic, and antioxidant effect,⁷⁰ by modifying directly the inflammatory molecules involved in this pro- cess.⁷¹ Insulin infusion had an inhibitory effect on Reactive Oxygen Spe- cies production and NF-kB expression in obese, insulin-resistant

 

subjects.⁷² Insulin possesses anti-inflammatory effects, as documented in intensive care unit patients,⁷³ in patients who undergo to coronary artery bypass grafting,^74,75 in acute myocardial infarction^76,77 and burned patients.⁷⁸ In patients with type-2 diabetes after myocardial infarction, long-term insulin administration improved survival and reduced the inci- dence of reinfarction,⁷⁷ confirming that excessive serum glucose levels are a strong predictor of mortality. Liepinsh et al⁷⁹ demonstrated that a chronic postprandial metabolic state, characterized by insulin elevation and conse- quent increased glucose and lactate utilization, has a protective effect against myocardial infarction.

However, insulin resistance has a detrimental effect on metabolic regu- lation, is a determining factor in the development of metabolic syndrome,⁸⁰ and is correlated with left ventricular diastolic dysfunction and structural alterations.⁸¹ Insulin resistance promotes the development of HF,⁸² inde- pendently from ischemic cardiac disease.^83,84 In cardiac hypertrophy induced by pressure-overload as aortic stenosis, insulin resistance, and reduced mitochondrial oxidative capacity are the early metabolic alteration favoring the progression toward HF.⁸⁵ Experimental clinical models in humans and animals have revealed an interdependence between insulin resistance and HF.⁸⁶ Insulin resistance in HF is associated with increased serum concentrations of proinflammatory cytokines, catecholamines, cata- bolic steroids,⁸⁷ and even with reduced testosterone and adiponectin levels in males.⁸⁸ The mechanism of action of insulin is complex and well sum- marized by Riehle et al.⁵⁹ Improvement in the biologic activity of insulin, after moderate weight loss and an appropriate diet in overweight and obese patients with ischemic cardiac disease, could be part of an overall therapeu- tic strategy to improve cardiovascular function and reduce HF events.

 

Effect of Weight Loss on Heart Function

Weight loss following a restricted calorie diet in obese patients is asso- ciated with metabolic and neurohumoral adaptations that may contribute to lifespan extension.⁸⁹ Calorie restriction improves mitochondrial func- tion, DNA repair, and autophagy,⁹⁰ and stimulates stem cell regeneration. In obese subjects, many clinical studies have shown that weight reduc- tion significantly improves cardiac function (see Table). Weight loss improved both left ventricular mass and cardiac function.^91-95 In obese patients with HF, intentional weight loss increased the cardiac efficiency and the quality of life.⁹⁶ Hypocaloric diets, with carbohydrate or fat restriction, associated with modest weight loss, reduce the triglycerides depot in the cardiomyocytes by approximately 25%.⁹⁷ However, Zamora

 

 

TABLE. Effect of weight loss on cardiac functions

Authors	Patients	Age	BMI	Intervention	Duration	Effects
Utz, 2013 (106)	38	45	29	Hypocaloric diet	6 months	Weight loss reduced myocardial

triglyceride      content Guglin, 2013 (103)                         433                  56.3                 27.9                 Spontaneous           3 months                   Both RV and LV systolic function

improves              Kardassis 2012 (101)                         44                    41.5                 42.5                 Bariatric surgery       10 years                     Left ventricular volume, stroke

volume and cardiac output primarily associated with lean body mass,

Haufe, 2012 (104)	170	44	32.9	Hypocaloric diet (low	6 months	Low CHO and Low fat diet
				CHO and low fat)		improved left ventricular mass
de la Fuentes, 2009 (102)	60	47	37	Diet women: 1200-	2 years	Moderate weight loss in obese
				1500 kcal/d;		subjects is associated with
				men:1500-1800		beneficial changes in
						cardiovascular structure and
						function.
Corrao, 2000 (105)	32	45	32	Hypocaloric diet	4 months	Improvements in LV structure and

 

 

LV, left ventricular; RV, right ventricular.

function.

 

 

 

et al⁹⁸ found that the spontaneous weight loss of about 5% in patients with HF is associated with long-term mortality. These discrepancies could be explained by the different effect of nutritional intake between a balanced calorie-restricted diet and spontaneous weight loss in HF patients. In obese patients with atrial fibrillation, a long-term sustained weight has been shown to substantially reduce arrhythmia burden and maintain sinus rhythm compared to controls.⁹⁹ De Lucia et al¹⁰⁰ have recently demon- strated that a long-term calorie restricted diet in HF patients improved the cardiac sympathetic innervation and inotropic reserve. In obese (??) chronic HF patients, a weight-reducing nutritional intervention was asso- ciated with improvement in NYHA classification and decreased HF- related rehospitalization.¹⁰¹ In patients with coronary artery disease, with- out HF, Ellsworth et al¹⁰² found that a weight loss of 7%-10% determined a down-regulation of the genes which modulated the vascular endothe- lium and decreased the cardiovascular risk. After 1 year, insulin level, C- reactive protein, and leptin levels were significantly reduced, and these changes were not observed in the control group.

In patients with metabolic syndrome, the restriction of calories and car- bohydrate intake have been found to improve insulin sensitivity, post- prandial hyperglycemia, and reduce cardiovascular risk, independently of the weight loss.¹⁰³ In other studies, body fat reduction following bariatric surgery improved ventricular and overall cardiac function in type-2 dia- betes patients, also resulting in improved glycemic control.^104,105

 

Effect of Calorie Restricted Diet on Heart Function

A caloric restricted diet has a beneficial effect on metabolism reducing the development of atherosclerosis,¹⁰⁶ preventing hypertension and car- diac hypertrophy,¹⁰⁷ reducing the pathogenesis of cardiac hypertrophy pressure overload-induced.¹⁰⁸ Furthermore, caloric restriction improves myocardial function by reducing the senescent process of myocardium suppressing mTOR and increasing autophagy.¹⁰⁹ De Lucia et¹⁰⁰ demon- strated that caloric restriction in male rats with HF improved cardiac function and inotropic reserve favoring sympathetic cardiac innervation and b-adrenergic receptor levels in the myocardium. However, the antiag- ing effect of caloric restriction on the myocardium has an opposite effect in old age compared to young age subjects.¹¹⁰

Caloric restriction acts mechanistically accelerating cardiac autophagy and reducing ATP content but modulated by AMPK,¹¹¹ and short-term calorie restriction improved AMPK myocardial expression in both young and old hearts.¹¹² AMPK plays an important role in protecting cardiac

 

function and homeostasis and myocardial adaptation to starvation.¹¹¹ The AMPK signaling becomes less responsive with advancing age, and after prolonged caloric restriction leads to cellular stress and dysfunction in cardiac contractility.¹¹³

Of high relevance is the autophagic process induced by prolonged star- vation in cardiac myocytes. In cultured cardiomyocyte cells, glucose dep- rivation activates the autophagic  flux  increasing  Sirt1,  required  for  the deacetylation of FOXO1 which is essential for maintaining left ventricular function during severe caloric restriction.¹¹⁴ Metabolic remodeling at the myocardial level precedes structural alterations activating the target of rapamycin complex 1 (mTORC1), a major regulator of cell growth, resulting in increased protein synthesis and hypertrophy.¹¹⁵ Autophagy is an essential biologic mechanism to maintain cellular and tissue  renovation  and  health.¹¹⁶  The  regulation of autophagy is not only a response to the starvation but in some tis-    sue occurs actively without starvation.¹¹⁷ Metabolic alteration includ-  ing glucose and amino acids oxidation may be responsible for mitochondrial dysfunction and antecedent to HF.¹¹⁸ Excessive activa- tion of autophagic flux can favor the transition to HF.¹¹⁹

Very-low-calorie diets can also be dangerous for cardiovascular metabolism and function.¹²⁰ Van der Meer et al¹²¹ showed that in 14 healthy men a very-low-calorie diets (471 kcal/day, 50.2 g carbohydrates, protein, and 6.9 g fat) for a period of 3 days resulted in an increase in myocardial deposition of triglycerides and decreases in left ventricular diastolic function, without changes in ejection fraction. Similar results were reported by Reinolds¹²² after a 2-day fast. The increased deposition of triglycerides in cardiomyocytes is a consequence of the excessive plasma NEFA levels, as observed in type-2 diabetes and obesity.¹²⁰

 

Severely Restricted Diet and Mortality Risk

Even though weight loss has beneficial effects on cardiac function in obese patients, severely restricted diets can cause a detrimental effect on cardiac function and increase mortality risk in patients who have low body mass index (BMI)^123,124 as well as healthy adults.¹²⁴ Significant weight loss (ie, intentional or unintentional) can profoundly affect cardiac metabolism, particularly in persons with known CAD.¹²⁵ Low BMI can be associated with immobility, poor nutrition,¹²⁶ and frailty in the elderly, but is often not considered in a typical clinical evaluation.¹²⁷ Notably, some HF patients have a reduced hunger sensation, nausea, and spontane- ously restrict food intake.¹²⁸ Despite its high incidence in geriatric

 

patients, malnutrition is rarely recognized and treated¹²⁹ and is often missed as a clinical sign in patients with chronic HF.¹³⁰ Spontaneous weight loss should be treated aggressively because it represents a higher risk of muscle wasting and cachexia.¹³¹ Among healthy obese subjects, weight loss generally does not reduce mortality risk.¹³²

 

Effect of Starvation on Cardiac Function

Starvation, as observed in patients affected by anorexia nervosa, is associated with tissue alteration and many  medical  complications¹³⁶  and induces a significant  deleterious  effect  on  cardiac  function.¹³⁷  The most concerning are those related to the cardiovascular  system, such as serious arrhythmias or  structural  cardiac  alterations  which  lead to increased mortality.¹³⁸ During starvation protein and fat catab- olism are increased, which lead to loss of cellular volume and atro-     phy of various tissues, including brain, liver, intestine, kidney, and muscle, in addition to the heart muscle. Morphologic studies by ultra- sound have shown decreased cardiac mass, reduced cardiac chamber volumes, and mitral valve prolapse.^139,140  Congestive  HF  has  also  been described as a cause of  death in anorexia nervosa.¹⁴¹  Siegel et  al¹⁴² described a grossly normal heart that weighed 250 g with focal inflammation of the conduction system in association with massive weight loss due to dieting. Isner et al¹⁴³ described a reduced cardiac weight of 120-140 g, with  a grossly normal aspect. Histologically,  it  has been reported that widespread interstitial fibrosis in the papillary muscles and myxoid material deposition occurs, which can be respon- sible for rhythm disturbances in patients with anorexia nervosa.¹⁴⁴ In some anorexic patients, the cause of death was associated withProlonged calorie restriction has a deleterious effect on cardiac physi- ology and function. Cordero-Reyes et al¹³³ showed that energy starvation in HF patients caused metabolic alteration through reduced mitochondrial number but not a reduction in mitochondrial electron transport capacity. Deficient carbohydrate diets ( 800 kcal/daily) may negatively impact vascular endothelial function while maintaining recommended carbohy- drate intake generates a more favorable vascular profile.¹³⁴ In mice, a restricted caloric diet (by 40%) for 30 weeks showed a decreased ventric- ular mass and cardiomyocyte contractility, elevated phosphorylation of AMPK, and depressed phosphorylation of mTOR and ULK1.¹³⁵ These data suggest an indispensable role of AMPK in the maintenance of car- diac metabolism under prolonged caloric restriction through autophagy regulation.¹³⁵

fibrosis and myxoid material deposition which are a direct conse-  quence of starvation.¹⁴⁴  In  patients  following  severe  restrictive  diets, a mild QTc prolongation has been observed,¹⁴⁵ but  the QTc  interval  was not correlated with the disease severity¹⁴⁶ but was negatively associated with serum potassium concentrations.¹⁴⁷

Nutrition in Chronic HF Patients

In patients with chronic HF, food intake is extremely important to improve the quality of life and survival rate. Overweight and mildly obese patients with CVD, compared with underweight patients, have a better prognosis as expressed by the obesity paradox concept.¹⁴⁸ BMI has been shown to be inversely correlated with all-cause mortality,¹⁴⁹ and overall cardiovascular mortality is reduced with higher BMI.^150,151 An increase in BMI of 5 units decreases the risk of mortality by 10%.¹⁵² Notably, the mortality rate is increased at the high end of the extreme of the BMI distribution resulting in a U-shaped pattern, with increased mor- tality at both the lowest and highest BMI.^153,154

Moreover, after adjustment for confounding factors,¹⁵⁵ the group with the lowest BMI (<18) exhibited the highest mortality. The obesity para- dox could be partially explained by a significantly lower sympathetic acti- vation in obese CHF patients¹⁵⁶ (impact of visceral obesity upon the metabolic syndrome). Importantly, however, only BMI has been used as the criterion for obesity in these studies, while fat-free mass and muscle mass are arguably more important given that they are stronger predictors of LV mass than fat mass.

Macronutrient ingestion influence blood substrates which has a signifi- cant effect on the insulin-sensitive tissue.¹⁵⁷ A reduction in calorie intake exerts a profound effect on weight loss representing the principal factor of reducing all metabolic syndrome components, independent from diet composition.¹⁵⁸ Daily caloric intake of about 125 kJ/kg (=29 kcal/kg) and a daily protein intake of 1.2-1.4 g/kg body weight is recommended for elderly patients at normal weights.¹⁵⁹ In overweight and obese patients less energy intake is required (20-24 kcal/kg/day). A reduction in dietary fat intake to about 25% of total caloric intake (0.6-0.8 g/kg/day) is ade- quate because high-fat diets associated with low-carbohydrate predispose to insulin resistance.¹⁶⁰ In overweight patients, restricted calorie diets cause an improvement in insulin resistance independent of macronutrient composition. Ketogenic diets improve insulin resistance,¹⁶¹ and  low  carbohydrate  and high protein diets enhance metabolic equilibrium and reduce cardiovascular risk.¹⁶² The reduction in calorie intake is effective to

 

reduce body fat independent of diet composition, but a diet with high-CHO and low-fat composition is more effective in reducing the markers of MetS.¹⁶³ A relatively high-carbohydrate diet is suggested during submaximal exercise because it increases the rate  of  whole- body fat oxidation and reduces the rate of muscle glycogenolysis.¹⁶⁴

Weight loss induced by a very low CHO and high-saturated-fat diet is detrimental to cardiac function and has a detrimental effect on CVD risk factors.¹⁶⁵ Nilsson et al¹⁶⁶ found that a low CHO-high fat diet in mice for 2 weeks caused an increase in body fat and a reduction in lean mass; after

4 weeks cardiac function also deteriorated. Low CHO-high fat diets impair cardiomyocytes function was reduce the myocardial response to ischemia. The increased fatty acid oxidation in the presence of reduced CHO availability compromises the recovery of left ventricular function.¹⁶⁷ Also, low CHO-high fat diets have been shown to be a limiting factor in endurance athletes in whom the adaptation to training and performance benefits are negated.¹⁶⁸ Low CHO-high fat diets may have some clinical applications, but this does not appear to be the case in patients with CVD or those with dyslipidemia or insulin resistance.¹⁶⁹ In the myocardium, oxi- dation of fatty acids is inhibited proportionate to the increased availability of fatty acids causing contractile dysfunction.¹⁷⁰ This metabolic change, if protracted for an extended time (weeks or months), can cause measurable damage to the cardiac tissue causing a dramatic lipid deposition within cardiomyocytes upon fasting.

Increasing FFA oxidation results in a reduction in glucose oxidation but causes a decrease in cardiac function and efficiency.¹⁷¹ CHO metabo- lism reduces FA oxidation and cardiac alteration under stress conditions of cardiac overloads, such as exercise, hypertension, and hypertrophy.¹⁷² Improving glucose utilization by myocardial tissue is an effective strategy to prevent the progression of cardiac dysfunction such as that associated with pathologic hypertrophy.¹⁷³ A high polyunsaturated and saturated fatty acid intake was significantly associated with 1-year mortality in patients with chronic HF.¹⁷⁴ In patients without HF, higher plasma FFA were associated with a 12% higher risk of HF.¹⁷⁵

Nutritional Intake in CHF Patients

The major nutritional dysfunction in HF patients is represented by mal- nutrition. Various clinical studies have found that patients with CHF are in a prevalent malnutrition state varying from 54%¹⁷⁶ to 60%-69%,¹⁷⁷ and the prognostic value of malnutrition, assessed by the Controlling Nutritional Status, demonstrated that represent the best predictor of

 

death.^178,179 After 1-year follows up, the mortality rate was 65% between patients malnourished and frail while only 1% between those who were neither frail nor malnourished.¹⁸⁰ However, an excess of nutritional intake leads to cardiac dysfunction and HF¹⁸¹ It appears evident that an adequate nutritional intake in HF patients is recommended.

Micronutrients

Micronutrients have been proposed to have a benefit in improving clin- ical management of HF patients.¹⁸² A sodium-restricted diet (2000-4000 mg/day) with a reduction in total fluid ingestion to 1.5 l/day has been sug- gested to result in clinical improvements in HF functional class.¹⁸³ Len- nie et al¹⁸⁴ showed that higher sodium intake (more than 3 g daily) increased the risk of rehospitalization more than 2 times compared to patients with lower sodium diets. Further analysis showed no advantages related to further sodium reduction in patients with stable HF.¹⁸⁵

Omega-6 and omega-3 are essential fatty acids that mediate cellular inflammatory responses¹⁸⁶ and decrease the risk of serious arrhythmias and sudden death.¹⁸⁷ The American Heart Association has recently expanded the list of Class recommendation for Omega 3 prescription in CVD patients for their medical benefits.¹⁸⁸ Although many supplements have been suggested for HF patients including coenzyme Q10, carnitine, and vitamin D, the potential benefits to cardiac function remain to be proven.¹⁸⁹ The administration of multiple micronutrient supplementa- tions in chronic stable HF patients taken for 12 months provided no evi- dence of any benefit.¹⁸⁵

Antioxidant vitamins (vitamin C, E, and b-carotene) did not show posi- tive evidence for a protective effect on CVD and mortality.¹⁹⁰ However, the serum level of vitamin E was negatively associated with endothelin function.¹⁹¹

Coenzyme Q10 is a component of cellular membranes and is involved in the production of ATP in the mitochondria improving the electron transport chain and reducing the redox reaction. In patients with chronic HF, the administration of CoQ10 (100 mg x 3 times daily) was safe and reduced some cardiovascular complications.¹⁹² However, the beneficial effects remain uncertain, and larger randomized clinical trials on CoQ10 supplementation in patients with CVD are needed.¹⁹³ Daily intake of res- veratrol at the dose of 150 mg/daily of for 4 weeks did not improve meta- bolic markers related to cardiovascular health.¹⁹⁴ Sciatti et al¹⁹⁵ in a review evaluating the effect of micronutrients in patients with HF

concluded that a beneficial role remains to be demonstrated and large  clinical trials with a single supplement method are required.

Future Perspectives

Clinical trials in patients with HF with specific calorie-restricted diet prescription with high CHO and protein and low fats contents are neces- sary to evaluate the myocardial efficiency. A low-calorie diet of 1200-kcal/daily in obese patients was safe for a long period up to 16 weeks,¹⁹⁶ and no different effect in improving insulin resistance between high vs the low glycemic index of CHO was found.¹⁹⁷ Calorie restriction with different modalities such as intermittent fasting (60% energy restric- tion on 2 days per week) or periodic fasting (a 5-day diet providing 750- 1100 kcal) and time-restricted feeding improved insulin resistance and the risk factors for CVD¹⁹⁸ have been evaluated in healthy and over- weight human subjects with positive effects. However, further investiga- tion on the effect of a restricted calorie diet and with balanced macronutrients in patients with CVD and HF is necessary. Furthermore, in association with nutrition, the anabolic hormone level should be con- sidered at the same time.

Conclusion

Nutrition has an essential impact upon the recovery of heart func-   tion in patients with CVD and HF for improving energy metabolism   and energy transfer, and for reducing HF mortality. Macronutrients regulate cardiomyocyte activity which can be improved by the opti- mization of glucose uptake, improved insulin activity, and by reduced  fat intake. Weight loss, through excess  fat  loss,  is  useful  for  obese and type-2 diabetes patients, while some  evidence  points  to  weight loss being detrimental to underweight  patients  for  whom  mortality  risk may be increased. Thus, from a clinical perspective, dietary interventions should be personalized, based on consideration of anthropometrics data representing states of excess adiposity, under- weight, or low lean body mass.

Overweight and obese individuals should adopt a gradual restriction of calories from unhealthy fats and refined carbohydrates while main- taining lean body mass through ingestion of healthful fats, complex car- bohydrates, and appropriate protein intake consistent with body mass requirements.

Overweight and obese subjects need a calorie-restricted diet, targeted to a 40% reduction in caloric ingestion and based on basal energy

 

expenditure with high protein, low-fat composition improving insulin activity and glucose utilization by cardiomyocytes. In lean or under- weight subjects, the diet should be nutritionally balanced, and isocaloric to maintain and preserve lean body mass calorie ingestion should counter- act the risk of malnutrition to prevent cardiac cachexia and increased risk of cardiac mortality.

 

REFERENCES

1. Gertz EW, Wisneski JA, Stanley WC, et al. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest 1988;82:2017–25.
2. Stanley WC, Lopaschuk GD, McCormack JG. Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res 1997;34:25–33.
3. Carley AN, Severson DL. Fatty acid metabolism is enhanced in type 2 diabetic Biochim Biophys Acta 2005;1734:112–26.
4. Rosano GM, Fini M, Caminiti G, et al. Cardiac metabolism in myocardial

Curr Pharm Des 2008;14:2551–62.

5. Schaffer Fatty acid transport: the roads taken. Am J Physiol Endocrinol Metab

2002;282:E239–46.

6. Young LH, Coven DL, Russell RR 3rd. Cellular and molecular regulation of cardiac glucose transport. J Nucl Cardiol 2000;7:267–76.
7. Coven DL, Hu X, Cong L, et al. Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. Am J Physiol Endocrinol Metab 2003;285:E629–36.
8. Randle PJ. Fuel selection in animals. Biochem Soc Trans 1986;14:799–806.
9. Lopaschuk GD, Belke DD, Gamble J, et al. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994;1213:263–76.
10. Randle PJ, Garland PB, Hales CN, et al. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1:785–9.
11. Balaban RS, Kantor HL, Katz LA, et al. Relation between work and phosphate metabolite in the in vivo paced mammalian heart. Science 1986;232:1121–3.
12. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 2005;85:1093–129.
13. Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical Curr Probl Cardiol 1994;19:59–113.
14. Kaijser L, Berglund B. Myocardial lactate extraction and release at rest and during heavy exercise in healthy men. Acta Physiol Scand 1992;144:39–45.
15. Sambandam N, Lopaschuk GD, Brownsey RW, et al. Energy metabolism in the hypertrophied heart. Heart Fail Rev 2002;7:161–73.
16. Schonekess BO, Allard MF, Henning SL, et Contribution of glycogen and exoge- nous glucose to glucose metabolism during ischemia in the hypertrophied rat heart. Circ Res 1997;81:540–9.

 

17. Neubauer S. The failing heart—an engine out of fuel. N Engl J Med 2007;356: 1140–51.
18. Sharov VG, Todor AV, Silverman N, et al. Abnormal mitochondrial respiration in failed human myocardium. J Mol Cell Cardiol 2000;32:2361–7.
19. Rosca MG, Tandler B, Hoppel CL. Mitochondria in cardiac hypertrophy and heart J Mol Cell Cardiol 2013;55:31–41.
20. Ussher JR, Wang W, Gandhi M, et al. Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury. Cardiovasc Res 2012;94:359–69.
21. Aubert G, Martin OJ, Horton JL, et al. The failing heart relies on ketone bodies as a Circulation 2016;133:698–705.
22. Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bod- ies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resis- tance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 2004;70:309–19.
23. Zou Z, Sasaguri S, Rajesh KG, et al. dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts. Am J Physiol Heart Circ Physiol 2002;283:H1968–74.
24. Prabhakar A, Quach A, Zhang H, et al. Acetone as biomarker for ketosis buildup capability—a study in healthy individuals under combined high fat and starvation Nutr J 2015;14:41.
25. Nagoshi T, Yoshimura M, Rosano GM, et al. Optimization of cardiac metabolism in heart failure. Curr Pharm Des 2011;17:3846–53.
26. Huss JM, Kelly DP. Mitochondrial energy metabolism in heart failure: a question of J Clin Invest 2005;115:547–55.
27. An D, Rodrigues B. Role of changes in cardiac metabolism in development of dia- betic cardiomyopathy. Am J Physiol Heart Circ Physiol 2006;291:H1489–506.
28. Yagyu H, Chen G, Yokoyama M, et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest 2003;111:419–26.
29. Atherton HJ, Dodd MS, Heather LC, et al. Role of pyruvate dehydrogenase inhibi- tion in the development of hypertrophy in the hyperthyroid rat heart: a combined magnetic resonance imaging and hyperpolarized magnetic resonance spectroscopy Circulation 2011;123:2552–61.
30. Abel ED. Glucose transport in the heart. Front Biosci 2004;9:201–15.
31. Frias MA, Montessuit C. JAK-STAT signaling and myocardial glucose metabolism.

JAKSTAT 2013;2:e26458.

32. Di Carli MF, Asgarzadie F, Schelbert HR, et al. Quantitative relation between myo- cardial viability and improvement in heart failure symptoms after revascularization in patients with ischemic cardiomyopathy. Circulation 1995;92:3436–44.
33. Bressler P, Bailey SR, Matsuda M, et al. Insulin resistance and coronary artery dis- Diabetologia 1996;39:1345–50.

 

34. Hannukainen JC, Lautamaki R, Mari A, et al. Elevated glucose oxidation, reduced insulin secretion and a fatty heart may be  protective adaptions in ischemic    J Clin Endocrinol Metab 2016:jc20154091.
35. van der Meer RW, Rijzewijk LJ, de Jong HW, et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac tri- glyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation 2009;119:2069–77.
36. Liu L, Shi X, Bharadwaj KG, et al. DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity. J Biol Chem 2009;284:36312–23.
37. Hwang YC, Bakr S, Ramasamy R, et al. Relative importance of enhanced glucose uptake versus attenuation of long-chain acyl carnitines in protecting ischemic myo- Coron Artery Dis 2002;13:313–8.
38. King LM, Opie Glucose delivery is a major determinant of glucose utilisation in the ischemic myocardium with a residual coronary flow. Cardiovasc Res 1998;39:381–92.
39. Hall JL, Henderson J, Hernandez LA, et al. Hyperglycemia results in an increase in myocardial interstitial glucose and glucose uptake during ischemia. Metabolism 1996;45:542–9.
40. Libby P, Maroko PR, Braunwald E. The effect of hypoglycemia on myocardial ischemic injury during acute experimental coronary artery occlusion. Circulation 1975;51:621–6.
41. Giorgino F, Leonardini A, Laviola L. Cardiovascular disease and glycemic control in type 2 diabetes: now that the dust is settling from large clinical trials. Ann NY Acad Sci 2013;1281:36–50.
42. Schisler JC, Grevengoed TJ, Pascual F, et Cardiac energy dependence on glucose increases metabolites related to glutathione and activates metabolic genes controlled by mechanistic target of rapamycin. J Am Heart Assoc 2015;4.
43. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011;12:21–35.
44. Russell RR 3rd, Li J, Coven DL, et AMP-activated protein kinase mediates ische- mic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 2004;114:495–503.
45. Aquilani R, La Rovere MT, Corbellini D, et al. Plasma Amino Acid Abnormalities in Chronic Heart Failure. Mechanisms, Potential Risks and Targets in Human Myo- cardium Metabolism. Nutrients 2017;9.
46. Young LH, McNulty PH, Morgan C, et al. Myocardial protein turnover in patients with coronary artery disease. Effect of branched chain amino acid infusion. J Clin Invest 1991;87:554–60.
47. Morgan HE, Earl DC, Broadus A, et Regulation of protein synthesis in heart mus- cle. I. Effect of amino acid levels on protein synthesis. J Biol Chem 1971;246: 2152–62.
48. Burns AH, Reddy Amino acid stimulation of oxygen and substrate utilization by cardiac myocytes. Am J Physiol 1978;235:E461–6.

 

49. Morgan HE, Jefferson LS, Wolpert EB, et Regulation of protein synthesis in heart muscle. II. Effect of amino acid levels and insulin on ribosomal aggregation. J Biol Chem 1971;246:2163–70.
50. Schwartz RG, Barrett EJ, Francis CK, et al. Regulation of myocardial amino acid balance in the conscious dog. J Clin Invest 1985;75:1204–11.
51. Lai L, Leone TC, Keller MP, et al. Energy metabolic reprogramming in the hyper- trophied and early stage failing heart: a multisystems approach. Circ Heart Fail 2014;7:1022–31.
52. Ruiz-Canela M, Toledo E, Clish CB, et al. Plasma branched-chain amino acids and incident cardiovascular disease in the PREDIMED trial. Clin Chem 2016;62: 582–92.
53. Kato T, Niizuma S, Inuzuka Y, et al. Analysis of metabolic remodeling in compen- sated left ventricular hypertrophy and heart failure. Circ Heart Fail 2010;3:420–30.
54. Sun H, Olson KC, Gao C, et al. Catabolic defect of branched-chain amino acids pro- motes heart failure. Circulation 2016;133:2038–49.
55. He J, Wofford MR, Reynolds K, et al. Effect of dietary protein supplementation on blood pressure: a randomized, controlled trial. Circulation 2011;124:589–95.
56. Virtanen HEK, Voutilainen S, Koskinen TT, et al. Intake of different dietary pro- teins and risk of heart failure in men: the Kuopio Ischaemic heart disease risk factor Circ Heart Fail 2018;11:e004531.
57. Lagiou P, Sandin S, Lof M, et al. Low carbohydrate-high protein diet and incidence of cardiovascular diseases in Swedish women: prospective cohort study. BMJ 2012;344:e4026.
58. Ribeiro RF Jr., Dabkowski ER, O’Connell KA, et al. Effect of a high-protein diet on development of heart failure in response to pressure overload. Appl Physiol Nutr Metab 2014;39:238–47.
59. Riehle C, Abel Insulin Signaling and Heart Failure. Circ Res 2016;118:1151–69.
60. Rubin J, Matsushita K, Ballantyne CM, et Chronic hyperglycemia and subclinical myocardial injury. J Am Coll Cardiol 2012;59:484–9.
61. Clark RJ, McDonough PM, Swanson E, et Diabetes and the accompanying hyper- glycemia impairs cardiomyocyte calcium cycling through increased nuclear O- GlcNAcylation. J Biol Chem 2003;278:44230–7.
62. Tang WH, Cheng WT, Kravtsov GM, et al. Cardiac contractile dysfunction during acute hyperglycemia due to impairment of SERCA by polyol pathway-mediated oxi- dative stress. Am J Physiol Cell Physiol 2010;299:C643–53.
63. Mohanty P, Hamouda W, Garg R, et al. Glucose challenge stimulates reactive oxy- gen species (ROS) generation by leucocytes. J Clin Endocrinol Metab 2000;85:2970–3.
64. Dandona P, Aljada A, Chaudhuri A, et al. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Cir- culation 2005;111:1448–54.
65. Carrasco-Sanchez FJ, Gomez-Huelgas R, Formiga F, et al. Association between type-2 diabetes mellitus and post-discharge outcomes in heart failure patients: find- ings from the RICA registry. Diabetes Res Clin Pract 2014;104:410–9.

 

66. Lind M, Svensson AM, Kosiborod M, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med 2014;371:1972–82.
67. Secrest AM, Becker DJ, Kelsey SF, et al. Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabe- tes 2010;59:3216–22.
68. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest

2006;116:1793–801.

69. Aljada A, Dandona P. Effect of insulin on human aortic endothelial nitric oxide syn- Metabolism 2000;49:147–50.
70. Mao XM, Liu H, Tao XJ, et al. Independent anti-inflammatory effect of insulin in newly diagnosed type 2 diabetes. Diabetes Metab Res Rev 2009;25:435–41.
71. Dandona P, Chaudhuri A, Ghanim H, et al. Insulin as an anti-inflammatory and anti- atherogenic modulator. J Am Coll Cardiol 2009;53:S14–20.
72. Aljada A, Ghanim H, Mohanty P, et al. Insulin inhibits the pro-inflammatory tran- scription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibi- tor-1 (PAI-1) concentrations. J Clin Endocrinol Metab 2002;87:1419–22.
73. Langouche L, Vanhorebeek I, Vlasselaers D, et al. Intensive insulin therapy protects the endothelium of critically ill patients. J Clin Invest 2005;115:2277–86.
74. Visser L, Zuurbier CJ, Hoek FJ, et al. Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: effects on inflammatory response during coronary artery surgery. Br J Anaesth 2005;95:448–57.
75. Sato H, Hatzakorzian R, Carvalho G, et al. High-dose insulin administration improves left ventricular function after coronary artery bypass graft surgery. J Car- diothorac Vasc Anesth 2011;25:1086–91.
76. Zhang L, Zhang L, Li YH, et al. High-dose glucose-insulin-potassium treatment reduces myocardial apoptosis in  patients  with  acute  myocardial    Eur J Clin Invest 2005;35:164–70.
77. Malmberg K, Ryden L, Wedel H, et al. Intense metabolic control by means of insu- lin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26:650–61.
78. Herndon DN, Tompkins RG. Support of the metabolic response to burn injury. Lan- cet 2004;363:1895–902.
79. Liepinsh E, Makrecka M, Kuka J, et The heart is better protected against myocar- dial infarction in the fed state compared to the fasted state. Metabolism 2014;63:127–36.
80. Einhorn D, Reaven GM, Cobin RH, et al. American College of Endocrinology posi- tion statement on the insulin resistance syndrome. Endocr Pract 2003;9:237–52.
81. Hwang YC, Jee JH, Kang M, et al. Metabolic syndrome and insulin resistance are associated with abnormal left ventricular diastolic function and structure indepen- dent of blood pressure and fasting plasma glucose level. Int J Cardiol 2012;159:107–11.
82. Ingelsson E, Sundstrom J, Arnlov J, et al. Insulin resistance and risk of congestive heart failure. JAMA 2005;294:334–41.

 

83. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham JAMA 1979;241:2035–8.
84. Dries DL, Sweitzer NK, Drazner MH, et Prognostic impact of diabetes mellitus in patients with heart failure according to the etiology of left ventricular systolic dys- function. J Am Coll Cardiol 2001;38:421–8.
85. Zhang L, Jaswal JS, Ussher JR, et al. Cardiac insulin-resistance and decreased mito- chondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy. Circ Heart Fail 2013;6:1039–48.
86. Velez M, Kohli S, Sabbah HN. Animal models of insulin resistance and heart fail- Heart Fail Rev 2014;19:1–13.
87. Anker SD, Chua TP, Ponikowski P, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circu- lation 1997;96:526–34.
88. Khan RS, Kato TS, Chokshi A, et al. Adipose tissue inflammation and adiponectin resistance in patients with advanced heart failure: correction after ventricular assist device implantation. Circ Heart Fail 2012;5:340–8.
89. Redman LM, Ravussin E. Endocrine alterations in response to calorie restriction in Mol Cell Endocrinol 2009;299:129–36.
90. Han X, Turdi S, Hu N, et Influence of long-term caloric restriction on myocardial and cardiomyocyte contractile function and autophagy in mice. J Nutr Biochem 2012;23:1592–9.
91. Kardassis D, Bech-Hanssen O, Schonander M, et Impact of body composition, fat distribution and sustained weight loss on cardiac function in obesity. Int J Cardiol 2012;159:128–33.
92. de las Fuentes L, Waggoner AD, Mohammed BS, et al. Effect of moderate diet- induced weight loss and weight regain on cardiovascular structure and function.  J Am Coll Cardiol 2009;54:2376–81.
93. Guglin M, Verma S, Chen R. Association between weight loss and improvement of ventricular systolic function in advanced heart failure. Congest Heart Fail 2013;19:186–91.
94. Haufe S, Utz W, Engeli S, et al. Left ventricular mass and function with reduced-fat or reduced-carbohydrate hypocaloric diets in overweight and obese subjects. Hyper- tension 2012;59:70–5.
95. Corrao S, Arnone S, Scaglione R, et al. Effects of a short-term hypoenergetic diet on morphofunctional left ventricular parameters in centrally obese subjects. An echo- cardiographic study. Panminerva Med 2000;42:123–9.
96. McDowell K, Petrie MC, Raihan NA, et al. Effects of intentional weight loss in patients with obesity and heart failure: a systematic review. Obes Rev
97. Utz W, Engeli S, Haufe S, et al. Moderate dietary weight loss reduces myocardial steatosis in obese and overweight women. Int J Cardiol 2013;167:905–9.
98. Zamora E, Diez-Lopez C, Lupon J, et al. Weight loss in obese patients with heart J Am Heart Assoc 2016;5:e002468.

 

99. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term effect of goal-directed weight management in an atrial fibrillation cohort: a Long-Term Follow-Up Study (LEGACY). J Am Coll Cardiol 2015;65:2159–69.
100. de Lucia C, Gambino G, Petraglia L, et al. Long-term caloric restriction improves cardiac function, remodeling, adrenergic responsiveness, and sympathetic innerva- tion in a model of postischemic heart failure. Circ Heart Fail 2018;11:e004153.
101. Wang XH, Qiu JB, Ju Y, et   Reduction  of  heart  failure  rehospitalization  using a weight management education intervention. J Cardiovasc Nurs 2014;29: 528–34.
102. Ellsworth DL, Mamula KA, Blackburn HL, et al. Importance of substantial weight loss for altering gene expression during cardiovascular lifestyle modification. Obe- sity (Silver Spring) 2015;23:1312–9.
103. von Bibra H, Strohle A, St John Sutton M, et Dietary therapy in heart failure with preserved ejection fraction and/or left ventricular diastolic dysfunction in patients with metabolic syndrome. Int J Cardiol 2017;234:7–15.
104. Leung M, Xie M, Durmush E, et al. Weight loss with sleeve gastrectomy in obese type 2 diabetes mellitus: impact on cardiac function. Obes Surg 2016;26:321–6.
105. Dzenkeviciute V, Petrulioniene Z, Sapoka V, et al. The effect of weight loss on the cardiac structure and function after laparoscopic adjustable gastric banding surgery in morbidly obese individuals. Obes Surg 2014;24:1961–8.
106. Fontana L, Meyer TE, Klein S, et Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci USA 2004;101:6659–63.
107. Dolinsky VW, Morton JS, Oka T, et Calorie restriction prevents hypertension and cardiac hypertrophy in the spontaneously hypertensive rat. Hypertension 2010;56: 412–21.
108. Seymour EM, Parikh RV, Singer AA, et al. Moderate calorie restriction improves cardiac remodeling and diastolic dysfunction in the Dahl-SS rat. J Mol Cell Cardiol 2006;41:661–8.
109. Shinmura K, Tamaki K, Sano M, et Impact of long-term caloric restriction on car- diac senescence: caloric restriction ameliorates cardiac diastolic dysfunction associ- ated with aging. J Mol Cell Cardiol 2011;50:117–27.
110. Sheng Y, Lv S, Huang M, et al. Opposing effects on cardiac function by calorie restriction in different-aged mice. Aging Cell 2017;16:1155–67.
111. Chen K, Kobayashi S, Xu X, et AMP activated protein kinase is indispensable for myocardial adaptation to caloric restriction in mice. PLoS One 2013;8:e59682.
112. Shinmura K, Tamaki K, Bolli R. Short-term caloric restriction improves ischemic tolerance independent of opening of ATP-sensitive K+ channels in both young and aged hearts. J Mol Cell Cardiol 2005;39:285–96.
113. Salminen A, Kaarniranta AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 2012;11:230–41.
114. Hariharan N, Maejima Y, Nakae J, et al. Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ Res 2010;107:1470–82.

 

115. Kundu BK, Zhong M, Sen S, et al. Remodeling of glucose metabolism precedes pressure overload-induced left ventricular hypertrophy: review of a hypothesis. Car- diology 2015;130:211–20.
116. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl  J Med 2013;368:651–62.
117. Mizushima N, Yamamoto A, Matsui M, et al. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent auto- phagosome marker. Mol Biol Cell 2004;15:1101–11.
118. Wende AR, Brahma MK, McGinnis GR, et Metabolic Origins of Heart Failure.

JACC Basic Transl Sci 2017;2:297–310.

119. Lavandero S, Chiong M, Rothermel BA, et al. Autophagy in cardiovascular

J Clin Invest 2015;125:55–64.

120. Christoffersen C, Bollano E, Lindegaard ML, et al. Cardiac lipid accumulation asso- ciated with diastolic dysfunction in obese mice. Endocrinology 2003;144:3483–90.
121. van der Meer RW, Hammer S, Smit JW, et al. Short-term caloric restriction induces accumulation of myocardial triglycerides and decreases left ventricular diastolic function in healthy subjects. Diabetes 2007;56:2849–53.
122. Reingold JS, McGavock JM, Kaka S, et al. Determination of triglyceride in the human myocardium by magnetic resonance spectroscopy: reproducibility and sensi- tivity of the method. Am J Physiol Endocrinol Metab 2005;289:E935–9.
123. Ostergaard JN, Gronbaek M, Schnohr P, et al. Combined effects of weight loss and physical activity on all-cause mortality of overweight men and women. Int J Obes 2010;34:760–9.
124. Nanri A, Mizoue T, Takahashi Y, et Weight change and all-cause, cancer and car- diovascular disease mortality in Japanese men and women: the Japan Public Health Center-Based Prospective Study. Int J Obes (Lond) 2010;34:348–56.
125. Pack QR, Rodriguez-Escudero JP, Thomas RJ, et al. The prognostic importance of weight loss in coronary artery disease: a systematic review and meta-analysis. Mayo Clin Proc 2014;89:1368–77.
126. Tamura BK, Bell CL, Masaki KH, et al. Factors associated with weight loss, low BMI, and malnutrition among nursing home patients: a systematic review of the lit- J Am Med Dir Assoc 2013;14:649–55.
127. Byard RW, Bellis M. Incidence of low body mass index in the elderly in forensic cases—a possible marker for frailty syndrome. J Forensic Sci 2016;61:676–8.
128. Lennie TA, Moser DK, Heo S, et al. Factors influencing food intake in patients with heart failure: a comparison with healthy elders. J Cardiovasc Nurs 2006;21:123–9.
129. Volkert D, Saeglitz C, Gueldenzoph H, et al. Undiagnosed malnutrition and nutri- tion-related problems in geriatric patients. J Nutr Health Aging 2010;14:387–92.
130. von Haehling S, Lainscak M, Doehner W, et Diabetes mellitus, cachexia and obesity in heart failure: rationale and design of the Studies Investigating Co-morbidities Aggra- vating Heart Failure (SICA-HF). J Cachexia Sarcopenia Muscle 2010;1:187–94.
131. von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. J Cachexia Sarcopenia Muscle 2010;1:1–5.

 

132. Harrington M, Gibson S, Cottrell RC. A review and meta-analysis of the effect of weight loss on all-cause mortality risk. Nutr Res Rev 2009;22:93–108.
133. Cordero-Reyes AM, Gupte AA, Youker KA, et al. Freshly isolated mitochondria from failing human hearts exhibit preserved respiratory J Mol Cell Cardiol 2014;68:98–105.
134. Jovanovski E, Zurbau A, Vuksan V. Carbohydrates and endothelial function: is a low-carbohydrate diet or a low-glycemic index diet favourable for vascular health. Clin Nutr Res 2015;4:69–75.
135. Zheng Q, Zhao K, Han X, et al. Inhibition of AMPK accentuates prolonged caloric restriction-induced change in cardiac contractile function through disruption of com- pensatory autophagy. Biochim Biophys Acta 2015;1852:332–42.
136. Meczekalski B, Podfigurna-Stopa A, Katulski K. Long-term consequences of anorexia nervosa. Maturitas 2013;75:215–20.
137. Rose M, Greene Cardiovascular complications during prolonged starvation.

West J Med 1979;130:170–7.

138. Casiero D, Frishman Cardiovascular complications of eating disorders. Cardiol Rev 2006;14:227–31.
139. Olivares JL, Vazquez M, Fleta J, et al. Cardiac findings in adolescents with anorexia nervosa at diagnosis and after weight restoration. Eur J Pediatr 2005;164:383–6.
140. de Simone G, Scalfi L, Galderisi M, et al. Cardiac abnormalities in young women with anorexia nervosa. Br Heart J 1994;71:287–92.
141. Turillazzi E, Bello S, Neri M, et al. Congestive heart failure as cause of death in an anorexia nervosa fatal case. Int J Cardiol 2013;165:e28–9.
142. Siegel RJ, Cabeen WR Jr., Roberts WC. Prolonged QT interval—ventricular tachy- cardia syndrome from massive rapid weight loss utilizing the liquid-protein-modi- fied-fast diet: sudden death with sinus node ganglionitis and neuritis. Am Heart J 1981;102:121–2.
143. Isner JM, Roberts WC, Heymsfield SB, et Anorexia nervosa and sudden death.

Ann Intern Med 1985;102:49–52.

144. Lamzabi I, Syed S, Reddy VB, et al. Myocardial changes in a patient with anorexia nervosa: a case report and review of literature. Am J Clin Pathol 2015;143:734–7.
145. Guerrier K, Mitan L, Wang Y, et al. Risk for prolonged QT interval and associated outcomes in children with early restrictive eating patterns. Cardiol Young 2016;26:644–9.
146. Krantz MJ, Sabel AL, Sagar U, et Factors influencing QT prolongation in patients hospitalized with severe anorexia nervosa. Gen Hosp Psychiatry 2012;34:173–7.
147. Koschke M, Boettger MK, Macholdt C, et al. Increased QT variability in patients with anorexia nervosa—an indicator for increased cardiac mortality. Int J Eat Dis- ord 2010;43:743–50.
148. Horwich TB, Fonarow GC, Hamilton MA, et al. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol 2001;38:789–95.
149. Lavie CJ, Milani RV, Ventura HO, et al. Disparate effects of left ventricular geome- try and obesity on mortality in patients with preserved left ventricular ejection frac- Am J Cardiol 2007;100:1460–4.

 

150. Oreopoulos A, Padwal R, Kalantar-Zadeh K, et Body mass index and mortality in heart failure: a meta-analysis. Am Heart J 2008;156:13–22.
151. Fonarow GC, Srikanthan P, Costanzo MR, et An obesity paradox in acute heart fail- ure: analysis of body mass index and inhospital mortality for 108,927 patients in the Acute Decompensated Heart Failure National Registry. Am Heart J 2007;153:74–81.
152. Clark AL, Chyu J, Horwich TB. The obesity paradox in men versus women with systolic heart failure. Am J Cardiol 2012;110:77–82.
153. Romero-Corral A, Montori VM, Somers VK, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a system- atic review of cohort studies. Lancet 2006;368:666–78.
154. De Schutter A, Lavie CJ, Patel DA, et al. Relation of body fat categories by Gal- lagher classification and by continuous variables to mortality in patients with coro- nary heart disease. Am J Cardiol 2013;111:657–60.
155. De Schutter A, Lavie CJ, Kachur S, et al. Body composition and mortality in a large cohort with preserved ejection fraction: untangling the obesity paradox. Mayo Clin Proc 2014;89:1072–9.
156. Farre N, Aranyo J, Enjuanes C, et Differences in neurohormonal activity partially explain the obesity paradox in patients with heart failure: the role of sympathetic activation. Int J Cardiol 2014;181C:120–6.
157. Hawley JA, Burke LM, Phillips SM, et al. Nutritional modulation of training- induced skeletal muscle adaptations. J Appl Physiol (1985) 2011;110:834–45.
158. Hill AM, Harris Jackson KA, Roussell MA, et al. Type and amount of dietary pro- tein in the treatment of metabolic syndrome: a  randomized controlled  Am     J Clin Nutr 2015;102:757–70.
159. Kopple JD. National Kidney Foundation KDWG. The National Kidney Foundation K/DOQI clinical practice guidelines for dietary protein intake for chronic dialysis Am J Kidney Dis: Off J Natl Kidney Found 2001;38:S68–73.
160. Arkinstall MJ, Bruce CR, Clark SA, et al. Regulation of fuel metabolism by preexer- cise muscle glycogen content and exercise intensity. J Appl Physiol 2004;97:2275–83.
161. Hussain TA, Mathew TC, Dashti AA, et al. Effect of low-calorie versus low-carbo- hydrate ketogenic diet in type 2 diabetes. Nutrition 2012;28:1016–21.
162. Ajala O, English P, Pinkney J. Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes. Am J Clin Nutr 2013;97:505–16.
163. Tay J, Brinkworth GD, Noakes M, et al. Metabolic effects of weight loss on a very- low-carbohydrate diet compared with an isocaloric high-carbohydrate diet in abdominally obese subjects. J Am Coll Cardiol 2008;51:59–67.
164. Burke LM, Angus DJ, Cox GR, et Effect of fat adaptation and carbohydrate resto- ration on metabolism and performance during prolonged cycling. J Appl Physiol 2000;89:2413–21.
165. Keogh JB, Brinkworth GD, Noakes M, et Effects of weight loss from a very-low- carbohydrate diet on endothelial function and markers of cardiovascular disease risk in subjects with abdominal obesity. Am J Clin Nutr 2008;87:567–76.

 

166. Nilsson J, Ericsson M, Joibari MM, et A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice. Nutr Metab (Lond) 2016;13:79.
167. Liu J, Wang P, Douglas SL, et al. Impact of high-fat, low-carbohydrate diet on myo- cardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia- Am J Physiol Heart Circ Physiol 2016;311:H1–H10.
168. Burke LM, Ross ML, Garvican-Lewis LA, et al. Low carbohydrate, high fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers. J Physiol 2017;595:2785–807.
169. Noakes TD, Windt J. Evidence that supports the prescription of low-carbohydrate high-fat diets: a narrative review. Br J Sports Med 2017;51:133–9.
170. Young ME, Guthrie PH, Razeghi P, et al. Impaired long-chain fatty acid oxida- tion and contractile dysfunction in the obese Zucker rat heart. Diabetes 2002;51:2587–95.
171. Hafstad AD, Khalid AM, Hagve M, et al. Cardiac peroxisome proliferator-activated receptor-alpha activation causes increased fatty acid oxidation, reducing efficiency and post-ischaemic functional loss. Cardiovasc Res 2009;83:519–26.
172. Gelinas R, Labarthe F, Bouchard B, et al. Alterations in carbohydrate metabolism and its regulation in PPARalpha null mouse Am J Physiol Heart Circ Physiol 2008;294:H1571–80.
173. Luptak I, Balschi JA, Xing Y, et al. Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization. Circulation 2005;112:2339–46.
174. Colin-Ramirez E, Castillo-Martinez L, Orea-Tejeda A, et al. Dietary fatty acids intake and mortality in patients with heart failure. Nutrition 2014;30:1366–71.
175. Djousse L, Benkeser D, Arnold A, et Plasma free fatty acids and risk of heart fail- ure: the Cardiovascular Health Study. Circ Heart Fail 2013;6:964–9.
176. Aquilani R, Opasich C, Verri M, et al. Is nutritional intake adequate in chronic heart failure patients. J Am Coll Cardiol 2003;42:1218–23.
177. Narumi T, Arimoto T, Funayama A, et al. Prognostic importance of objective nutri- tional indexes in patients with chronic heart failure. J Cardiol 2013;62:307–13.
178. Iwakami N, Nagai T, Furukawa TA, et al. Prognostic value of malnutrition assessed by Controlling Nutritional Status score for long-term mortality in patients with acute heart failure. Int J Cardiol 2017;230:529–36.
179. Shirakabe A, Hata N, Kobayashi N, et al. The prognostic impact of malnutrition in patients with severely decompensated acute heart failure, as assessed using the Prog- nostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) Heart Vessels 2018;33:134–44.
180. Sze S, Zhang J, Pellicori P, et al. Prognostic value of simple frailty and malnutrition screening tools in patients with acute heart failure due to left ventricular systolic Clin Res Cardiol 2017;106:533–41.
181. Chess DJ, Stanley WC. Role of diet and fuel overabundance in the development and progression of heart failure. Cardiovasc Res 2008;79:269–78.

 

182. Lennie TA. Nutritional recommendations for patients with heart failure. J Cardio- vasc Nurs 2006;21:261–8.
183. Colin Ramirez E, Castillo Martinez L, Orea Tejeda A, et al. Effects of a nutritional intervention on body composition, clinical status, and quality of life in patients with heart failure. Nutrition 2004;20:890–5.
184. Lennie TA, Song EK, Wu JR, et Three gram sodium intake is associated with lon- ger event-free survival only in patients with advanced heart failure. J Card Fail 2011;17:325–30.
185. McKeag NA, McKinley MC, Harbinson MT, et The effect of multiple micronutrient supplementation on left ventricular ejection fraction in patients with chronic stable heart failure: a randomized, placebo-controlled trial. JACC Heart Fail 2014;2:308–17.
186. Heller AR, Theilen HJ, Koch Fish or chips. News Physiol Sci 2003;18:50–4.
187. Harris WS. The omega-3 index as a risk factor for coronary heart disease. Am J Clin Nutr 2008;87:1997S–2002S.
188. Elagizi A, Lavie CJ, Marshall K, et al. Omega-3 polyunsaturated fatty acids and car- diovascular health: a comprehensive review. Prog Cardiovasc Dis
189. Lee JH, Jarreau T, Prasad A, et Nutritional assessment in heart failure patients.

Congest Heart Fail 2011;17:199–203.

190. Stepaniak U, Micek A, Grosso G, et al. Antioxidant vitamin intake and mortality in three Central and Eastern  European urban  populations:  the HAPIEE study. Eur    J Nutr 2016;55:547–60.
191. Ashor AW, Siervo M, Lara J, et al. Effect of vitamin C and vitamin E supplementa- tion on endothelial function: a systematic review and meta-analysis of randomised controlled trials. Br J Nutr 2015;113:1182–94.
192. Mortensen SA, Rosenfeldt F, Kumar A, et al. The effect of coenzyme Q10 on mor- bidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail 2014;2:641–9.
193. Sharma A, Fonarow GC, Butler J, et al. Coenzyme Q10 and heart failure: a state-of- the-art review. Circ Heart Fail 2016;9:e002639.
194. van der Made SM, Plat J, Mensink Resveratrol does not influence metabolic risk markers related to cardiovascular health in overweight and slightly obese subjects: a randomized, placebo-controlled crossover trial. PLoS One 2015;10:e0118393.
195. Sciatti E, Lombardi C, Ravera A, et al. Nutritional deficiency in patients with heart Nutrients 2016;8:E442.
196. Doherty JU, Wadden TA, Zuk L, et al. Long-term evaluation of cardiac function in obese patients treated with a very-low-calorie diet: a controlled clinical study of patients without underlying cardiac disease. Am J Clin Nutr 1991;53:854–8.
197. Sacks FM, Carey VJ, Anderson CA, et al. Effects of high vs low glycemic index of dietary carbohydrate on cardiovascular disease risk factors and insulin sensitivity: the OmniCarb randomized clinical trial. JAMA 2014;312:2531–41.
198. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and dis- ease processes. Ageing Res Rev 2017;39:46–58.

The importance of nutrition in the recovery of heart function in patients with CVD and HF have several potential benefits.

Several perspectives can be drawn from Dr Bianchi’s review.

Macronutrients regulate cardiomyocyte activity. Heart function can be can be improved by optimizing glucose uptake, insulin activity, and by reduced fat intake.

Weight loss, through excess fat loss, is useful for obese and type-2 diabetes patients. However, in patients that are underweight weight loss could be detrimental.

Dietary interventions should be personalized, based on consideration of anthropometrics representing states of excess adiposity, underweight, and low lean body mass.

Overweight and obese individuals should adopt a gradual restriction of calories from unhealthy fats and refined carbohydrates while maintain lean body mass through ingestion of healthful fats, complex carbohydrates, and appropriate protein intake.

Diets in underweight and lean patients, should be nutritionally balanced and isocaloric to maintain and preserve lean body mass in order to prevent cardiac cachexia.

I want to thank Dr Bianchi for an interesting review of nutrition, a very important subject in the management of cardiovascular diseases.