Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized LDL, and lipoproteins (a, b) are toxic to kidney and heart function. Energy production for renal proximal tubule resorption of critical fuels and electrolytes is required for homeostasis. Cardiac energy for ventricular contraction/relaxation is preferentially supplied by long chain fatty acids. Metabolism of long chain fatty acids is accomplished within the cardiomyocyte cytoplasm and mitochondria by means of the glycolytic, tricarboxylic acid, and electron transport cycles. Toxic lipids and excessive lipid concentrations may inhibit cardiac function. Cardiac contraction requires calcium movement from the sarcoplasmic reticulum from a high to a low concentration at relatively low energy cost. Cardiac relaxation involves calcium return to the sarcoplasmic reticulum from a lower to a higher concentration and requires more energy consumption. Diastolic cardiac dysfunction occurs when cardiomyocyte energy conversion is inadequate. Diastolic dysfunction from diminished ATP availability occurs in the presence of inadequate blood pressure, glycemia, or lipid control and may lead to heart failure. Similar disruption of renal proximal tubular resorption of fuels/electrolytes has been found to be associated with phospholipid (sphingolipid) accumulation. Elevated concentrations of tissue oxidized low-density lipoprotein cholesterols are associated with loss of filtration efficiency at the level of the renal glomerular podocyte. Macroscopically excessive deposits of epicardial and intra-nephric adipose are associated with vascular pathology, fibrosis, and inhibition of essential functions in both heart and kidney. Chronic triglyceride accumulation is associated with fibrosis of the liver, cardiac and renal structures. Successful liver, kidney, or cardiac allograft of these vital organs does not eliminate the risk of lipid toxicity. Lipid lowering therapy may assist in protecting vital organ function before and after allograft transplantation.

This study aimed at identifying the predictive parameters on quantitative gated myocardial perfusion single-photon emission computed tomography (QG-SPECT) in diabetic patients with normal perfusion but impaired function.

Among the 533 consecutive diabetic patients, 379 patients with normal perfusion on rest Tl-201/dipyridamole-stress Tc-99m sestamibi Gated SPECT were enrolled. Patients were grouped into those with normal post-stress left ventricular function (Group I) and those with impaired function (EF <50 or impaired regional wall motion, Group II). We investigated cardiac events and cause of death by chart review and telephone interview. Survival analysis and Cox proportional hazard model analysis were performed.

Between the Group I and II, cardiac events as well as chest pain symptoms, smoking, diabetic complications were significantly different (P < 0.05). On survival analysis, event free survival rate in Group II was significantly lower than in Group I (P = 0.016). In univariate Cox proportional hazard analysis on overall cardiac event, Group (II over I), diabetic nephropathy, summed motion score (SMS), summed systolic thickening score (STS), numbers of abnormal segmental wall motion and systolic thickening predicted more cardiac events (P < 0.05). Multivariate analysis showed that STS was the only independent predictor cardiac event.

The functional parameter, especially summed systolic thickening score on QG-SPECT had prognostic values, despite normal perfusion, in predicting cardiac events in diabetic patients, and QG-SPECT provides clinically useful risk stratification in diabetic patients with normal perfusion.

Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.

Several experimental, pathological, epidemiological, and clinical studies have clearly depicted that diabetes mellitus results in cardiac functional and structural changes. Diabetic cardiomyopathy results in both structural and functional alterations in the myocardium. Several mechanisms have been implicated in the pathophysiology of diabetic cardiomyopathy. Of these, metabolic disturbances, myocardial fibrosis, small vessel disease, and cardiac autonomic neuropathy are the major players in the pathophysiology of diabetic cardiomyopathy. This review is intended to discuss various such pathophysiological mechanisms of diabetic cardiomyopathy. We have also described the systolic and diastolic dysfunctioning and its corelation to structural changes in diabetes.

While left ventricular dysfunction has been recognized to be a common complication of diabetes mellitus, data regarding right ventricular (RV) performance in patients with diabetes are incomplete. The aim of the study was to determine the preclinical effects of diabetes on regional RV systolic and diastolic function in asymptomatic persons with diabetes using the echocardiographic strain/strain rate technique.

Groups studied consisted of 33 subjects with diabetes only (DM; aged 57.3 +/- 12.9 years) and 40 subjects with coexisting diabetes and hypertension (DMHT; aged 57.5 +/- 10.5 years). In all patients with diabetes, coronary artery disease and pulmonary hypertension were excluded. Thirty-six healthy age-matched persons served as control subjects. In each patient an echocardiographic study with strain/strain rate imaging was performed. Analysis of RV deformation data included assessment of systolic strain, peak systolic strain rate (SRs) and peak early diastolic strain rate (SRe) obtained from the basal and apical segments of the RV free wall.

Significantly lower values of systolic strain and SRs in the basal and apical segment of the RV free wall in the DM and DMHT groups as compared with control subjects indicated impairment of RV systolic function. Similarly, decreased SRe in patients with diabetes in both RV segments examined reflected abnormalities of RV diastolic performance. The systolic defects were more pronounced in the apical than in the basal segment. All measured parameters were similar in the two groups with diabetes.

Diabetes mellitus is associated with subclinical RV systolic and diastolic dysfunction, regardless of coexisting hypertension.

Diabetes mellitus (DM) has been found to be associated with depressed left ventricular (LV) function. Right ventricular (RV) function in DM patients, however, has not been well studied. The goal of this study was to evaluate the occurrence of LV and RV dysfunction in patients with DM. A series of 157 patients underwent simultaneous measurement of LV ejection fraction (LVEF) and RV ejection fraction (RVEF). Four of 26 DM patients had RVEF <30% (15.4%) vs 4 of 126 controls (3.2%) (P=.01). Eleven of 27 (40.7%) patients with DM had LVEF <30% vs 9 of 128 controls (7%) (P<.0001). Using multivariate analysis, DM remained independently associated with severely decreased biventricular function (RVEF <30%; odds ratio, 5.7; confidence interval, 1.3-25.4 [P=.02] and LVEF <30%; odds ratio, 12.9; confidence interval, 3.8-43.7 [P<.0001]). These results suggest that diabetic cardiomyopathy involves both ventricles as an independent pathologic process.

Heart failure and diabetes mellitus are frequently associated, with diabetes potentiating the development of heart failure after other myocardial insults. This review documents the evidence in support of a specific primary myocardial disease in diabetes. The strongest clinical evidence relates to the detection of otherwise unexplained diastolic dysfunction in apparently healthy diabetic subjects, but recent studies with sensitive echocardiographic markers have shown systolic disturbances as well. The mechanism of this myocardial disease is multifactorial, with contributions from metabolic effects on the myocyte, structural changes in the myocardium and interstitium, autonomic neuropathy, and perhaps coronary vascular disease. The common pathway appears to be related to glycemic control and new evidence suggests better metabolic control to be beneficial, as well as angiotensin-converting enzyme inhibition and cross-link breakers.

To investigate the effect of angiotensin converting enzyme inhibition (ACE-I) or angiotensin receptor blockade (ARB), and their combination, on both diabetic autonomic neuropathy (DAN) and left ventricular (LV) diastolic dysfunction (LVDD) in asymptomatic patients with diabetes mellitus (DM).

Sixty-two patients (34 women) with long-term DM (24 with Type 1) and DAN, aged 51.7+/-13.9 years, free of coronary artery disease (CAD) or arterial hypertension (HT) at baseline, were studied for a 12-month period. Diagnosis of DAN was established if two or more of the standard cardiovascular reflex tests (CRT) were abnormal. Patients were randomly allocated to quinapril (20 mg/day), losartan (100 mg/day), or quinapril plus losartan (20 mg/day+100 mg/day). LV systolic and diastolic function was assessed using radionuclide ventriculography (RNV) at baseline and after 12 months of treatment.

In all three treatment groups, abnormal CRT values were improved. In the quinapril group, the first third filling fraction (1/3FF, 48.9+/-17.8% vs. 39.2+/-12.9% at baseline, P=.005) was increased and the atrial contribution to ventricular filling (25.1+/-6.3 vs. 30.1+/-7.8, P=.027) was reduced in the losartan group; the peak filling rate (PFR) was improved (3.41+/-.62 vs. 3.11+/-.44 volumes/s, P=.05), and in the combination group, the 1/3FF (39.4+/-11.8% vs. 29.6+/-11.9%, P=.018) was markedly increased, while the time to peak filling (TPF; 147+/-42 vs. 184+/-33 ms, P=.02) and the TPF/filling time (TPF/FT; 32.5+/-6.2% vs. 38.2+/-5.7%, P=.016) were reduced.

Early ACE-I or ARB improve both DAN and LVDD in asymptomatic patients with Type 1 or 2 DM, after 1 year of treatment. Their combination may be slightly better than monotherapies on DAN and LVDD. The clinical importance of these effects should be validated by larger studies.

In contrast to in-depth studies on the chronic hazardous effects of smoking, the immediate effects of smoking on left ventricular function have not been evaluated in detail.

We aimed to assess the hypothesis that smoking a cigarette might have more deleterious immediate impacts on left ventricular function in patients with diabetes mellitus than in healthy volunteers.

In all, 20 patients with type 2 diabetes mellitus and 25 healthy volunteers were consecutively enrolled. Mitral inflow parameters (peak early and late diastolic velocities, and deceleration time of early diastolic mitral inflow) and mitral annulus velocity parameters (systolic, late, and early diastolic velocity [E']) were obtained together with heart rate and blood pressure before and 5, 15, 30, 45, 60, and 75 minutes after smoking a cigarette.

Transient elevations in heart rate and blood pressure were observed after smoking in both groups. In terms of mitral inflow parameters, transient trends toward abnormal relaxation were noted in both groups. For mitral annulus velocity parameters, in contrast to a temporary decrease in E' in healthy volunteers, reduction in E' persisted throughout the study for patients with diabetes. No significant change in peak early diastolic velocity/E' ratio was observed in healthy volunteers; however, a significant increase in peak early diastolic velocity/E' ratio lasted throughout the study period for patients with diabetes. Systolic velocity had no significant change during the study in either group.

Even one cigarette can induce more protracted and more severe left ventricular diastolic dysfunction in patients with type 2 diabetes mellitus than in healthy volunteers. Our results have clinically relevant implications in the current era of increasing recognition of the diabetes epidemic and of the associated cardiovascular risks.

The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial. This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications. The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes. The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity). This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.

This study evaluated myocardial function in relation to high-energy phosphate (HEP) metabolism in asymptomatic patients with uncomplicated type 2 diabetes mellitus using magnetic resonance (MR) techniques.

Myocardial dysfunction may occur in patients with type 2 diabetes mellitus in the absence of coronary artery disease or left ventricular (LV) hypertrophy. The mechanisms underlying this diabetic cardiomyopathy are largely unknown, but may involve altered myocardial energy metabolism.

We assessed myocardial systolic and diastolic function and HEP metabolism in 12 asymptomatic normotensive male patients with recently diagnosed, well-controlled type 2 diabetes and 12 controls, using MR imaging and phosphorus-31-nuclear MR spectroscopy (31P-MRS) on a 1.5 T clinical scanner; 31P-MR spectra were quantified, and myocardial HEP metabolism was expressed as phosphocreatine to adenosine-triphosphate (PCr/ATP) ratio.

No differences were found in LV mass and systolic function between patients and controls. However, early (E) acceleration peak, deceleration peak, peak filling rate, and transmitral early-to-late diastolic peak flow (E/A) ratio, all indexes of diastolic function, were significantly decreased in patients compared with controls (p < 0.02). In addition, myocardial PCr/ATP in patients was significantly lower than in controls (1.47 vs. 1.88, p < 0.01). Inverse associations were found between myocardial PCr/ATP and E acceleration peak, E deceleration peak, and E peak filling rate (all, p < 0.05).

These results indicate that altered myocardial energy metabolism may contribute to LV diastolic functional changes in patients with recently diagnosed, well-controlled and uncomplicated type 2 diabetes.